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WO2025240738A1 - Device, system and method for photodynamic treatment of epithelial dysplasia and neoplasia - Google Patents

Device, system and method for photodynamic treatment of epithelial dysplasia and neoplasia

Info

Publication number
WO2025240738A1
WO2025240738A1 PCT/US2025/029555 US2025029555W WO2025240738A1 WO 2025240738 A1 WO2025240738 A1 WO 2025240738A1 US 2025029555 W US2025029555 W US 2025029555W WO 2025240738 A1 WO2025240738 A1 WO 2025240738A1
Authority
WO
WIPO (PCT)
Prior art keywords
light
wavelengths
riboflavin
cells
light guide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/029555
Other languages
French (fr)
Inventor
Alia RAHMAN
Reid Warren Von Borstel
Cleve ZIEGLER
Jason Michael Carbol
Valent TURKOVIC
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amplexd Therapeutics Inc
Original Assignee
Amplexd Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amplexd Therapeutics Inc filed Critical Amplexd Therapeutics Inc
Publication of WO2025240738A1 publication Critical patent/WO2025240738A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/062—Photodynamic therapy, i.e. excitation of an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0601—Apparatus for use inside the body
    • A61N5/0603—Apparatus for use inside the body for treatment of body cavities
    • A61N2005/0611—Vagina

Definitions

  • Cervical squamous epithelial abnormalities are graded from low to high, the lowest identifiable form being Atypical Squamous Cells (ASC), which is divided into two groups: Undetermined Significance (ASCUS) and “Cannot exclude HSIL (high-grade squamous intraepithelial lesions)” (ASC-H), followed by Cervical Intraepithelial Neoplasia 1 (CIN1) to higher grades, CIN2 and CIN3, using the CIN classification system.
  • ASC Atypical Squamous Cells
  • ASCUS Undetermined Significance
  • HSIL high-grade squamous intraepithelial lesions
  • CIN1 Cervical Intraepithelial Neoplasia 1
  • LSIL Low- Grade Squamous Intraepithelial Lesions
  • HSIL High-Grade Squamous Intraepithelial Lesions
  • squamous cell abnormalities are either described as having “features suspicious for invasion” or Squamous Cell Carcinoma.
  • Glandular abnormalities are described as low-grade Cervical Glandular Intraepithelial Neoplasia (L-CGIN) to high-grade (H-CGIN) or as CGIN1, 2 and 3.
  • Cervical glandular epithelial abnormalities are graded as “Atypical” (e.g.
  • Atypical Glandular Cells APC
  • endocervical, endometrial and glandular that can be classified as “Specified” or “Not Otherwise Specified” (-NOS); or for Endocervical and Glandular cells “Favor Neoplastic” (-FN); Endocervical Adenocarcinoma in situ; and Adenocarcinomas of the Endocervical, Endometrial, Extrauterine, and NOS varieties.
  • -FN Endocervical Adenocarcinoma in situ
  • Adenocarcinomas of the Endocervical, Endometrial, Extrauterine, and NOS varieties The umbrella term for such cervical epithelial cell abnormalities, whether squamous or glandular, is “cervical dysplasia”.
  • Cervical dysplasia can be diagnosed several ways, including by naked eye visual examination using acetic acid (visual inspection with acetic acid (VIA)) or Lugol’s iodine (visual 323503294.1 1 Attorney Docket No.: A2001-7005WO inspection with Lugol’s iodine (VILI)) or with the assistance of an intravaginal microscope known as a colposcope. In certain cases, diagnostic biopsies are taken and assessed via histology, at which point, the CIN classification system is used.
  • Cervical dysplasia can also be diagnosed using exfoliative cytology (Papanicolaou Test, “Pap smear”, or “Pap test”), in which a scraping of cervical epithelial cells are collected and analyzed using appropriate staining methods. Cervical dysplasia diagnosed by cytology is graded using The Bethesda System (TBS) where LSIL (encompassing HPV/mild dysplasia) is an appropriate surrogate for CIN1, and HSIL (encompassing moderate and severe dysplasia/ Carcinoma in situ) an appropriate surrogate for CIN2/3.
  • TBS Bethesda System
  • LSIL encompassing HPV/mild dysplasia
  • HSIL encompassing moderate and severe dysplasia/ Carcinoma in situ
  • ASCUS, CIN1/LSIL are often managed by an observational approach, requiring repeat cervical examination known colloquially as “watching- and-waiting”. Surgical intervention is typically warranted at the CIN2/3 and CGIN stage but can damage the cervix, compromising the ability to have a successful pregnancy, and are therefore not considered warranted for ASCUS and CIN1, and undesirable for CIN2.
  • almost all cervical cancer begins as CIN, so a relatively benign method for eliminating dysplastic cells would have a large impact on the risk of developing cervical cancer in individuals and on its incidence in populations. This is especially important in low-resource populations where cervical dysplasia screening and treatment are not widespread or affordable.
  • CIN1 progresses to CIN2/3 or if there is glandular cell involvement, the risk of progression to malignant cervical cancer is considered greater and therefore ablative or excisional intervention is warranted.
  • the most widely employed treatments are surgical excision, including LEEP (loop electrosurgical excision procedure) and thermal ablation (thermoablation) involving destruction of dysplastic regions and associated margins of nontransformed epithelial cells with a heated (or freezing) probe.
  • LEEP loop electrosurgical excision procedure
  • thermal ablation thermal ablation
  • cryoablation involving destruction of dysplastic regions and associated margins of nontransformed epithelial cells with a cryogenic probe
  • conization either using a cold-knife or laser, also involving epithelial destruction with margins
  • Thermoablation a widely accepted, portable, low-cost solution used in “see and treat” settings where patients are treated during the same visit as a diagnosis takes place (typically visual in nature), is not suitable for treatment of glandular lesions which is one its major deficiencies.
  • LEEP is a popular and relatively well-tolerated procedure, but is excisional in nature, requiring surgical expertise and associated equipment and facilities, including a reliable electricity supply, often prohibitive in low and middle-income regions (LMIRs).
  • LMIRs low and middle-income regions
  • Both excisional and ablative surgical treatments require an average of two to six weeks post-procedure to heal, may cause ongoing discomfort, discharge, and generally cannot be repeated for recurrent dysplasia due to excessive cervical damage.
  • Surgical procedures require local or general anesthetic, and run the risk of causing infections, bleeding, scarring to the cervix, and may compromise the ability to become pregnant and carry a pregnancy to term.
  • Thermal ablation similarly damages normal tissues surrounding areas of dysplasia, causes cramping, and the combination of smoke generated by the procedure and smell of cauterized mucosal tissue is unpleasant and can cause distress to the patient.
  • Surgical procedures also require extensive operator expertise, years of training, and associated certification to perform successfully, access to surgical facilities, costly and often heavy surgical machinery or equipment, and a reliable supply of corresponding disposable surgical equipment, resulting in limits to access to appropriate treatment for cervical dysplasia. Cervical procedures frequently induce a vagal response which can lead to dizziness, fainting, nausea, ringing ears, and sweating.
  • a relatively benign non-surgical treatment capable of inducing regression of ASCUS, LSIL/CIN1, HSIL/CIN2/3 and glandular lesions (CGIN, AGC-X, AIS), thereby reducing or eliminating risk of progression to cervical cancer, without compromising fertility or requiring extensive operator expertise, which would have a large impact on both personal health and upon healthcare costs for populations.
  • SUMMARY The present disclosure generally relates to cancer prevention and treatment device, system and method, and more particularly relates to photodynamic therapy (PDT) of precancerous and early cancerous lesions of mucosal and cutaneous epithelium. Enumerated Embodiments: 1.
  • a device comprising: one or more light sources configured to produce one or more wavelengths of light; a component configured to control the one or more light sources; and 323503294.1 3 Attorney Docket No.: A2001-7005WO a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 2.
  • a device comprising: an elongated body having a longitudinal axis extending from a proximal end to a distal end; one or more light sources housed in the elongated body and configured to produce one or more wavelengths of light; and a light guide implemented on the distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix.
  • a device comprising: one or more light sources configured to produce one or more wavelengths of light; a component configured to control the one or more light sources; and a treatment probe including a light guide implemented on a distal end, wherein the treatment probe has a length of 15-25 cm, a diameter of 1-2 cm, and wherein the light guide has a tapered extension with a length of 0-40 mm. 4.
  • a device comprising: an elongated body having a longitudinal axis extending from a proximal end to a distal end, wherein the elongated body has a length of 17-30 cm, a diameter of 1-2.5 cm; one or more light sources housed in the elongated body and configured to produce one or more wavelengths of light; and a light guide implemented on a distal end of the elongated body, wherein the light guide has a tapered extension with a length of 0-40 mm. 5.
  • the one or more light sources include a plurality of light emitting diodes (LEDs) or one or more optical fibers. 6.
  • a system for photodynamic therapy (PDT) comprising the device of any of proceeding embodiments and a photosensitizing composition. 19.
  • a system for photodynamic therapy comprising: a photosensitizing composition; and a PDT device, comprising: 323503294.1 5 Attorney Docket No.: A2001-7005WO one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 20.
  • a system for photodynamic therapy comprising: a photosensitizing composition comprising riboflavin; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject.
  • a system for photodynamic therapy comprising: a photosensitizing composition comprising quinine; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject.
  • a PDT device comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject.
  • a method of treating or preventing a cancer or infection in a subject in need thereof comprising illuminating the cancer cells, dysplastic cells, or infected area using the device. 37. The method or use of embodiment 35 or 36, wherein the method comprises illuminating the cervix of the subject using the device. 38. The method or use of embodiment 35 or 36, wherein the method further comprises applying the photosensitizing composition to the cancer cells, dysplastic cells, or infected area. 39. The method or use of embodiment 35 or 36, wherein the method further comprises applying the photosensitizing composition to the cervix of the subject. 40.
  • any of embodiments 35-39 which comprises illuminating the affected area with the device for about 1-50, 5-40, or about 10 minutes.
  • 41. A device or system of any of the preceding embodiments, for use in diagnosing a dysplasia or cancer in a subject in need thereof.
  • 42. A method of detecting a dysplasia, cancer, or infection in a subject in need thereof, the method comprising: applying the pharmaceutical composition of any of embodiments 43-50 to the cervix of the subject, and illuminating the cervix of the subject using the device of any of embodiments 1-17, wherein fluorescence above a baseline level indicates the presence of the cancer or infection. 43.
  • a pharmaceutical composition comprising two or more of (e.g., all of): quinine or an analog thereof; and riboflavin or an analog thereof; wherein the pharmaceutical composition is a gel.
  • the pharmaceutical composition of embodiment 43 or 44, wherein the analog of quinine is quinidine. 323503294.1 8 Attorney Docket No.: A2001-7005WO 46.
  • the pharmaceutical composition of any of embodiments 43-45, wherein the concentration of the quinine or analog thereof is 0.1 – 25 mg/ml. 47.
  • the pharmaceutical composition of embodiment 48, wherein the gelling agent is a polyacrylic acid such as carbomer.
  • the system of any of embodiments 18-34, wherein the photosensitizing composition comprises quinine or an analog thereof. 52.
  • the system of any of embodiments 18-34, wherein the photosensitizing composition comprises riboflavin or an analog thereof. 53. The system of any of embodiments 18-34, wherein the photosensitizing composition is a gel. 54. The system of any of embodiments 18-34, wherein the photosensitizing composition is a pharmaceutical composition according to any of embodiments 43-54. 55. The pharmaceutical composition of any of embodiments 43-54, for use in photosensitizing dysplastic cells or infected cells. 56. A method of using the pharmaceutical composition of any of embodiments 43-54 for photosensitizing dysplastic cells or infected cells, the method comprising applying the pharmaceutical composition to the dysplastic cells or infected cells. 57.
  • a device comprising: one or more light sources configured to produce one or more wavelengths of light; 323503294.1 9 Attorney Docket No.: A2001-7005WO a component configured to control the one or more light sources; and a probe including an endoscope implemented on a distal end, wherein the probe and the endoscope are configured to direct the one or more wavelengths of light onto the cervix.
  • the endoscope is retractable up to 4 cm.
  • the one or more light sources are arranged in concentric circles and each concentric circle is controlled to produce the one or more wavelengths of light independently. 60.
  • the device of embodiment 57 wherein the probe includes a first portion joined with a second portion via a connection portion, wherein the first portion is for placement the probe into an endocervical canal of a patient, and the second portion connects with a handle portion of the probe.
  • the connection portion is made of malleable materials.
  • an extension length of the endoscope is controlled by syringe like mechanism or a hydraulic function of the device.
  • the device of embodiment 57 further comprising image and video sensors configured to provide endoscopic vision of the cervix.
  • the device of embodiment 57, wherein the endoscope has a diameter up to 7 mm. 65.
  • the present disclosure provides a topically administered pharmaceutical composition comprising quinine for photodynamic therapy of epithelial dysplasia.
  • the pharmaceutical composition further comprises glycerol and a thickening agent selected from carbomers or modified cellulosics including but not limited to hydroxyethylcellulose, hydroxypropylmethylcellulose, and methylcellulose.
  • the composition further comprises propylene glycol.
  • the composition further comprises a surfactant selected from polysorbates.
  • the composition further comprises riboflavin or riboflavin phosphate.
  • the present disclosure provides a method for treating epithelial dysplasia or neoplasia by applying a pharmaceutical composition of the invention to an epithelial surface and then exposing the treated epithelial area to light at a wavelength of 405 nm with a cumulative intensity of approximately 100 J/cm 2 .
  • FIG. 1 illustrates a top view of an example PDT device and system in an open state, according to an exemplary aspect of the present disclosure
  • Fig.2 illustrates a perspective view of a base halve of the example PDT device and system of Fig. 1, according to an exemplary aspect of the present disclosure
  • Fig. 3 illustrates a perspective view of the example PDT device and system of Fig. 1 and a number of parts, according to an exemplary aspect of the present disclosure
  • Fig. 4 illustrates a control module of the example PDT device and system of Fig.
  • Fig.5 illustrates a cross-sectional side view of a first design of a probe having a light guide attached on one distal end, according to an exemplary aspect of the present disclosure
  • 323503294.1 11 Attorney Docket No.: A2001-7005WO
  • Fig. 6 illustrates a cross-sectional side view of a second design of a probe having a light guide attached on one distal end, according to an exemplary aspect of the present disclosure
  • Fig. 7 illustrates a cross-sectional side view of a light guide, according to an exemplary aspect of the present disclosure;
  • Fig. 6 illustrates a cross-sectional side view of a first design of a probe having a light guide attached on one distal end, according to an exemplary aspect of the present disclosure
  • 323503294.1 11 Attorney Docket No.: A2001-7005WO
  • Fig. 6 illustrates a cross-sectional side view of a second design of a probe having a light guide attached on one distal end, according to an
  • Fig. 8 illustrates a top plan view of a distal end of a probe having a retractable endoscope integrated therein, according to an exemplary aspect of the present disclosure
  • Fig. 9 illustrates a probe having a retractable endoscope in a regressed position, according to an exemplary aspect of the present disclosure
  • Fig. 10 illustrates a probe having a retractable endoscope in a fully extended position, according to an exemplary aspect of the present disclosure
  • Fig. 11 is a bar graph showing RLU (luminescence) 24 hours after photodynamic therapy treatment in SiHa cells.
  • Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm.
  • No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure.
  • Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute.
  • Luminescence was measured using CellTiter-Glo ® 24 hours post LED exposure;
  • Fig. 12 is a bar graph showing percent viability 24 hours after photodynamic therapy treatment in SiHa cells.
  • Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm.
  • No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure.
  • Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Percent viability was measured using CellTiter-Glo ® 24 hours post LED exposure;
  • Fig. 13 is a bar graph showing RLU (luminescence) 48 hours after photodynamic therapy treatment in SiHa cells.
  • Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 323503294.1 12 Attorney Docket No.: A2001-7005WO 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm. No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure. Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Luminescence was measured using CellTiter-Glo ® 48 hours post LED exposure; and Fig.
  • FIG. 14 is a bar graph showing percent viability 48 hours after photodynamic therapy treatment in SiHa cells.
  • Treated cells Q+R, leftmost bar of each pair
  • No treatment cells No treatment, rightmost bar of each pair
  • Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Percent viability was measured using CellTiter-Glo ® 48 hours post LED exposure.
  • PDT of dysplastic or neoplastic cells feature selective destruction of pre-malignant cells with relative exclusion of normal cells.
  • Exogenous photosensitizers that are not selectively concentrated in dysplastic cells must rely on operator skill to focus the activating light only on dysplastic sites, avoiding surrounding normal epithelium.
  • one of the goals of the present disclosure is to provide photosensitizing compounds for PDT that are taken up into intracellular spaces with selectivity for pre-malignant and malignant cells versus normal epithelium.
  • Suitable photosensitizing compounds of the present disclosure may comprise quinine and riboflavin, including riboflavin derivatives such as flavin mononucleotide (also called riboflavin- 5′-phosphate).
  • riboflavin derivatives such as flavin mononucleotide (also called riboflavin- 5′-phosphate).
  • a method according to the present disclosure may use a solvent system in which both compounds are adequately soluble and stable, and which further enables creation of a suitable pharmaceutical formulation.
  • release of the quinine and riboflavin from the formulation occurs readily to facilitate a relatively brief interval between application of the topical formulation and the photodynamic light treatment using e.g., a PDT device that will be described fully below.
  • the present disclosure may comprise topical gels, emulsions, and creams that can deliver both quinine and riboflavin into epithelial cells as preparation for PDT-induced destruction of dysplastic cells.
  • Quinine is relatively soluble in glycerol, at concentrations up to approximately 5% (50 grams per liter).
  • riboflavin phosphate improves the solubility of quinine in glycerol or glycerol/propylene glycol in the presence of one or more gelling agents, including carbomers, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), and methylcellulose and other modified cellulosic thickeners.
  • gelling agents including carbomers, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), and methylcellulose and other modified cellulosic thickeners.
  • quinine improves the solubility of riboflavin or riboflavin phosphate in nonaqueous media, including glycerol and propylene glycol of mixtures of these two solvents.
  • compositions of the present disclosure may optionally comprise surfactants, including but not limited to polysorbates and penetration enhancers including but not limited to Transcutol.
  • surfactants including but not limited to polysorbates and penetration enhancers including but not limited to Transcutol.
  • Such excipients improve delivery for active agents from the gel into epithelial cells, both by facilitating release from the gel and penetration of keratinocyte layers.
  • the present disclosure relates to selective or preferential uptake of the active photosensitizing compounds into dysplastic or neoplastic cells. It is believed that quinine is taken up into and retained by dysplastic and neoplastic cells by cation trapping. Quinine has a net neutral charge at pH ⁇ 7, which enables permeation of cell membranes.
  • quinine In lower pH environments, such as the interior of lysosomes and other acidic endosomes, quinine has a cationic charge, which limits its egress, thereby enabling accumulation in such acidic vacuoles.
  • a stereotyped feature of dysplastic and neoplastic cells is enhanced lysosomal acidification, leading to a lower intralysosomal pH than in corresponding normal cells, with consequent enhanced accumulation of quinine versus non-neoplastic epithelial cells.
  • Quinine is a photosensitizing agent, activated to fluoresce by light in the ultraviolet and short wavelength visible part of the spectrum. Ultraviolet light has the potential to cause undesirable genotoxic damage in cells promoting dysplasia and oncogenesis.
  • light at a wavelength greater than 400 nm, advantageously 405 nm may be used for PDT with quinine as a photosensitizer.
  • Normal vaginal mucosal cells can tolerate light at 405 nm at a cumulative intensity of about 100 Joules/cm 2 in a single PDT session.
  • Riboflavin and riboflavin phosphate are precursors to intracellular flavin nucleotides, including FAD (flavin adenine dinucleotide).
  • FAD is a cofactor responsible for transfer of electrons from the TCA (tricarboxylic acid cycle) cycle to Complex II (succinate dehydrogenase) of mitochondria.
  • FAD concentrations and electron flux mediated by it are elevated in dysplastic and neoplastic cells relative to surrounding normal cells, as a cellular strategy for increasing bioenergetic support for cell proliferation.
  • Endogenous FAD fluorescence may be used to identify and grade cervical dysplasia and neoplasia.
  • the propensity of dysplastic cells to elevate FAD and other bioenergy cofactors may be mediated in part by an enhanced ability to assimilate and retain exogenous precursors including riboflavin and riboflavin phosphate, the latter of which is dephosphorylated by cell-surface and extracellular nucleotidases or phosphatases prior to cellular uptake.
  • Acid phosphatase activity has been identified as a marker for cervical dysplasia, with activity directly correlated with severity of dysplastic lesions; acid phosphatase is produced in and released from lysosomes of preneoplastic and neoplastic cells.
  • riboflavin 5’- phosphate results in relatively selective elevation of FAD and related metabolites in dysplastic and neoplastic cells versus surrounding normal epithelial cells.
  • Riboflavin and intracellular flavin nucleotides fluoresce when exposed to light at 405 nm, but the absorbance maximum for flavins is at about 450 nm, with an absorbance coefficient about three times greater at 450 than at 405 nm.
  • the therapeutic synergy of quinine and riboflavin of the present disclosure may be at least attributable to the fact that quinine, both intracellular and on the cell surface, emits light at 450 nm during exposure to light at 405 nm. This boosts photodynamic activation of riboflavin and flavin nucleotides beyond that yielded by exposure to 405 nm light alone, amplifying the combined therapeutic effect of quinine and riboflavin against dysplastic or neoplastic cells.
  • active photosensitizers of this disclosure may be formulated in a topical composition that is applied to the dysplastic areas of the cervix, with a blunt syringe, swab or other applicator.
  • the topical composition can be a cream, ointment or gel.
  • a gel is prepared with a solvent that acts as an “optical clearing agent.”
  • solvents such as glycerol, propylene glycol, Polyethylene glycol (PEG; advantageously low molecular weight PEG including but not limited to PEG 400), 1,2-propanediol, 1,3-propanediol or transcutol, or mixtures of two or more of these solvents.
  • PEG Polyethylene glycol
  • Nonionic thickening agents may be used, especially cellulosic thickeners including hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose.
  • the same PDT illumination device may be used to activate both quinine and riboflavin simultaneously during a single treatment session, with the same light intensity and duration of exposure, generally up to about 100 Joules/cm 2 cumulative exposure per treatment session.
  • the photosensitizing composition comprises: quinine (e.g., quinine hydrochloride), riboflavin-5-phosphate, glycerol, propylene glycol, and hydroxyethylcellulose.
  • the photosensitizing composition comprises quinine (e.g., quinine hydrochloride) and riboflavin-5-phosphate.
  • the photosensitizing composition comprises quinine (e.g., quinine hydrochloride) and glycerol.
  • the photosensitizing composition comprises riboflavin-5-phosphate and propylene glycol.
  • the photosensitizing composition comprises glycerol, propylene glycol, and hydroxyethylcellulose.
  • the photosensitizing composition is a gel.
  • the photosensitizing composition is a gel comprising quinine or an analog thereof.
  • the photosensitizing composition is a gel comprising riboflavin or an analog thereof.
  • the photosensitizing composition comprises quinine or an analog thereof and riboflavin or an analog thereof. In some embodiments, the quinine or analog thereof is present at about 0.5 g per 20 ml volume or about 25 mg/ml in the photosensitizing composition. In some embodiments, the quinine 323503294.1 16 Attorney Docket No.: A2001-7005WO or analog thereof is present at about 0.1 – 25 mg/ml or about 5 – 25 mg/ml in the photosensitizing composition. In some embodiments, the quinine or analog thereof is present at about 0.1-1, 1-5, 5- 10, 10-15, 15-20, or 20-25 mg/ml in the photosensitizing composition.
  • the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) is present at about 0.1 g per 20 ml volume or about 5 mg/ml in the photosensitizing composition. In some embodiments, the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) is present at 0.01 - 10 mg/ml in the photosensitizing composition. In some embodiments, the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) is present at about 0.01-0.1, 0.1-1, 1-5, or 5-10 mg/ml in the photosensitizing composition.
  • the hydroxyethylcellulose is present at about 1 g per 20 ml volume or about 50 mg/ml in the photosensitizing composition. In some embodiments, the hydroxyethylcellulose is present at about 30-70 mg/ml or 40-60 mg/ml in the photosensitizing composition.
  • the photosensitizing composition is made by a method comprising one or more (e.g., all) of the following steps: a) combining the quinine or analog thereof with glycerol, b) combining the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) with the propylene glycol, c) combining a) and b), d), adding the hydroxyethylcellulose, and e) heating the mixture, e.g., to about 80 C. In some embodiments, the mixture is heated to a temperature of about 70-90C or 75-85C. In some embodiments, the mixture forms a gel over about 24 hours.
  • Riboflavin-5-phosphate and quinine are suitable photosensitizers, but compositions and devices of the disclosure can include alternative or additional photosensitizers activated by light at 405 nm. Both endogenous and exogenous porphyrins are activated at this wavelength.
  • Porphyrin photosensitizers for optional use within the scope of the disclosure include the porphyrin precursor 5-aminolevulinic acid. Without wishing to be bound by theory, 5-aminolevulinic acid is converted to protoporphyrin and other photosensitive molecules by metabolism after application.
  • Other suitable photosensitizers include porphyrins that do not require biotransformation including but not limited to haematoporphyrin or porfimer.
  • Phthalocyanine photosensitizers are also optionally used within the scope of this disclosure.
  • the photosensitizing composition e.g., gel
  • the photosensitizing composition is administered to the subject (e.g., to the cervix of a subject) using a blunt syringe, medical swab or applicator.
  • the photosensitizing composition is administered at a volume of about 0.5 ml – 2 ml, or 0.5 ml – 1 ml. 323503294.1 17 Attorney Docket No.: A2001-7005WO
  • unabsorbed material is rinsed or swabbed from the cervix.
  • a photosensitizing composition as described in this section may be activated using a photodynamic therapy device, e.g., one described in the following section.
  • Photodynamic therapy devices In accordance with aspects of the present disclosure, referring to Figs. 1-4, a PDT device and system 100 for epithelial dysplasia and neoplasia treatment may include a plurality of components enclosed in a portable, compact case.
  • the PDT device and system 100 of the present disclosure may be used in hospitals, clinics, nursing homes, remote settings, and the like, and is designed for convenient portability. As shown in Fig.
  • the main case of the PDT device which may primarily comprise a base half 102 and a top half 104, is dimensioned to store, protect and carry multiple PDT treatment components and medical items and supplies.
  • the two half 102 and 104 may be made of a same or different lightweight and substantially rigid structural material, such as plastic, metal or a composite material.
  • the base half 102 comprises four base sidewalls and a base bottom surface, together forming a base interior space.
  • the top half 104 comprises four top sidewalls and a top surface, together forming a top interior space.
  • the two halves 102 and 104 may have asymmetrical dimensions. For example, as shown in Fig.
  • the base interior space of the base half 102 may have a depth greater than that of the top half 104, or vice versa.
  • the two halves 102 and 104 may have symmetrical dimensions.
  • the top half 104 may be attached using hinges to the base half 102. Specifically, a peripheral edge of a first sidewall 106 of the top half 104 and a peripheral edge of a second sidewall 108 of the base half 102 are pivotally attached to each other by one or more hinge members 110a, 110b.
  • Pivotal engagement of the base and top halves 102, 104 via the hinge members 110a, 110b may allow the portable case of the PDT device and system 100 to assume a plurality of positions between a completely open position and a completely closed position, as shown in Figs. 1, 2, and 3.
  • the portable case When in the open position, the portable case allows a user to access the PDT treatment components and medical items and supplies stored therein. As shown in Figs.
  • two locking members 112a, 112b may be implemented on two corresponding front sidewalls of the base and 323503294.1 18 Attorney Docket No.: A2001-7005WO top halves 102, 104, respectively, for securely holding the two halves in a completely closed position.
  • the locking member 112a which may be implemented on a front sidewall of the top half 104, may include a tongue portion configured to releasably engage with a latching member 112b disposed on a corresponding front sidewall of the base half 102.
  • the portable case of the PDT device and system 100 includes a handle 114 for convenient transporting and handling of the portable case.
  • the handle 114 may be implemented on an outer side of a front side wall of the base half 102. In other embodiments (not shown), the handle 114 may be implemented on either or both left and right sidewalls of the portable case.
  • a shoulder strap may be attached to one or more attachment fixtures (e.g., strap pins or hooks) implemented on an outer surface of a selected side wall of the portable case.
  • attachment fixtures e.g., strap pins or hooks
  • the top interior space of the top half 104 may hold various medical items such as a plurality of PDT gel containers 116 (single-use vial of gel) which will be used with single-use applicators 118 (blunt syringes, single use rayon or cotton swabs) for precise application. It should be appreciated that the arrangement and contents of the top interior space may vary and the various components are not necessarily shown to scale.
  • the top interior space may comprise a plurality of compartments for holding each of PDT gel containers 116 and syringes 118 via a plurality of loop-like structures 120 in a substantially upright position when the portable case is in an open state.
  • the loop-like structures 120 or similar structures for securing the items within the top interior space may be configured to avoid any dislodgment of each item during the movement of the portable case of the PDT device and system 100.
  • Each PDT gel container 116 contains gel that is specifically formulated for use with the PDT device and system 100 of the present disclosure for the treatment of epithelial dysplasia and neoplasia, ensuring effective treatment delivery. As shown in Figs.
  • the interior space of the base half 102 may comprise a plurality of compartments for holding a control module 122, a probe 124, a power supply cable 126, and other electrical components 128 (e.g., charging cables and connectors).
  • the probe 124 is directly 323503294.1 19 Attorney Docket No.: A2001-7005WO involved in the treatment process, working in tandem with the control module 122 to deliver the desired therapeutic effects.
  • the probe 124 may be a rigid, linear optical probe, composed of a light delivery core (optical fiber or waveguide), whether enclosed in a biocompatible sheath or not.
  • Such a probe 124 may include a first end connected to a light source (e.g., LED or laser diode) and a second end configured to emit light directly onto a treatment site. Light shaping may be achieved using a flat window, microlens, or diffuser tip. According to additional embodiments, the probe 124 may include a bendable portion that is positioned on a selected location along the elongated body of the probe 124, as will be described fully below with respect to Figs. 9 and 10. Such a probe 124 may become straight if needed but also bendable for different physiologies. For example, if the bend portion is implemented near a light-emitting element, light from the light source may navigate a curved path soon after emission, through a flexible or articulated waveguide.
  • a light source e.g., LED or laser diode
  • Such a bendable probe design may use side-emitting fibers, angle-polished reflectors, or light-steering elements to redirect light post-bend. If the bend portion is implemented near the treatment site, light emitted from a light source may travel a straight path until it reaches the bend, where it is redirected to the treatment target.
  • a tip portion of such a probe design may feature side-firing optics, angle-polished mirrors, or total internal reflection structures.
  • the PDT device and system 100 may operate without an external power supply.
  • the control module 122 may be configured to serve as a power source for probe 124.
  • the control module 122 may also comprise circuitry such as a microcontroller or microprocessor for regulating one or more light-emitting diodes (LEDs).
  • the control module 122 features a user-friendly interface designed for simplicity and efficiency in clinical settings.
  • the control module 122 may include a touchscreen for displaying and prompting a user to input information.
  • the interface may comprise a number of analog buttons and LED indicators, which collectively facilitate intuitive operation and clear communication of the device’s status and settings.
  • an ON/OFF power button and several functional buttons may be implemented on the control module 122.
  • buttons may be used for setting the appropriate treatment duration and for switching between, e.g., two light modes - white light for optical examinations and UV light for therapeutic treatment.
  • the PDT device and system 100 of the present disclosure may be activated using the ON/OFF 323503294.1 20 Attorney Docket No.: A2001-7005WO power button 130. Initially, when the device is turned on, none of the LED lights are illuminated. To control white LED light, a user may press a first button on the interface of the control module 122 to activate white LED light, for example, at 50% intensity. The intensity of the white light may be adjusted up or down, for instance, by 10% increments, offering flexibility in lighting conditions for optical examinations.
  • the user may press a second button on the control module 122 to enter interval selection.
  • the white LED is turned off.
  • the user may set the duration of the treatment interval using e.g., “Plus” and “Minus” buttons implemented on the interface of the control module 122.
  • a default interval may be set at 15 minutes, but the user may adjust the interval from 1 to 30 minutes in 1 to 5-minute increments.
  • the selected interval may be displayed via green LED indicators on the interface of the control module 122.
  • the PDT device and system 100 of the present disclosure may begin the countdown for the selected interval.
  • the UV light is activated, and all of the buttons on the control module 122 may be locked to prevent any inadvertent changes, except for the OFF power button which can be used to turn off the PDT device and system 100 at any time.
  • the PDT device and system 100 may automatically return to its initial state, as if it had just been turned on, ready for the next use.
  • This interface design emphasizes ease of use and safety, ensuring that healthcare providers can quickly and accurately set up the PDT device and system 100 of the present disclosure for treatment, with clear indicators and safeguards to prevent unintended modifications during the treatment process.
  • one or more single-use transparent plastic sheaths, one or more single-use or reusable clips, and various medical tools, cleaning solutions and supplies may be stored in the portable case of the PDT device and system 100 or separately.
  • each single-use plastic sheath may be configured to fit the probe 124, thereby reducing the risk of cross-contamination between uses of the probe 124.
  • Each single-use or reusable clip may be used for appropriate seating of device.
  • additional internal compartments may be implemented in the base or top interior spaces for storing one or more plastic sheaths and clips.
  • one or more cervical cups may be included for retention of the PDT gel on the cervix of a patient between application and light treatment.
  • Swabs and sterile saline that 323503294.1 21 Attorney Docket No.: A2001-7005WO are generally used during PDT treatments may be used for first removing excess cervical mucus before PDT gel application and then for removing excess unabsorbed PDT gel and photosensitizers before application of light. These additional medical tools or supplies may be stored in containers, separate from the portable case of the PDT device and system 100 of the present disclosure.
  • a distal end of the probe 124 may be adapted to have approximately the same diameter as the cervix and is placed in sufficient proximity to the cervix to expose essentially the entirety of the visible dysplastic lesions to the activating light of the PDT device and system 100.
  • the distal end 152 of probe 124 may be attached to light guide 150 to fit within the endocervical canal for treatment of dysplasia within the endocervix.
  • the light guide 150 may be integral with the probe 124, or may be a separate removable and/or replaceable and/or disposable component.
  • the light guide 159 may have a shape suitable for easy placement and maneuverability within the endocervical canal. Example shapes may include pointed conical, rounded conical, nippled, or combinations thereof.
  • the length and design of probe 124 and light guide 150 may be determined and optimized to facilitate ease of use and utility for healthcare providers. According to a first example design illustrated in Fig.
  • probe 124 may have an elongated body having a longitudinal axis extending from a proximal end 154 to a distal end 152.
  • the term “distal” refers to a direction away from a healthcare provider using the PDT device and system 100, which is also the direction of insertion of the probe 124 into the body.
  • the “proximal” direction may generally refer to the direction toward the physician, and the opposite direction toward the distal end.
  • the elongated body of probe 124 may be a generally cylindrical body with one or more light sources or endoscope implemented within. In some embodiments, the probe 124 may have a length of 15-25 cm and a diameter of 1-2 cm.
  • the elongated body of the probe 124 may have a length of 17-30 cm and a diameter of 1-2.5 cm.
  • the probe 124 may include a bend that is positioned on the upper third portion of the device, closest to the light. The area that precedes the bend may occupy 2 ⁇ 3 of the overall length. It should be appreciated that the exact dimensions and shapes of the probe 124 may be determined based on certain selected criteria.
  • the proximal end 154 may be flush with and share the same width with the main portion of the elongated body of probe 124, thereby providing an aesthetically pleasing appearance.
  • the light guide 150 may be releasably attached to the distal end 152 via any suitable attachment or 323503294.1 22 Attorney Docket No.: A2001-7005WO interlocking means (e.g., snap-fit attachment means including cantilever, torsional, or annular).
  • the light guide may have a tapered extension with a length of 0-40 mm, where 0 mm indicates that the light guide is flush with the connection portion of the probe 124 when in an initial, un-extended position.
  • Probe 124 and/or light guide 150 may be made of biocompatible materials or coatings of biocompatible materials to minimize or eliminate any damage to cervical canal tissue that comes in contact with the probe 124 and/or light guide 150.
  • At least one or more selected portions of the elongated body and/or the light guide 150 may be made of bendable, rather than resilient, materials, such that the PDT device and system 100 may address one of the challenges that the anatomical positioning of the cervix and vaginal canals are typically offset by about 90-100 degrees.
  • an integrated endoscope may be used to facilitate optimum placement of the tip of the probe 124 with or without the light guide 150 on or near the cervix.
  • the proximal end 152 of probe 124 may be configured to extend out of the main portion of the elongated body of probe 124 with gradually increasing width to facilitate easy handling by healthcare providers during treatment.
  • light guide 150 may be ergonomically designed to fit comfortably inside the cervix, ensuring optimal light distribution within.
  • the length of the light guide 150 and/or probe 124 may be determined and selected to facilitate effective light application to the internal areas of the cervix, particularly targeting the columnar epithelium.
  • a length of the light guide 150 may be equal to or less than 40 mm (e.g., 0-40 mm).
  • the light guide 150 may be made of polymethyl methacrylate (PMMA).
  • PMMA is a lightweight, synthetic polymer that exhibits transparency to both UV and visible light wavelengths and is certified for medical use.
  • Alternative suitable materials may include softer and higher elasticity materials, such as polymethyl acrylate or transparent silicone.
  • Fig. 7 illustrates a cross-sectional side view of the light guide 150 which may be an integral component including a main body 160 and a spherical dome portion 162 joined with each other along a longitudinal axis 164 of the main body 160.
  • the length of the main body 160 together with the height of the spherical dome portion 162 define the total length of the light guide 150.
  • the total length may be in the range of 0-40 mm.
  • the main body 160 may have a tapered conical shape with a narrowed distal end 166. Referring back 323503294.1 23 Attorney Docket No.: A2001-7005WO to Figs.
  • the dome portion 162 may be releasably attached to the distal end 152 of probe 124 which has a shape symmetrical to that of the dome portion 162.
  • the PDT device and system 100 of the present disclosure may include one or more distinct light sources using one or more LEDs.
  • a first light source may include a standard white LED light
  • a second light source may include an LED that operates in a suitable spectrum for treatment of cervical dysplasia.
  • the LED may operate in the blue light spectrum or the near ultraviolet spectrum.
  • such a first light source may be used for the illumination of a treatment area, for instance with illumination of surrounding or nearby non-neoplastic or normal tissue.
  • each light source of the present disclosure may be configured to emit light continuously.
  • each light source may be configured to have a selected power, center wavelength, spectral bandwidth, beam spot size or cross-section, and beam profile (e.g., Gaussian, flat-top beams).
  • each light source may emit light in a pulse mode. Providing intervals in light illumination may enhance tissue oxygenation and the effect of PDT. Further, pulsed light may prevent unacceptable heating of tissue and allow for the re-accumulation of intracellular photosensitizers from precursors in surviving cells that can be treated with repeated illuminations.
  • control module 122 may include a microprocessor to control a function generator for generating pulsed light.
  • the frequency and length of the pulses can be chosen according to the requirements of the treatment regime and set within the control circuit.
  • the one or more light sources of the PDT device and system 100 may be configured to produce one or more wavelengths of light to activate e.g., the photosensitizing composition stored in each PDT gel container 116 of Fig. 1.
  • the one or more light sources may include a plurality of LEDs emitting light having a wavelength range of 400 nm - 700 nm.
  • a first portion of the LEDs may emit light with a peak emission spectrum near 450 nm (absorbance maximum for riboflavin), and a second portion of the LEDs may emit light with a peak emission spectrum near 650 nm (near-infrared for use with e.g., porphyrin photosensitizers).
  • the LEDs may be configured to emit light with a peak 323503294.1 24 Attorney Docket No.: A2001-7005WO emission spectrum near 405 nm light, because this wavelength is suitable for cancerous cell-killing with riboflavin.
  • the plurality of LEDs may emit multiple wavelengths of light concurrently.
  • control module 122 and the probe 124 may be configured to control the intensity of light emission by the plurality of LEDs, thereby allowing healthcare providers to adjust the light irradiation intensity according to the specific needs of each treatment.
  • the radiance (J/cm 2 ) of a light source may be set to be high in order to provide a good therapeutic response for thick, dark, and deep lesions, whereas the irradiance may be set to be low to reduce pain and avoid scar formation for superficial lesions.
  • the light intensity of light sources may be set to a fixed level. By standardizing the intensity, the PDT device and system 100 of the present disclosure may simplify the operation of the device for clinicians, ensuring consistency and reliability in treatment delivery.
  • an advantageous light energy delivered in a treatment session may be about 100 J/cm 2 , optionally at a fluence of about 50-150 mW/cm 2 .
  • the light intensity and/or the fluence rate of the PDT device and system 100 may be selected depending on patient’s tolerance determined in clinical trials, as there is evidence that a patient’s pain tolerance may be high in the treatment region per studies on tolerability of thermal-ablation. Higher energy delivery may yield shorter treatment time which would allow for higher patient throughput.
  • the light probe 124 may be configured to include an integrated endoscope or any suitable inspection instrument for documentation of lesions via one or more image sensors, optical lens, light sources and other mechanical/electrical components.
  • Example embodiments may include multiple lens or a universal lens which has a retractable lens for treatment in the endocervical canal, extending up to ⁇ 3-4 cm.
  • the retractable lens may be extended using a motorized system (not shown) that may be configured to raise and lower the retractable lens based on whether endocervical disease is present. If only squamous infection exists on the ectocervix, the lens may be fully flat or up to 0.5 cm extended to appropriately seat the PDT device within the external cervical os, so it does not move during treatment.
  • the motorized system may be configured to extend the retractable lens up to 1 cm, which is not be achievable through current thermoablation methods, and is greatly limited through cryoablative probes in treating the endocervical canal.
  • the lens 323503294.1 25 Attorney Docket No.: A2001-7005WO of the present disclosure may have variable lighting where it can treat a small circular area where disease is found and a large area if disease is more extensive via selectable settings on the PDT device.
  • an integrated miniature endoscope may be implemented at the tip of the retractable lens for assistance with appropriate placement, as well as the surrounding lights, which will also improve visibility for placement.
  • the PDT device of the present disclosure may have a “placement” (white-colored) light and a “treatment” (405 nm) light.
  • a tip containing the endoscope may in some embodiments not be able to emit 405 nm light, only white light for placement.
  • the CIN2/3 lesions should accumulate the photosensitizers and fluoresce under blue light illumination.
  • the PDT device and system 100 may include an LED illumination device having an acrylic cylinder approximately 2 cm in diameter at the proximal end where the LEDs are fixed. The cylinder may be 15 to 25 cm, advantageously about 20 cm long.
  • the distal end of the cylinder may be placed close to the cervical epithelial surface.
  • the acrylic cylinder may be drawn or machined into a thinner end, approximately 4.5 mm wide at the tip, widening to about 7 mm over the distal 20 mm of the rod.
  • the tip of the rod is inserted within the endocervical canal for photodynamic illumination, stabilized either by hand or by clipping it to a speculum.
  • the portion of the cervix that opens into the uterus is called the internal os and the opening of the cervix which faces the vagina is called the external os.
  • the average endocervical canal length between the internal os and external os is approximately 3-4 cm (but can range from 1-4 cm).
  • the external os varies greatly from female to female and ranges from small and round, to horizontally oblong, to crescent shaped, to amorphous, each with characteristic individual anatomical variation, as influenced by menarche, parity, vaginal childbirth, and post-menarche status, as observed via speculum examination in lithotomy position.
  • a retractable endoscope e.g., 1 to 7 mm or 2 to 5 mm in diameter
  • a retractable endoscope may be integrated at a distal end of the PDT device and system 100 for placement, rather than e.g., examination, of patient’s cervix.
  • the endoscope of the 323503294.1 26 Attorney Docket No.: A2001-7005WO present disclosure may be configured to extend and view up to 4 cm in length for placement in the endocervical canal, with a range of view up to 3 cm horizontally (1.5 cm in every direction) when flush before insertion into the endocervical canal.
  • Fig.8 illustrates a top plan view 800 of the distal end of the probe with a retractable endoscope 802 incorporated therein.
  • a plurality of micro LED arrays or the tips of one or more optical fibers may be arranged in an array of concentric circles 804, 806 in the distal end with the ability to activate light delivery from each individual concentric circles increasing sequentially, one at a time, which may, in some embodiments, have a diameter totaling up to 3 cm. Other suitable diameters may be used. It should be appreciated that more than two concentric circles of LED arrays or optical fibers may be implemented, such that the light intensity may be controllable one concentric circle or one selected segment of the LED of optical fiber array at a time. That is, different segments or circles of the micro LED of fiber optic arrays may be operated independently. Referring to Fig.
  • the endoscope 802 may be in a regressed position initially with, e.g., white LED light on to guide the placement of the probe of the PDT device and system 100 into a treatment region of a patient.
  • the elongated body of the probe may include an endocervical canal portion 810 joined with an extension portion 812 via a connection portion 814.
  • the connection portion 814 may be made of flexible polymer materials or any suitable malleable materials to facilitate maneuver, manipulation, and passage of the endoscope 802 into the endocervical canal of the patient, thereby providing a user of the PDT device and system 100 with an endoscopic view (e.g., a 360 ⁇ endoscopic view) of the patient’s endocervical canal.
  • an image sensor may be integrated in the endoscope 802, such that a user of the PDT device and system 100 of the present disclosure may insert and navigate the endoscope 802 within the vaginal canal, endocervical canal and uterine cavity of the patient with endoscopic vision.
  • a handle portion 816 of the PDT device and system 100 may include a finger-actuated control panel (not shown) with buttons or switches for adjusting light intensity of the micro LED arrays and/or changing operating parameters of other components attached to the PDT device and system 100 (e.g., capturing images or videos from sensor(s)).
  • the handle portion or a handpiece 816 may have an angled grip implementation.
  • the extrusion length of the retractable endoscope 802 may be adjusted by a syringe like mechanism or hydraulic function 818, as shown in Fig. 10.
  • the endoscope 802 may extend from the initial flat position up to 4 cm for placement of the probe of the PDT device and 323503294.1 27 Attorney Docket No.: A2001-7005WO system 100 into a patient’s endocervical canal.
  • Micro LED arrays or optical fibers may be controlled to illuminate the treatment area but without delivering treatment wavelengths of light into the uterus of the patient.
  • an electrical cable 820 may extend from the handle portion 816 to an imaging processor (not shown) and corresponding image/video display.
  • Some common infections of mucosal epithelium are also treatable with photodynamic therapy using quinine and/or riboflavin derivatives as photosensitizers.
  • gels comprising quinine, riboflavin (or a riboflavin derivative including but not limited to riboflavin phosphate) or a combination of quinine plus riboflavin are applied followed by exposure to light at 405 nm. Further details on treatment of vaginal infections with compositions and methods of the present disclosure are provided in Example 4 below.
  • the present disclosure provides a pharmaceutical compositions comprising quinine and a riboflavin derivative in a pharmaceutically acceptable formulation for topical application to mucosal or cutaneous epithelial surfaces, for elimination of dysplastic or neoplastic cells during localized exposure of the area, treated with the topical composition, to light at an appropriate wavelength and intensity.
  • a pharmaceutical composition comprising quinine and a riboflavin derivative in a pharmaceutically acceptable formulation for topical application to mucosal or cutaneous epithelial surfaces, for elimination of dysplastic or neoplastic cells during localized exposure of the area, treated with the topical composition, to light at an appropriate wavelength and intensity.
  • Essentially the same composition and light source, modified for broader light exposure are also useful for treating a range of fungal and bacterial infections.
  • a saturated solution of riboflavin phosphate (flavin mononucleotide) in 500 ml propylene glycol was prepared. The two solutions were mixed. 10 grams of Carbopol 934 powder was mixed into the solutions, which was then heated to 60 degrees C, causing the carbomer to dissolve and form a gel.
  • Example 2 For preparation of a gel for co-delivery of quinine and riboflavin to an epithelial surface, 25 grams of quinine hydrochloride were dissolved in 500 mL glycerol while heating to 50 degrees C. A saturated solution of riboflavin phosphate (flavin mononucleotide) in 500 ml propylene glycol was prepared. The two solutions were mixed.
  • hydroxyethylcellulose powder 323503294.1 28 Attorney Docket No.: A2001-7005WO 50 grams of hydroxyethylcellulose powder 323503294.1 28 Attorney Docket No.: A2001-7005WO was mixed into the solution, which was then heated to 60 degrees C.
  • the hydroxyethylcellulose required about 48 hours to fully thicken in the glycerol and propylene glycol solvent system.
  • heating to 80 degrees C after addition of hydroxyethylcellulose solubilized the hydroxyethylcellulose more rapidly and completely, improving reproducibility of gel characteristics.
  • a solution with a defined concentration below the solubility limit at room temperature is optionally used, for example, 0.1 grams riboflavin-5-phosphate per 10 ml of propylene glycol, or 5 grams per 500 ml.
  • Example 3 For preparation of a gel for co-delivery of quinine and riboflavin to an epithelial surface, 25 grams of quinine hydrochloride were dissolved in 450 mL PEG 450 (polyethylene glycol, average molecular weight 400) combined with 50 ml 1,2-propanediol while heating to 50 degrees C.
  • PEG 450 polyethylene glycol, average molecular weight 400
  • Example 4 For treatment of cervical dysplasia, the Gel of Example 1 is applied to the cervix of a subject displaying ASCUS, CIN1, CIN2 or CIN3.
  • 1 to 5 ml of the Gel is applied directly to the cervix via a blunt syringe; the specific amount is determined by the size of the dysplastic region, and the thickness of the gel layer, which should be a minimum of 1 mm thick.
  • a disposable tampon or cervical cap is optionally used to help contain the gel in the immediate area of the cervix.
  • a speculum is inserted in the vagina and the cervix is rinsed and gently dried, e.g. with a cotton or rayon swab.
  • the cervix is exposed to light at a wavelength of approximately 405 nm, with a total energy of 100 Joules/cm 2 .
  • the time required for exposure is advantageously 30 minutes or less.
  • Example 5 323503294.1 29 Attorney Docket No.: A2001-7005WO
  • vaginal epithelial infections including but not limited to candidiasis, gonorrhea, chlamydia, bacterial vaginosis, and trichomoniasis
  • the Gel of Example 1 is applied to the vagina with a blunt syringe.
  • a quantity sufficient to cover the affected areas to a thickness of approximately 1 mm is applied.
  • a wand with LEDs that emit light at 405 nm is inserted in the vagina, and light is applied with a total energy of approximately 100 Joules/cm 2 .
  • the time required for exposure is advantageously 30 minutes or less.
  • a light wand with LEDs along an extended length of the shaft is advantageous, versus a PDT illumination device specifically for treatment of dysplasia localized to the cervix, to permit treatment of the epithelial infection in essentially the whole of the vaginal canal.
  • Example 6 Cells treated with quinine and riboflavin 5’-phosphate have reduced viability after LED exposure This example demonstrates that cells treated with quinine and riboflavin 5’-phosphate, then exposed to LED, have reduced viability compared to cells exposed to LED only.
  • SiHa cells (a cell line derived from human cervical cancer cells) were plated in a 384 well plate in 5% FBS media.
  • Cells were treated with 100 ug/mL quinine and 10 ug/mL riboflavin 5’- phosphate for 1 hour. After 1 hour, the quinine and riboflavin 5’-phosphate were washed from the cells. The cells were then exposed to LED at a 17.5 cm distance (equivalent to 0.030 Watts) for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. No treatment control cells were only subjected to LED exposure. Cell viability was measured 24 hours and 48 hours after LED exposure using the CellTiter-Glo® assay (Figs. 11-14).
  • non-treated cells had greater than 80% viability 48 hours 323503294.1 30 Attorney Docket No.: A2001-7005WO after LED exposure of the same lengths of time (Fig. 14).
  • Treated cells showed lower viability 48 hours after 30, 25, 20, 15, 10, or 5 minutes of LED exposure compared to non-treated cells. (Fig. 14).
  • Example 7 Dose response of cells to quinine and riboflavin 5’-phosphate combined with LED light exposure This Example demonstrates determination of the IC50 of quinine and riboflavin 5’- phosphate in combination with LED light exposure in vitro in four cell lines. Cell Culture Four different cell lines were used: Ca Ski, DoTc2-4510, SiHa, and Ect1/E6E7.
  • Cells were plated in 384-well tissue culture treated assay plates and allowed to adhere overnight at 37°C and 5% CO 2 .
  • SiHa and Ca Ski cells were plated at a density of 5,000 cells/well.
  • Ect1/E6E7 and DoTc2- 4510 cells were plated at a density of 7,500 cells/well.
  • IC50 is defined as the inflection point on the dose response curve (half of the distance between the min and max of the curve fit). NA denotes that the maximum of the curve is below 50% viability, or the IC50 is otherwise unable to be calculated.
  • EC50 of quinine in vitro with and without LED exposure 323503294.1 31 Attorney Docket No.: A2001-7005WO Cells were exposed to 0, 10, 25, 50, 100, 250, or 500 ⁇ g/mL quinine with or without LED exposure as described above. Cells were re-treated at 24 hours after initial treatment, including LED exposure. Results are shown in Tables E1, E2, and E3. Table E1. EC50 of quinine in vitro (no LED exposure) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours SiHa >500 ⁇ g/mL 139 ⁇ g/mL 121 ⁇ g/mL Table E2.
  • Table E7 EC50 of quinine combined with riboflavin 5’-phosphate in vitro (no LED exposure) at 0 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 2 L L 1 L L L Table E8. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (no LED exposure) at 24 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 323503294.1 34 Attorney Docket No.: A2001-7005WO Table E9.
  • EC50 of quinine combined with riboflavin 5 -phosphate in vitro (LED exposure for 30 minutes) at 48 hours
  • EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes after media replacement) at 0 hours
  • Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 323503294.1 36 Attorney Docket No.: A2001-7005WO Table E14.
  • EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes after media replacement) at 24 hours
  • Photodynamic Therapy Gel Surgical removal or laser ablation of cervical dysplasia can be painful and can compromise structure of the cervix, with a substantially increased risk of preterm birth.
  • This example describes a less tissue-destructive treatment modality, photodynamic therapy (PDT), which can destroy dysplastic cells while sparing the normal structure and function of the cervix.
  • Photodynamic therapy for treatment of cervical dysplasia involves application of fluorescent photosensitizer compounds to areas in need of treatment, in some embodiments with preferential uptake of the photosensitizer into abnormal or neoplastic cells versus surrounding normal epithelium.
  • Selectivity for dysplastic versus normal cells can be achieved via several modes of action; 1) direct application of photosensitizers only to dysplastic areas; 2) preferential uptake of photosensitizers into abnormal cells (exploiting metabolic differences between normal and dysplastic cells); and 3) selective application of light to dysplastic areas while avoiding surrounding normal tissue.
  • This Example describes the use of riboflavin-5-phosphate and quinine, which have desirable profiles for safety and effectiveness as photosensitizers. Both of these agents are fluorescent and have high quantum efficiency for excitation and generation of singlet oxygen that can destroy dysplastic cells when exposed to visible light in the near-UV range, via a PDT light probe, e.g., as described herein.
  • This enzyme allows for local dephosphorylation of R5P, followed by uptake of riboflavin into cells.
  • Riboflavin transporters are upregulated in cervical dysplasia, further promoting preferential destruction of abnormal cells.
  • Some riboflavin produced by dephosphorylation of R5P will precipitate on dysplastic regions (but can be rinsed off of normal epithelium prior to light activation), providing amplification of PDT activity, and also allowing for a readily visible fluorescent diagnostic for detection of dysplasia in situ.
  • PDT Gel Preparation Ingredients • Quinine Hydrochloride • Riboflavin-5-phosphate • Glycerol • Propylene Glycol • Hydroxyethylcellulose
  • the solvents of the PDT Gel, glycerol and propylene glycol (PG), were selected based in part on providing adequate solubility of both quinine and R5P, while also being nonaqueous to reduce risk of hydrolysis of the phosphate group on R5P. Furthermore, both glycerol and PG act as “optical clearing agents”, increasing light permeability of mucosal tissue, and these solvents also work well with hydroxyethylcellulose to form a stable gel.
  • Vials may also be used, as the PDT Gel may be applied to the cervix with a blunt syringe, medical swab, or other applicator.
  • a typical treatment volume will be about 1 ml or less.
  • One or more components may be referred to herein as “configured to,” “configurable to,” “operable/operative to,” “adapted/adaptable,” “able to,” “conformable/conformed to,” etc.
  • “configured to” can generally encompass active-state components and/or inactive-state components and/or standby-state components, unless context requires otherwise.
  • any reference to “one aspect,” “an aspect,” “an exemplification,” “one exemplification,” and the like means that a particular feature, structure, or characteristic described in connection with the aspect is included in at least one aspect.
  • appearances of the phrases “in one aspect,” “in an aspect,” “in an exemplification,” and “in one exemplification” in various places throughout the specification are not necessarily all referring to the same aspect.
  • the particular features, structures or characteristics may be combined in any suitable manner in one or more aspects.
  • treatment refers to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent or cure a disease, pathological condition, or disorder.
  • photosensitizing composition refers to a composition comprising one or more photosensitizing compound.
  • a “photosensitizing compound,” as used herein, refers to: (i) a compound that produces a reactive oxygen species or toxicity to a cell comprising the compound when activated by a suitable wavelength of light, or (ii) a precursor that is metabolized in a patient’s body into a compound as described in (i).
  • the photosensitizing composition comprises more than one photosensitizing compound.
  • the photosensitizing compounds can be activated by the same or different wavelengths of light.
  • the photosensitizing compound is riboflavin-5’-phosphate or quinine.
  • activate refers to the light causing the compound to produce a reactive oxygen species or toxicity to a cell comprising the compound.
  • an “analog” of a compound refers to a metabolite and/or a metabolic precursor of the compound.
  • riboflavin-5′-phosphate is an analog of riboflavin.
  • quinidine is an analog of quinine.

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Abstract

Photodynamic therapy device and system comprising one or more light sources configured to produce one or more wavelengths of light, a component configured to control the one or more light sources, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix, and methods for using the device and system to induce regression of mucosal dysplasia are provided.

Description

Attorney Docket No.: A2001-7005WO DEVICE, SYSTEM AND METHOD FOR PHOTODYNAMIC TREATMENT OF EPITHELIAL DYSPLASIA AND NEOPLASIA CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63/648,111, filed May 15, 2024. The contents of the aforementioned application are hereby incorporated by reference in their entirety. BACKGROUND The present invention is in the technical field of cancer prevention and treatment. More particularly, the present invention is in the technical field of topical treatment of precancerous and early cancerous lesions of mucosal and cutaneous epithelium. Most cases of cervical cancer are initiated by infection of cells with Human Papillomavirus (HPV); the same is true of other mucosal epithelial cancers, including vulvar, vaginal, anal and oropharyngeal malignancies. Cervical squamous epithelial abnormalities are graded from low to high, the lowest identifiable form being Atypical Squamous Cells (ASC), which is divided into two groups: Undetermined Significance (ASCUS) and “Cannot exclude HSIL (high-grade squamous intraepithelial lesions)” (ASC-H), followed by Cervical Intraepithelial Neoplasia 1 (CIN1) to higher grades, CIN2 and CIN3, using the CIN classification system. Using The 2014 Bethesda System (TBS), the terminology “Low- Grade Squamous Intraepithelial Lesions (LSIL)” to “High-Grade Squamous Intraepithelial Lesions (HSIL)” are employed. Beyond CIN3 or HSIL lesions, squamous cell abnormalities are either described as having “features suspicious for invasion” or Squamous Cell Carcinoma. Glandular abnormalities are described as low-grade Cervical Glandular Intraepithelial Neoplasia (L-CGIN) to high-grade (H-CGIN) or as CGIN1, 2 and 3. Cervical glandular epithelial abnormalities are graded as “Atypical” (e.g. Atypical Glandular Cells (AGC)), with a variety of cell types including endocervical, endometrial and glandular that can be classified as “Specified” or “Not Otherwise Specified” (-NOS); or for Endocervical and Glandular cells “Favor Neoplastic” (-FN); Endocervical Adenocarcinoma in situ; and Adenocarcinomas of the Endocervical, Endometrial, Extrauterine, and NOS varieties. The umbrella term for such cervical epithelial cell abnormalities, whether squamous or glandular, is “cervical dysplasia”. Cervical dysplasia can be diagnosed several ways, including by naked eye visual examination using acetic acid (visual inspection with acetic acid (VIA)) or Lugol’s iodine (visual 323503294.1 1 Attorney Docket No.: A2001-7005WO inspection with Lugol’s iodine (VILI)) or with the assistance of an intravaginal microscope known as a colposcope. In certain cases, diagnostic biopsies are taken and assessed via histology, at which point, the CIN classification system is used. Cervical dysplasia can also be diagnosed using exfoliative cytology (Papanicolaou Test, “Pap smear”, or “Pap test”), in which a scraping of cervical epithelial cells are collected and analyzed using appropriate staining methods. Cervical dysplasia diagnosed by cytology is graded using The Bethesda System (TBS) where LSIL (encompassing HPV/mild dysplasia) is an appropriate surrogate for CIN1, and HSIL (encompassing moderate and severe dysplasia/ Carcinoma in Situ) an appropriate surrogate for CIN2/3. Low-grade dysplastic lesions (e.g. ASCUS, CIN1/LSIL) are often managed by an observational approach, requiring repeat cervical examination known colloquially as “watching- and-waiting”. Surgical intervention is typically warranted at the CIN2/3 and CGIN stage but can damage the cervix, compromising the ability to have a successful pregnancy, and are therefore not considered warranted for ASCUS and CIN1, and undesirable for CIN2. However, almost all cervical cancer begins as CIN, so a relatively benign method for eliminating dysplastic cells would have a large impact on the risk of developing cervical cancer in individuals and on its incidence in populations. This is especially important in low-resource populations where cervical dysplasia screening and treatment are not widespread or affordable. If CIN1 progresses to CIN2/3 or if there is glandular cell involvement, the risk of progression to malignant cervical cancer is considered greater and therefore ablative or excisional intervention is warranted. The most widely employed treatments are surgical excision, including LEEP (loop electrosurgical excision procedure) and thermal ablation (thermoablation) involving destruction of dysplastic regions and associated margins of nontransformed epithelial cells with a heated (or freezing) probe. To a lesser extent, cryoablation (involving destruction of dysplastic regions and associated margins of nontransformed epithelial cells with a cryogenic probe), and conization (either using a cold-knife or laser, also involving epithelial destruction with margins), are used. Thermoablation, a widely accepted, portable, low-cost solution used in “see and treat” settings where patients are treated during the same visit as a diagnosis takes place (typically visual in nature), is not suitable for treatment of glandular lesions which is one its major deficiencies. LEEP is a popular and relatively well-tolerated procedure, but is excisional in nature, requiring surgical expertise and associated equipment and facilities, including a reliable electricity supply, often prohibitive in low and middle-income regions (LMIRs). Furthermore, both surgical and 323503294.1 2 Attorney Docket No.: A2001-7005WO ablative techniques result in consequent pain and risk of pregnancy-impairing damage. Both excisional and ablative surgical treatments require an average of two to six weeks post-procedure to heal, may cause ongoing discomfort, discharge, and generally cannot be repeated for recurrent dysplasia due to excessive cervical damage. Surgical procedures require local or general anesthetic, and run the risk of causing infections, bleeding, scarring to the cervix, and may compromise the ability to become pregnant and carry a pregnancy to term. Thermal ablation similarly damages normal tissues surrounding areas of dysplasia, causes cramping, and the combination of smoke generated by the procedure and smell of cauterized mucosal tissue is unpleasant and can cause distress to the patient. Surgical procedures also require extensive operator expertise, years of training, and associated certification to perform successfully, access to surgical facilities, costly and often heavy surgical machinery or equipment, and a reliable supply of corresponding disposable surgical equipment, resulting in limits to access to appropriate treatment for cervical dysplasia. Cervical procedures frequently induce a vagal response which can lead to dizziness, fainting, nausea, ringing ears, and sweating. There exists a need for a relatively benign non-surgical treatment capable of inducing regression of ASCUS, LSIL/CIN1, HSIL/CIN2/3 and glandular lesions (CGIN, AGC-X, AIS), thereby reducing or eliminating risk of progression to cervical cancer, without compromising fertility or requiring extensive operator expertise, which would have a large impact on both personal health and upon healthcare costs for populations. A treatment that is safe, non-invasive, economical, portable, effective, battery-powered, appropriate for remote settings, does not require onerous operator training or expertise, and capable of treating squamous and glandular lesions simultaneously, would be especially advantageous. SUMMARY The present disclosure generally relates to cancer prevention and treatment device, system and method, and more particularly relates to photodynamic therapy (PDT) of precancerous and early cancerous lesions of mucosal and cutaneous epithelium. Enumerated Embodiments: 1. A device, comprising: one or more light sources configured to produce one or more wavelengths of light; a component configured to control the one or more light sources; and 323503294.1 3 Attorney Docket No.: A2001-7005WO a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 2. A device, comprising: an elongated body having a longitudinal axis extending from a proximal end to a distal end; one or more light sources housed in the elongated body and configured to produce one or more wavelengths of light; and a light guide implemented on the distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 3. A device, comprising: one or more light sources configured to produce one or more wavelengths of light; a component configured to control the one or more light sources; and a treatment probe including a light guide implemented on a distal end, wherein the treatment probe has a length of 15-25 cm, a diameter of 1-2 cm, and wherein the light guide has a tapered extension with a length of 0-40 mm. 4. A device, comprising: an elongated body having a longitudinal axis extending from a proximal end to a distal end, wherein the elongated body has a length of 17-30 cm, a diameter of 1-2.5 cm; one or more light sources housed in the elongated body and configured to produce one or more wavelengths of light; and a light guide implemented on a distal end of the elongated body, wherein the light guide has a tapered extension with a length of 0-40 mm. 5. The device of any of embodiments 1-4, wherein the one or more light sources include a plurality of light emitting diodes (LEDs) or one or more optical fibers. 6. The device of embodiment 5, wherein at least a first portion of the LEDs emit light having a wavelength range of 400-700 nm. 7. The device of embodiment 5, wherein at least a second portion of the LEDs emit light with a peak emission spectrum near 400 nm. 323503294.1 4 Attorney Docket No.: A2001-7005WO 8. The device of embodiment 5, wherein at least a third portion of the LEDs emit light with a peak emission spectrum near 405 nm. 9. The device of embodiment 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 390-415 nm, e.g., 395-410 nm, e.g., 400-410 nm. 10. The device of embodiment 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 440-460 nm, e.g., 445-455 nm, e.g., about 450 nm. 11. The device of embodiment 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 390-460 nm. 12. The device of embodiment 5, wherein at least a fourth portion of the LEDs emit light with a peak emission spectrum near 650 nm. 13. The device of embodiment 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 620-660 nm, e.g., 630-655 nm. 14. The device of embodiment 5, wherein at least a portion of the LEDs are capable of emitting light that is free of or substantially free of ultraviolet light. 15. The device of embodiment 5, wherein at least a portion of the LEDs are capable of emitting light that is free of or substantially free of red light. 16. The device of embodiment 5, wherein the plurality of LEDs emit the one or more wavelengths of light contemporaneously. 17. The device of embodiment 6, wherein the plurality of LEDs emit the one or more wavelengths of light continuously. 18. A system for photodynamic therapy (PDT) comprising the device of any of proceeding embodiments and a photosensitizing composition. 19. A system for photodynamic therapy (PDT), the system comprising: a photosensitizing composition; and a PDT device, comprising: 323503294.1 5 Attorney Docket No.: A2001-7005WO one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 20. A system for photodynamic therapy (PDT), the system comprising: a photosensitizing composition comprising riboflavin; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject. 21. A system for photodynamic therapy (PDT), the system comprising: a photosensitizing composition comprising quinine; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject. 22. The system of any of embodiments 18-21, further comprising a power source, wherein optionally the power source includes a built-in battery and a charging circuit for supplying power to the one or more light sources. 23. The system of any of embodiments 18-22, further comprising a module configured to switch operational modes of the one or more light sources. 24. The system of any of embodiments 18-23, further comprising a module configured to allow a user to adjust a light irradiation intensity of the one or more light sources. 323503294.1 6 Attorney Docket No.: A2001-7005WO 25. The system of any of embodiments 18-24, wherein the light irradiation intensity includes maximum light energy delivered in each PDT treatment session of 40-160 J/cm2, e.g., 80-120 J/cm2, e.g., 90-110 J/cm2, e.g., approximately 100 J/cm2. 26. The system of any of embodiments 18-25, wherein the light irradiation is at a fluence rate of approximately 25-300 mW/cm2. 27. The system of any of embodiments 18-26, wherein the light guide has a length of 0-40 mm. 28. The system of any of embodiments 18-27, wherein the light guide is made from polymethyl methacrylate. 29. The system of any of embodiments 18-28, wherein the light guide is made from materials having transparency to the first and the one or more second lights. 30. The system of any of embodiments 18-29, wherein the light guide is made from materials appropriate for medical use. 31. The system of any of embodiments 18-30, wherein the light guide is made from materials with high elasticity. 32. The system of any of embodiments 18-31, further comprising one or more single-use plastic sheathes for the treatment probe. 33. The system of any of embodiments 18-32, further comprising one or more cervical cups for retention of the photosensitizing composition on the cervix of a patient between application and light treatment. 34. The system of any of embodiments 18-33, further comprising swabs and sterile saline for removing excess cervical mucus or the photosensitizing composition. 35. A device or system of any of the preceding embodiments, for use in treating or preventing a cancer or infection in a subject in need thereof. 323503294.1 7 Attorney Docket No.: A2001-7005WO 36. A method of treating or preventing a cancer or infection in a subject in need thereof, the method comprising illuminating the cancer cells, dysplastic cells, or infected area using the device. 37. The method or use of embodiment 35 or 36, wherein the method comprises illuminating the cervix of the subject using the device. 38. The method or use of embodiment 35 or 36, wherein the method further comprises applying the photosensitizing composition to the cancer cells, dysplastic cells, or infected area. 39. The method or use of embodiment 35 or 36, wherein the method further comprises applying the photosensitizing composition to the cervix of the subject. 40. The method or use of any of embodiments 35-39, which comprises illuminating the affected area with the device for about 1-50, 5-40, or about 10 minutes. 41. A device or system of any of the preceding embodiments, for use in diagnosing a dysplasia or cancer in a subject in need thereof. 42. A method of detecting a dysplasia, cancer, or infection in a subject in need thereof, the method comprising: applying the pharmaceutical composition of any of embodiments 43-50 to the cervix of the subject, and illuminating the cervix of the subject using the device of any of embodiments 1-17, wherein fluorescence above a baseline level indicates the presence of the cancer or infection. 43. A pharmaceutical composition comprising two or more of (e.g., all of): quinine or an analog thereof; and riboflavin or an analog thereof; wherein the pharmaceutical composition is a gel. 44. The pharmaceutical composition of embodiments 43, wherein the analog of riboflavin is riboflavin -5’-phosphate. 45. The pharmaceutical composition of embodiment 43 or 44, wherein the analog of quinine is quinidine. 323503294.1 8 Attorney Docket No.: A2001-7005WO 46. The pharmaceutical composition of any of embodiments 43-45, wherein the concentration of the quinine or analog thereof is 0.1 – 25 mg/ml. 47. The pharmaceutical composition of any of embodiments 43-46, wherein the concentration of the riboflavin or analog thereof is 0.01 - 10 mg/ml. 48. The pharmaceutical composition of any of embodiments 43-47, further comprising a gelling agent. 49. The pharmaceutical composition of embodiment 48, wherein the gelling agent is a cellulosic thickener such as hydroxyethylcellulose, hydroxypropylmethylcellulose, or methylcellulose. 50. The pharmaceutical composition of embodiment 48, wherein the gelling agent is a polyacrylic acid such as carbomer. 51. The system of any of embodiments 18-34, wherein the photosensitizing composition comprises quinine or an analog thereof. 52. The system of any of embodiments 18-34, wherein the photosensitizing composition comprises riboflavin or an analog thereof. 53. The system of any of embodiments 18-34, wherein the photosensitizing composition is a gel. 54. The system of any of embodiments 18-34, wherein the photosensitizing composition is a pharmaceutical composition according to any of embodiments 43-54. 55. The pharmaceutical composition of any of embodiments 43-54, for use in photosensitizing dysplastic cells or infected cells. 56. A method of using the pharmaceutical composition of any of embodiments 43-54 for photosensitizing dysplastic cells or infected cells, the method comprising applying the pharmaceutical composition to the dysplastic cells or infected cells. 57. A device, comprising: one or more light sources configured to produce one or more wavelengths of light; 323503294.1 9 Attorney Docket No.: A2001-7005WO a component configured to control the one or more light sources; and a probe including an endoscope implemented on a distal end, wherein the probe and the endoscope are configured to direct the one or more wavelengths of light onto the cervix. 58. The device of embodiment 57, wherein the endoscope is retractable up to 4 cm. 59. The device of embodiment 57, wherein the one or more light sources are arranged in concentric circles and each concentric circle is controlled to produce the one or more wavelengths of light independently. 60. The device of embodiment 57, wherein the probe includes a first portion joined with a second portion via a connection portion, wherein the first portion is for placement the probe into an endocervical canal of a patient, and the second portion connects with a handle portion of the probe. 61. The device of embodiment 60, wherein the connection portion is made of malleable materials. 62. The device of embodiment 57, wherein an extension length of the endoscope is controlled by syringe like mechanism or a hydraulic function of the device. 63. The device of embodiment 57, further comprising image and video sensors configured to provide endoscopic vision of the cervix. 64. The device of embodiment 57, wherein the endoscope has a diameter up to 7 mm. 65. The device of embodiment 57, wherein the distal end of the probe has a diameter up to 3 cm. 66. The device of embodiment 57, wherein the endoscope includes micro LED arrays for emitting the one or more wavelengths of light to surrounding cervical tissues with no treatment light wavelengths into the uterus. In some aspects, the present disclosure provides a topically administered pharmaceutical composition comprising quinine for photodynamic therapy of epithelial dysplasia. In some embodiments, the pharmaceutical composition further comprises glycerol and a thickening agent selected from carbomers or modified cellulosics including but not limited to hydroxyethylcellulose, hydroxypropylmethylcellulose, and methylcellulose. In some 323503294.1 10 Attorney Docket No.: A2001-7005WO embodiments, the composition further comprises propylene glycol. In some embodiments, the composition further comprises a surfactant selected from polysorbates. In some embodiments, the composition further comprises riboflavin or riboflavin phosphate. In some aspects, the present disclosure provides a method for treating epithelial dysplasia or neoplasia by applying a pharmaceutical composition of the invention to an epithelial surface and then exposing the treated epithelial area to light at a wavelength of 405 nm with a cumulative intensity of approximately 100 J/cm2. The above simplified summary of example aspects serves to provide an understanding of the present disclosure. This summary is not an extensive overview of all contemplated aspects, and is intended to neither identify key or critical elements of all aspects nor delineate the scope of any or all aspects of the present disclosure. Its sole purpose is to present one or more aspects in a simplified form as a prelude to the more detailed description of the disclosure that follows. To the accomplishment of the foregoing, the one or more aspects of the present disclosure include the features set out in the claims. BRIEF DESCRIPTION OF THE DRAWINGS The accompanying drawings, which are incorporated into and constitute a part of this specification, illustrate one or more example aspects of the present disclosure and, together with the detailed description, serve to explain their principles and implementations. Fig. 1 illustrates a top view of an example PDT device and system in an open state, according to an exemplary aspect of the present disclosure; Fig.2 illustrates a perspective view of a base halve of the example PDT device and system of Fig. 1, according to an exemplary aspect of the present disclosure; Fig. 3 illustrates a perspective view of the example PDT device and system of Fig. 1 and a number of parts, according to an exemplary aspect of the present disclosure; Fig. 4 illustrates a control module of the example PDT device and system of Fig. 1 being connected to a probe having a light guide attached on one distal end, according to an exemplary aspect of the present disclosure; Fig.5 illustrates a cross-sectional side view of a first design of a probe having a light guide attached on one distal end, according to an exemplary aspect of the present disclosure; 323503294.1 11 Attorney Docket No.: A2001-7005WO Fig. 6 illustrates a cross-sectional side view of a second design of a probe having a light guide attached on one distal end, according to an exemplary aspect of the present disclosure; Fig. 7 illustrates a cross-sectional side view of a light guide, according to an exemplary aspect of the present disclosure; Fig. 8 illustrates a top plan view of a distal end of a probe having a retractable endoscope integrated therein, according to an exemplary aspect of the present disclosure; Fig. 9 illustrates a probe having a retractable endoscope in a regressed position, according to an exemplary aspect of the present disclosure; Fig. 10 illustrates a probe having a retractable endoscope in a fully extended position, according to an exemplary aspect of the present disclosure; Fig. 11 is a bar graph showing RLU (luminescence) 24 hours after photodynamic therapy treatment in SiHa cells. Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm. No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure. Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Luminescence was measured using CellTiter-Glo® 24 hours post LED exposure; Fig. 12 is a bar graph showing percent viability 24 hours after photodynamic therapy treatment in SiHa cells. Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm. No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure. Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Percent viability was measured using CellTiter-Glo® 24 hours post LED exposure; Fig. 13 is a bar graph showing RLU (luminescence) 48 hours after photodynamic therapy treatment in SiHa cells. Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 323503294.1 12 Attorney Docket No.: A2001-7005WO 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm. No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure. Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Luminescence was measured using CellTiter-Glo® 48 hours post LED exposure; and Fig. 14 is a bar graph showing percent viability 48 hours after photodynamic therapy treatment in SiHa cells. Treated cells (Q+R, leftmost bar of each pair) were exposed to 100ug/mL quinine and 10 ug/mL riboflavin 5’-phosphate for 1 hour and then subjected to LED exposure at 17.5 cm distance for varying amounts of time, delivering 30 mW at 405 nm. No treatment cells (No treatment, rightmost bar of each pair) were only subjected to LED exposure. Cells were exposed to LED for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. Percent viability was measured using CellTiter-Glo® 48 hours post LED exposure. DETAILED DESCRIPTION In accordance with aspects of the present disclosure, PDT of dysplastic or neoplastic cells feature selective destruction of pre-malignant cells with relative exclusion of normal cells. Exogenous photosensitizers that are not selectively concentrated in dysplastic cells must rely on operator skill to focus the activating light only on dysplastic sites, avoiding surrounding normal epithelium. Among other features, one of the goals of the present disclosure is to provide photosensitizing compounds for PDT that are taken up into intracellular spaces with selectivity for pre-malignant and malignant cells versus normal epithelium. Photosensitizing compositions Suitable photosensitizing compounds of the present disclosure may comprise quinine and riboflavin, including riboflavin derivatives such as flavin mononucleotide (also called riboflavin- 5′-phosphate). For co-delivery of both agents to an epithelial surface, a method according to the present disclosure may use a solvent system in which both compounds are adequately soluble and stable, and which further enables creation of a suitable pharmaceutical formulation. As a result, release of the quinine and riboflavin from the formulation occurs readily to facilitate a relatively brief interval between application of the topical formulation and the photodynamic light treatment using e.g., a PDT device that will be described fully below. Since quinine is very poorly soluble 323503294.1 13 Attorney Docket No.: A2001-7005WO in aqueous media, and riboflavin phosphate is potentially unstable in water, nonaqueous solvents and formulations may be advantageous. Furthermore, both quinine and riboflavin are poorly soluble in most pharmaceutically acceptable solvents. In some aspects, the present disclosure may comprise topical gels, emulsions, and creams that can deliver both quinine and riboflavin into epithelial cells as preparation for PDT-induced destruction of dysplastic cells. Quinine is relatively soluble in glycerol, at concentrations up to approximately 5% (50 grams per liter). However, addition of gelling agents suitable for glycerol-based anhydrous gels such as carbomers can cause precipitation of quinine. Without wishing to be bound by theory, riboflavin phosphate improves the solubility of quinine in glycerol or glycerol/propylene glycol in the presence of one or more gelling agents, including carbomers, hydroxyethylcellulose, hydroxypropylmethylcellulose (HPMC), and methylcellulose and other modified cellulosic thickeners. Conversely, quinine improves the solubility of riboflavin or riboflavin phosphate in nonaqueous media, including glycerol and propylene glycol of mixtures of these two solvents. Compositions of the present disclosure may optionally comprise surfactants, including but not limited to polysorbates and penetration enhancers including but not limited to Transcutol. Such excipients improve delivery for active agents from the gel into epithelial cells, both by facilitating release from the gel and penetration of keratinocyte layers. In certain aspects, the present disclosure relates to selective or preferential uptake of the active photosensitizing compounds into dysplastic or neoplastic cells. It is believed that quinine is taken up into and retained by dysplastic and neoplastic cells by cation trapping. Quinine has a net neutral charge at pH ~7, which enables permeation of cell membranes. In lower pH environments, such as the interior of lysosomes and other acidic endosomes, quinine has a cationic charge, which limits its egress, thereby enabling accumulation in such acidic vacuoles. A stereotyped feature of dysplastic and neoplastic cells is enhanced lysosomal acidification, leading to a lower intralysosomal pH than in corresponding normal cells, with consequent enhanced accumulation of quinine versus non-neoplastic epithelial cells. Quinine is a photosensitizing agent, activated to fluoresce by light in the ultraviolet and short wavelength visible part of the spectrum. Ultraviolet light has the potential to cause undesirable genotoxic damage in cells promoting dysplasia and oncogenesis. Therefore, according 323503294.1 14 Attorney Docket No.: A2001-7005WO to some embodiments of the present disclosure, light at a wavelength greater than 400 nm, advantageously 405 nm, may be used for PDT with quinine as a photosensitizer. Normal vaginal mucosal cells can tolerate light at 405 nm at a cumulative intensity of about 100 Joules/cm2 in a single PDT session. Riboflavin and riboflavin phosphate are precursors to intracellular flavin nucleotides, including FAD (flavin adenine dinucleotide). FAD is a cofactor responsible for transfer of electrons from the TCA (tricarboxylic acid cycle) cycle to Complex II (succinate dehydrogenase) of mitochondria. FAD concentrations and electron flux mediated by it are elevated in dysplastic and neoplastic cells relative to surrounding normal cells, as a cellular strategy for increasing bioenergetic support for cell proliferation. Endogenous FAD fluorescence may be used to identify and grade cervical dysplasia and neoplasia. In certain aspects of the present disclosure, the propensity of dysplastic cells to elevate FAD and other bioenergy cofactors may be mediated in part by an enhanced ability to assimilate and retain exogenous precursors including riboflavin and riboflavin phosphate, the latter of which is dephosphorylated by cell-surface and extracellular nucleotidases or phosphatases prior to cellular uptake. Acid phosphatase activity has been identified as a marker for cervical dysplasia, with activity directly correlated with severity of dysplastic lesions; acid phosphatase is produced in and released from lysosomes of preneoplastic and neoplastic cells. Provision of exogenous riboflavin with compositions and compounds of the present disclosure delivering riboflavin 5’- phosphate results in relatively selective elevation of FAD and related metabolites in dysplastic and neoplastic cells versus surrounding normal epithelial cells. Riboflavin and intracellular flavin nucleotides fluoresce when exposed to light at 405 nm, but the absorbance maximum for flavins is at about 450 nm, with an absorbance coefficient about three times greater at 450 than at 405 nm. In some aspects, the therapeutic synergy of quinine and riboflavin of the present disclosure may be at least attributable to the fact that quinine, both intracellular and on the cell surface, emits light at 450 nm during exposure to light at 405 nm. This boosts photodynamic activation of riboflavin and flavin nucleotides beyond that yielded by exposure to 405 nm light alone, amplifying the combined therapeutic effect of quinine and riboflavin against dysplastic or neoplastic cells. Without wishing to be bound by theory, quinine and riboflavin accumulate selectively or preferentially in dysplastic or neoplastic cells via fundamentally different mechanisms, such that 323503294.1 15 Attorney Docket No.: A2001-7005WO the combined use of these agents can further enhance overall selectivity of methods of the present disclosure for elimination of dysplastic and neoplastic cells. For delivery into cervical epithelial cells, active photosensitizers of this disclosure may be formulated in a topical composition that is applied to the dysplastic areas of the cervix, with a blunt syringe, swab or other applicator. The topical composition can be a cream, ointment or gel. In one embodiment, a gel is prepared with a solvent that acts as an “optical clearing agent.” Certain solvents, such as glycerol, propylene glycol, Polyethylene glycol (PEG; advantageously low molecular weight PEG including but not limited to PEG 400), 1,2-propanediol, 1,3-propanediol or transcutol, or mixtures of two or more of these solvents. These liquids are absorbed into mucosal or cutaneous epithelium and reduce light scattering, enabling improved penetration of light into the tissue to be subjected to PDT treatment. Nonionic thickening agents may be used, especially cellulosic thickeners including hydroxyethylcellulose, methylcellulose, hydroxypropylmethylcellulose. Because both riboflavin and quinine are activated by light at 405 nm, the same PDT illumination device may be used to activate both quinine and riboflavin simultaneously during a single treatment session, with the same light intensity and duration of exposure, generally up to about 100 Joules/cm2 cumulative exposure per treatment session. In some embodiments, the photosensitizing composition comprises: quinine (e.g., quinine hydrochloride), riboflavin-5-phosphate, glycerol, propylene glycol, and hydroxyethylcellulose. In some embodiments, the photosensitizing composition comprises quinine (e.g., quinine hydrochloride) and riboflavin-5-phosphate. In some embodiments, the photosensitizing composition comprises quinine (e.g., quinine hydrochloride) and glycerol. In some embodiments, the photosensitizing composition comprises riboflavin-5-phosphate and propylene glycol. In some embodiments, the photosensitizing composition comprises glycerol, propylene glycol, and hydroxyethylcellulose. In some embodiments, the photosensitizing composition is a gel. In some embodiments, the photosensitizing composition is a gel comprising quinine or an analog thereof. In some embodiments, the photosensitizing composition is a gel comprising riboflavin or an analog thereof. In some embodiments, the photosensitizing composition comprises quinine or an analog thereof and riboflavin or an analog thereof. In some embodiments, the quinine or analog thereof is present at about 0.5 g per 20 ml volume or about 25 mg/ml in the photosensitizing composition. In some embodiments, the quinine 323503294.1 16 Attorney Docket No.: A2001-7005WO or analog thereof is present at about 0.1 – 25 mg/ml or about 5 – 25 mg/ml in the photosensitizing composition. In some embodiments, the quinine or analog thereof is present at about 0.1-1, 1-5, 5- 10, 10-15, 15-20, or 20-25 mg/ml in the photosensitizing composition. In some embodiments, the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) is present at about 0.1 g per 20 ml volume or about 5 mg/ml in the photosensitizing composition. In some embodiments, the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) is present at 0.01 - 10 mg/ml in the photosensitizing composition. In some embodiments, the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) is present at about 0.01-0.1, 0.1-1, 1-5, or 5-10 mg/ml in the photosensitizing composition. In some embodiments, the hydroxyethylcellulose is present at about 1 g per 20 ml volume or about 50 mg/ml in the photosensitizing composition. In some embodiments, the hydroxyethylcellulose is present at about 30-70 mg/ml or 40-60 mg/ml in the photosensitizing composition. In some embodiments, the photosensitizing composition is made by a method comprising one or more (e.g., all) of the following steps: a) combining the quinine or analog thereof with glycerol, b) combining the riboflavin or analog thereof (e.g., riboflavin-5-phosphate) with the propylene glycol, c) combining a) and b), d), adding the hydroxyethylcellulose, and e) heating the mixture, e.g., to about 80 C. In some embodiments, the mixture is heated to a temperature of about 70-90C or 75-85C. In some embodiments, the mixture forms a gel over about 24 hours. Riboflavin-5-phosphate and quinine are suitable photosensitizers, but compositions and devices of the disclosure can include alternative or additional photosensitizers activated by light at 405 nm. Both endogenous and exogenous porphyrins are activated at this wavelength. Porphyrin photosensitizers for optional use within the scope of the disclosure include the porphyrin precursor 5-aminolevulinic acid. Without wishing to be bound by theory, 5-aminolevulinic acid is converted to protoporphyrin and other photosensitive molecules by metabolism after application. Other suitable photosensitizers include porphyrins that do not require biotransformation including but not limited to haematoporphyrin or porfimer. Phthalocyanine photosensitizers are also optionally used within the scope of this disclosure. In some embodiments, the photosensitizing composition (e.g., gel) is administered to the subject (e.g., to the cervix of a subject) using a blunt syringe, medical swab or applicator. In some embodiments, the photosensitizing composition is administered at a volume of about 0.5 ml – 2 ml, or 0.5 ml – 1 ml. 323503294.1 17 Attorney Docket No.: A2001-7005WO In some embodiments, after administration of the photosensitizing composition to the subject, unabsorbed material is rinsed or swabbed from the cervix. A photosensitizing composition as described in this section may be activated using a photodynamic therapy device, e.g., one described in the following section. Photodynamic therapy devices In accordance with aspects of the present disclosure, referring to Figs. 1-4, a PDT device and system 100 for epithelial dysplasia and neoplasia treatment may include a plurality of components enclosed in a portable, compact case. The PDT device and system 100 of the present disclosure may be used in hospitals, clinics, nursing homes, remote settings, and the like, and is designed for convenient portability. As shown in Fig. 1, the main case of the PDT device, which may primarily comprise a base half 102 and a top half 104, is dimensioned to store, protect and carry multiple PDT treatment components and medical items and supplies. The two half 102 and 104 may be made of a same or different lightweight and substantially rigid structural material, such as plastic, metal or a composite material. The base half 102 comprises four base sidewalls and a base bottom surface, together forming a base interior space. Similarly, the top half 104 comprises four top sidewalls and a top surface, together forming a top interior space. In one embodiment, the two halves 102 and 104 may have asymmetrical dimensions. For example, as shown in Fig. 3, the base interior space of the base half 102 may have a depth greater than that of the top half 104, or vice versa. In another embodiment (not shown), the two halves 102 and 104 may have symmetrical dimensions. As shown in Figs. 1 and 2, the top half 104 may be attached using hinges to the base half 102. Specifically, a peripheral edge of a first sidewall 106 of the top half 104 and a peripheral edge of a second sidewall 108 of the base half 102 are pivotally attached to each other by one or more hinge members 110a, 110b. Pivotal engagement of the base and top halves 102, 104 via the hinge members 110a, 110b may allow the portable case of the PDT device and system 100 to assume a plurality of positions between a completely open position and a completely closed position, as shown in Figs. 1, 2, and 3. When in the open position, the portable case allows a user to access the PDT treatment components and medical items and supplies stored therein. As shown in Figs. 1 and 3, opposite to the one or more hinge members 110a, 110b connecting the two halves 102, 104 together via two corresponding back sidewalls, two locking members 112a, 112b may be implemented on two corresponding front sidewalls of the base and 323503294.1 18 Attorney Docket No.: A2001-7005WO top halves 102, 104, respectively, for securely holding the two halves in a completely closed position. In some embodiments, the locking member 112a, which may be implemented on a front sidewall of the top half 104, may include a tongue portion configured to releasably engage with a latching member 112b disposed on a corresponding front sidewall of the base half 102. It should be appreciated that any suitable locking mechanism for releasably engaging the base and top halves 102, 104 may be used. For example, any suitable snap-fit enclosures may be used to enable convenient and secure opening and closure of the top and base halves 102, 104 through appropriate interlocking features without additional fasteners. Further, the portable case of the PDT device and system 100 includes a handle 114 for convenient transporting and handling of the portable case. In some embodiments, as shown in Figs.1-3, the handle 114 may be implemented on an outer side of a front side wall of the base half 102. In other embodiments (not shown), the handle 114 may be implemented on either or both left and right sidewalls of the portable case. In yet other embodiments of the present disclosure, a shoulder strap (not shown) may be attached to one or more attachment fixtures (e.g., strap pins or hooks) implemented on an outer surface of a selected side wall of the portable case. As shown in Fig. 1, according to some embodiments, the top interior space of the top half 104 may hold various medical items such as a plurality of PDT gel containers 116 (single-use vial of gel) which will be used with single-use applicators 118 (blunt syringes, single use rayon or cotton swabs) for precise application. It should be appreciated that the arrangement and contents of the top interior space may vary and the various components are not necessarily shown to scale. Specifically, the top interior space may comprise a plurality of compartments for holding each of PDT gel containers 116 and syringes 118 via a plurality of loop-like structures 120 in a substantially upright position when the portable case is in an open state. The loop-like structures 120 or similar structures for securing the items within the top interior space may be configured to avoid any dislodgment of each item during the movement of the portable case of the PDT device and system 100. Each PDT gel container 116 contains gel that is specifically formulated for use with the PDT device and system 100 of the present disclosure for the treatment of epithelial dysplasia and neoplasia, ensuring effective treatment delivery. As shown in Figs. 1-3, the interior space of the base half 102 may comprise a plurality of compartments for holding a control module 122, a probe 124, a power supply cable 126, and other electrical components 128 (e.g., charging cables and connectors). The probe 124 is directly 323503294.1 19 Attorney Docket No.: A2001-7005WO involved in the treatment process, working in tandem with the control module 122 to deliver the desired therapeutic effects. According to some embodiments, the probe 124 may be a rigid, linear optical probe, composed of a light delivery core (optical fiber or waveguide), whether enclosed in a biocompatible sheath or not. Such a probe 124 may include a first end connected to a light source (e.g., LED or laser diode) and a second end configured to emit light directly onto a treatment site. Light shaping may be achieved using a flat window, microlens, or diffuser tip. According to additional embodiments, the probe 124 may include a bendable portion that is positioned on a selected location along the elongated body of the probe 124, as will be described fully below with respect to Figs. 9 and 10. Such a probe 124 may become straight if needed but also bendable for different physiologies. For example, if the bend portion is implemented near a light-emitting element, light from the light source may navigate a curved path soon after emission, through a flexible or articulated waveguide. Such a bendable probe design may use side-emitting fibers, angle-polished reflectors, or light-steering elements to redirect light post-bend. If the bend portion is implemented near the treatment site, light emitted from a light source may travel a straight path until it reaches the bend, where it is redirected to the treatment target. A tip portion of such a probe design may feature side-firing optics, angle-polished mirrors, or total internal reflection structures. In certain embodiments, relying upon a built-in battery and a charging circuit, the PDT device and system 100 may operate without an external power supply. The control module 122 may be configured to serve as a power source for probe 124. The control module 122 may also comprise circuitry such as a microcontroller or microprocessor for regulating one or more light-emitting diodes (LEDs). In some aspects, the control module 122 features a user-friendly interface designed for simplicity and efficiency in clinical settings. As shown in Figs. 1 and 2, the control module 122 may include a touchscreen for displaying and prompting a user to input information. In other embodiments, the interface may comprise a number of analog buttons and LED indicators, which collectively facilitate intuitive operation and clear communication of the device’s status and settings. As shown in Fig. 4, in yet another embodiment, an ON/OFF power button and several functional buttons may be implemented on the control module 122. These functional buttons may be used for setting the appropriate treatment duration and for switching between, e.g., two light modes - white light for optical examinations and UV light for therapeutic treatment. Specifically, the PDT device and system 100 of the present disclosure may be activated using the ON/OFF 323503294.1 20 Attorney Docket No.: A2001-7005WO power button 130. Initially, when the device is turned on, none of the LED lights are illuminated. To control white LED light, a user may press a first button on the interface of the control module 122 to activate white LED light, for example, at 50% intensity. The intensity of the white light may be adjusted up or down, for instance, by 10% increments, offering flexibility in lighting conditions for optical examinations. Subsequently, the user may press a second button on the control module 122 to enter interval selection. As a result, the white LED is turned off. The user may set the duration of the treatment interval using e.g., “Plus” and “Minus” buttons implemented on the interface of the control module 122. In some embodiments, a default interval may be set at 15 minutes, but the user may adjust the interval from 1 to 30 minutes in 1 to 5-minute increments. The selected interval may be displayed via green LED indicators on the interface of the control module 122. Upon confirming the interval with a button, the PDT device and system 100 of the present disclosure may begin the countdown for the selected interval. During this time, the UV light is activated, and all of the buttons on the control module 122 may be locked to prevent any inadvertent changes, except for the OFF power button which can be used to turn off the PDT device and system 100 at any time. After the treatment interval elapses, the PDT device and system 100 may automatically return to its initial state, as if it had just been turned on, ready for the next use. This interface design emphasizes ease of use and safety, ensuring that healthcare providers can quickly and accurately set up the PDT device and system 100 of the present disclosure for treatment, with clear indicators and safeguards to prevent unintended modifications during the treatment process. According to some embodiments (not shown), one or more single-use transparent plastic sheaths, one or more single-use or reusable clips, and various medical tools, cleaning solutions and supplies may be stored in the portable case of the PDT device and system 100 or separately. Specifically, each single-use plastic sheath may be configured to fit the probe 124, thereby reducing the risk of cross-contamination between uses of the probe 124. Each single-use or reusable clip may be used for appropriate seating of device. For example, additional internal compartments may be implemented in the base or top interior spaces for storing one or more plastic sheaths and clips. Further, one or more cervical cups may be included for retention of the PDT gel on the cervix of a patient between application and light treatment. Swabs and sterile saline that 323503294.1 21 Attorney Docket No.: A2001-7005WO are generally used during PDT treatments may be used for first removing excess cervical mucus before PDT gel application and then for removing excess unabsorbed PDT gel and photosensitizers before application of light. These additional medical tools or supplies may be stored in containers, separate from the portable case of the PDT device and system 100 of the present disclosure. In accordance with aspects, during the treatment of cervical dysplasia, a distal end of the probe 124 may be adapted to have approximately the same diameter as the cervix and is placed in sufficient proximity to the cervix to expose essentially the entirety of the visible dysplastic lesions to the activating light of the PDT device and system 100. In some embodiments, as shown in Fig.4, the distal end 152 of probe 124 may be attached to light guide 150 to fit within the endocervical canal for treatment of dysplasia within the endocervix. The light guide 150 may be integral with the probe 124, or may be a separate removable and/or replaceable and/or disposable component. The light guide 159 may have a shape suitable for easy placement and maneuverability within the endocervical canal. Example shapes may include pointed conical, rounded conical, nippled, or combinations thereof. The length and design of probe 124 and light guide 150 may be determined and optimized to facilitate ease of use and utility for healthcare providers. According to a first example design illustrated in Fig. 5, probe 124 may have an elongated body having a longitudinal axis extending from a proximal end 154 to a distal end 152. The term “distal” refers to a direction away from a healthcare provider using the PDT device and system 100, which is also the direction of insertion of the probe 124 into the body. The “proximal” direction may generally refer to the direction toward the physician, and the opposite direction toward the distal end. The elongated body of probe 124 may be a generally cylindrical body with one or more light sources or endoscope implemented within. In some embodiments, the probe 124 may have a length of 15-25 cm and a diameter of 1-2 cm. In other embodiments, the elongated body of the probe 124 may have a length of 17-30 cm and a diameter of 1-2.5 cm. According to one implementation, the probe 124 may include a bend that is positioned on the upper third portion of the device, closest to the light. The area that precedes the bend may occupy ⅔ of the overall length. It should be appreciated that the exact dimensions and shapes of the probe 124 may be determined based on certain selected criteria. The proximal end 154 may be flush with and share the same width with the main portion of the elongated body of probe 124, thereby providing an aesthetically pleasing appearance. The light guide 150 may be releasably attached to the distal end 152 via any suitable attachment or 323503294.1 22 Attorney Docket No.: A2001-7005WO interlocking means (e.g., snap-fit attachment means including cantilever, torsional, or annular). In some embodiments, the light guide may have a tapered extension with a length of 0-40 mm, where 0 mm indicates that the light guide is flush with the connection portion of the probe 124 when in an initial, un-extended position. Probe 124 and/or light guide 150 may be made of biocompatible materials or coatings of biocompatible materials to minimize or eliminate any damage to cervical canal tissue that comes in contact with the probe 124 and/or light guide 150. In one embodiment, at least one or more selected portions of the elongated body and/or the light guide 150 may be made of bendable, rather than resilient, materials, such that the PDT device and system 100 may address one of the challenges that the anatomical positioning of the cervix and vaginal canals are typically offset by about 90-100 degrees. According to additional embodiments, an integrated endoscope may be used to facilitate optimum placement of the tip of the probe 124 with or without the light guide 150 on or near the cervix. According to a second example design illustrated in Fig. 6, the proximal end 152 of probe 124 may be configured to extend out of the main portion of the elongated body of probe 124 with gradually increasing width to facilitate easy handling by healthcare providers during treatment. In accordance with certain aspects of the present disclosure, light guide 150 may be ergonomically designed to fit comfortably inside the cervix, ensuring optimal light distribution within. The length of the light guide 150 and/or probe 124 may be determined and selected to facilitate effective light application to the internal areas of the cervix, particularly targeting the columnar epithelium. In one embodiment, a length of the light guide 150 may be equal to or less than 40 mm (e.g., 0-40 mm). The light guide 150 may be made of polymethyl methacrylate (PMMA). PMMA is a lightweight, synthetic polymer that exhibits transparency to both UV and visible light wavelengths and is certified for medical use. Alternative suitable materials may include softer and higher elasticity materials, such as polymethyl acrylate or transparent silicone. According to some embodiments, Fig. 7 illustrates a cross-sectional side view of the light guide 150 which may be an integral component including a main body 160 and a spherical dome portion 162 joined with each other along a longitudinal axis 164 of the main body 160. The length of the main body 160 together with the height of the spherical dome portion 162 define the total length of the light guide 150. For example, the total length may be in the range of 0-40 mm. The main body 160 may have a tapered conical shape with a narrowed distal end 166. Referring back 323503294.1 23 Attorney Docket No.: A2001-7005WO to Figs. 5 and 6, the dome portion 162 may be releasably attached to the distal end 152 of probe 124 which has a shape symmetrical to that of the dome portion 162. According to some aspects, the PDT device and system 100 of the present disclosure may include one or more distinct light sources using one or more LEDs. In one example implementation, a first light source may include a standard white LED light, and a second light source may include an LED that operates in a suitable spectrum for treatment of cervical dysplasia. For instance, the LED may operate in the blue light spectrum or the near ultraviolet spectrum. Specifically, such a first light source may be used for the illumination of a treatment area, for instance with illumination of surrounding or nearby non-neoplastic or normal tissue. In other implementations, an additional light may be used in conjunction with a speculum to facilitate accurate illumination of the dysplastic area. According to some embodiments, each light source of the present disclosure may be configured to emit light continuously. For example, each light source may be configured to have a selected power, center wavelength, spectral bandwidth, beam spot size or cross-section, and beam profile (e.g., Gaussian, flat-top beams). In alternate embodiments, each light source may emit light in a pulse mode. Providing intervals in light illumination may enhance tissue oxygenation and the effect of PDT. Further, pulsed light may prevent unacceptable heating of tissue and allow for the re-accumulation of intracellular photosensitizers from precursors in surviving cells that can be treated with repeated illuminations. For example, the control module 122 may include a microprocessor to control a function generator for generating pulsed light. The frequency and length of the pulses can be chosen according to the requirements of the treatment regime and set within the control circuit. In accordance with some aspects, the one or more light sources of the PDT device and system 100 may be configured to produce one or more wavelengths of light to activate e.g., the photosensitizing composition stored in each PDT gel container 116 of Fig. 1. The one or more light sources may include a plurality of LEDs emitting light having a wavelength range of 400 nm - 700 nm. For example, a first portion of the LEDs may emit light with a peak emission spectrum near 450 nm (absorbance maximum for riboflavin), and a second portion of the LEDs may emit light with a peak emission spectrum near 650 nm (near-infrared for use with e.g., porphyrin photosensitizers). In some embodiments, the LEDs may be configured to emit light with a peak 323503294.1 24 Attorney Docket No.: A2001-7005WO emission spectrum near 405 nm light, because this wavelength is suitable for cancerous cell-killing with riboflavin. The plurality of LEDs may emit multiple wavelengths of light concurrently. In some aspects, the control module 122 and the probe 124 may be configured to control the intensity of light emission by the plurality of LEDs, thereby allowing healthcare providers to adjust the light irradiation intensity according to the specific needs of each treatment. For example, the radiance (J/cm2) of a light source may be set to be high in order to provide a good therapeutic response for thick, dark, and deep lesions, whereas the irradiance may be set to be low to reduce pain and avoid scar formation for superficial lesions. In yet other embodiments, the light intensity of light sources may be set to a fixed level. By standardizing the intensity, the PDT device and system 100 of the present disclosure may simplify the operation of the device for clinicians, ensuring consistency and reliability in treatment delivery. For example, an advantageous light energy delivered in a treatment session may be about 100 J/cm2, optionally at a fluence of about 50-150 mW/cm2. In some embodiments, the light intensity and/or the fluence rate of the PDT device and system 100 may be selected depending on patient’s tolerance determined in clinical trials, as there is evidence that a patient’s pain tolerance may be high in the treatment region per studies on tolerability of thermal-ablation. Higher energy delivery may yield shorter treatment time which would allow for higher patient throughput. According to additional embodiments, the light probe 124 may be configured to include an integrated endoscope or any suitable inspection instrument for documentation of lesions via one or more image sensors, optical lens, light sources and other mechanical/electrical components. It should be appreciated that different lens shapes and sizes may be implemented depending on selected criteria. Example embodiments may include multiple lens or a universal lens which has a retractable lens for treatment in the endocervical canal, extending up to ~3-4 cm. The retractable lens may be extended using a motorized system (not shown) that may be configured to raise and lower the retractable lens based on whether endocervical disease is present. If only squamous infection exists on the ectocervix, the lens may be fully flat or up to 0.5 cm extended to appropriately seat the PDT device within the external cervical os, so it does not move during treatment. If there is disease visible throughout the transformation zone (or squamocolumnar junction), the motorized system may be configured to extend the retractable lens up to 1 cm, which is not be achievable through current thermoablation methods, and is greatly limited through cryoablative probes in treating the endocervical canal. According to some embodiments, the lens 323503294.1 25 Attorney Docket No.: A2001-7005WO of the present disclosure may have variable lighting where it can treat a small circular area where disease is found and a large area if disease is more extensive via selectable settings on the PDT device. In additional embodiments, an integrated miniature endoscope may be implemented at the tip of the retractable lens for assistance with appropriate placement, as well as the surrounding lights, which will also improve visibility for placement. For example, the PDT device of the present disclosure may have a “placement” (white-colored) light and a “treatment” (405 nm) light. Such a tip containing the endoscope may in some embodiments not be able to emit 405 nm light, only white light for placement. Specifically, when using the photosensitizing composition stored in each PDT gel container 116 of Fig. 1 for diagnosis purposes, the CIN2/3 lesions should accumulate the photosensitizers and fluoresce under blue light illumination. In another embodiment, the PDT device and system 100 may include an LED illumination device having an acrylic cylinder approximately 2 cm in diameter at the proximal end where the LEDs are fixed. The cylinder may be 15 to 25 cm, advantageously about 20 cm long. The distal end of the cylinder may be placed close to the cervical epithelial surface. For treatment of dysplasia or neoplasia within the cervical canal, the acrylic cylinder may be drawn or machined into a thinner end, approximately 4.5 mm wide at the tip, widening to about 7 mm over the distal 20 mm of the rod. The tip of the rod is inserted within the endocervical canal for photodynamic illumination, stabilized either by hand or by clipping it to a speculum. The portion of the cervix that opens into the uterus is called the internal os and the opening of the cervix which faces the vagina is called the external os. The average endocervical canal length between the internal os and external os is approximately 3-4 cm (but can range from 1-4 cm). The external os varies greatly from female to female and ranges from small and round, to horizontally oblong, to crescent shaped, to amorphous, each with characteristic individual anatomical variation, as influenced by menarche, parity, vaginal childbirth, and post-menarche status, as observed via speculum examination in lithotomy position. The majority of endocervical disease may be located within 1 cm of the external os, and the cervical width excised for loop electrosurgical excision procedure (LEEP) is generally around 1.2-2.5 cm, with a depth ranging from 0.5 – 2 cm (e.g., 1 cm). Referring now to Figs.8, 9, and 10, in accordance with additional embodiments of the present disclosure, a retractable endoscope (e.g., 1 to 7 mm or 2 to 5 mm in diameter) may be integrated at a distal end of the PDT device and system 100 for placement, rather than e.g., examination, of patient’s cervix. According to certain aspects related to viewing capabilities, the endoscope of the 323503294.1 26 Attorney Docket No.: A2001-7005WO present disclosure may be configured to extend and view up to 4 cm in length for placement in the endocervical canal, with a range of view up to 3 cm horizontally (1.5 cm in every direction) when flush before insertion into the endocervical canal. Fig.8 illustrates a top plan view 800 of the distal end of the probe with a retractable endoscope 802 incorporated therein. In some implementations, a plurality of micro LED arrays or the tips of one or more optical fibers may be arranged in an array of concentric circles 804, 806 in the distal end with the ability to activate light delivery from each individual concentric circles increasing sequentially, one at a time, which may, in some embodiments, have a diameter totaling up to 3 cm. Other suitable diameters may be used. It should be appreciated that more than two concentric circles of LED arrays or optical fibers may be implemented, such that the light intensity may be controllable one concentric circle or one selected segment of the LED of optical fiber array at a time. That is, different segments or circles of the micro LED of fiber optic arrays may be operated independently. Referring to Fig. 9, the endoscope 802 may be in a regressed position initially with, e.g., white LED light on to guide the placement of the probe of the PDT device and system 100 into a treatment region of a patient. The elongated body of the probe may include an endocervical canal portion 810 joined with an extension portion 812 via a connection portion 814. According to some aspects, the connection portion 814 may be made of flexible polymer materials or any suitable malleable materials to facilitate maneuver, manipulation, and passage of the endoscope 802 into the endocervical canal of the patient, thereby providing a user of the PDT device and system 100 with an endoscopic view (e.g., a 360˚ endoscopic view) of the patient’s endocervical canal. In certain implementations, an image sensor (not shown) may be integrated in the endoscope 802, such that a user of the PDT device and system 100 of the present disclosure may insert and navigate the endoscope 802 within the vaginal canal, endocervical canal and uterine cavity of the patient with endoscopic vision. A handle portion 816 of the PDT device and system 100 may include a finger-actuated control panel (not shown) with buttons or switches for adjusting light intensity of the micro LED arrays and/or changing operating parameters of other components attached to the PDT device and system 100 (e.g., capturing images or videos from sensor(s)). In one embodiment, the handle portion or a handpiece 816 may have an angled grip implementation. The extrusion length of the retractable endoscope 802 may be adjusted by a syringe like mechanism or hydraulic function 818, as shown in Fig. 10. For example, the endoscope 802 may extend from the initial flat position up to 4 cm for placement of the probe of the PDT device and 323503294.1 27 Attorney Docket No.: A2001-7005WO system 100 into a patient’s endocervical canal. Micro LED arrays or optical fibers may be controlled to illuminate the treatment area but without delivering treatment wavelengths of light into the uterus of the patient. According to some implementations, an electrical cable 820 may extend from the handle portion 816 to an imaging processor (not shown) and corresponding image/video display. Some common infections of mucosal epithelium are also treatable with photodynamic therapy using quinine and/or riboflavin derivatives as photosensitizers. In some embodiment of the present disclosure, gels comprising quinine, riboflavin (or a riboflavin derivative including but not limited to riboflavin phosphate) or a combination of quinine plus riboflavin are applied followed by exposure to light at 405 nm. Further details on treatment of vaginal infections with compositions and methods of the present disclosure are provided in Example 4 below. In some aspects, the present disclosure provides a pharmaceutical compositions comprising quinine and a riboflavin derivative in a pharmaceutically acceptable formulation for topical application to mucosal or cutaneous epithelial surfaces, for elimination of dysplastic or neoplastic cells during localized exposure of the area, treated with the topical composition, to light at an appropriate wavelength and intensity. Essentially the same composition and light source, modified for broader light exposure are also useful for treating a range of fungal and bacterial infections. EXAMPLES Example 1 For preparation of a gel for co-delivery of quinine and riboflavin to an epithelial surface, 25 grams of quinine hydrochloride were dissolved in 500 mL glycerol while heating to 50 degrees C. A saturated solution of riboflavin phosphate (flavin mononucleotide) in 500 ml propylene glycol was prepared. The two solutions were mixed. 10 grams of Carbopol 934 powder was mixed into the solutions, which was then heated to 60 degrees C, causing the carbomer to dissolve and form a gel. Example 2 For preparation of a gel for co-delivery of quinine and riboflavin to an epithelial surface, 25 grams of quinine hydrochloride were dissolved in 500 mL glycerol while heating to 50 degrees C. A saturated solution of riboflavin phosphate (flavin mononucleotide) in 500 ml propylene glycol was prepared. The two solutions were mixed. 50 grams of hydroxyethylcellulose powder 323503294.1 28 Attorney Docket No.: A2001-7005WO was mixed into the solution, which was then heated to 60 degrees C. The hydroxyethylcellulose required about 48 hours to fully thicken in the glycerol and propylene glycol solvent system. In subsequent batches, it was found that heating to 80 degrees C after addition of hydroxyethylcellulose solubilized the hydroxyethylcellulose more rapidly and completely, improving reproducibility of gel characteristics. Instead of a saturated solution of riboflavin phosphate, a solution with a defined concentration below the solubility limit at room temperature is optionally used, for example, 0.1 grams riboflavin-5-phosphate per 10 ml of propylene glycol, or 5 grams per 500 ml. Example 3 For preparation of a gel for co-delivery of quinine and riboflavin to an epithelial surface, 25 grams of quinine hydrochloride were dissolved in 450 mL PEG 450 (polyethylene glycol, average molecular weight 400) combined with 50 ml 1,2-propanediol while heating to 50 degrees C. A saturated solution of riboflavin phosphate (flavin mononucleotide) in 500 ml of the same solvent combination was prepared. The two solutions were mixed. 50 grams of hydroxyethylcellulose powder was mixed into the solution, which was then heated to 60 degrees C. The hydroxyethylcellulose required about 48 hours to fully thicken in the PEG 400 + 1,2- propanediol solvent system. Example 4 For treatment of cervical dysplasia, the Gel of Example 1 is applied to the cervix of a subject displaying ASCUS, CIN1, CIN2 or CIN3. 1 to 5 ml of the Gel is applied directly to the cervix via a blunt syringe; the specific amount is determined by the size of the dysplastic region, and the thickness of the gel layer, which should be a minimum of 1 mm thick. A disposable tampon or cervical cap is optionally used to help contain the gel in the immediate area of the cervix. After 15 minutes to one hour, a speculum is inserted in the vagina and the cervix is rinsed and gently dried, e.g. with a cotton or rayon swab. The cervix is exposed to light at a wavelength of approximately 405 nm, with a total energy of 100 Joules/cm2. The time required for exposure is advantageously 30 minutes or less. Example 5 323503294.1 29 Attorney Docket No.: A2001-7005WO For treatment of vaginal epithelial infections (including but not limited to candidiasis, gonorrhea, chlamydia, bacterial vaginosis, and trichomoniasis) the Gel of Example 1 is applied to the vagina with a blunt syringe. A quantity sufficient to cover the affected areas to a thickness of approximately 1 mm is applied. After a period of approximately 30 minutes, a wand with LEDs that emit light at 405 nm is inserted in the vagina, and light is applied with a total energy of approximately 100 Joules/cm2. The time required for exposure is advantageously 30 minutes or less. In this embodiment of the present disclosure, a light wand with LEDs along an extended length of the shaft is advantageous, versus a PDT illumination device specifically for treatment of dysplasia localized to the cervix, to permit treatment of the epithelial infection in essentially the whole of the vaginal canal. Example 6 Cells treated with quinine and riboflavin 5’-phosphate have reduced viability after LED exposure This example demonstrates that cells treated with quinine and riboflavin 5’-phosphate, then exposed to LED, have reduced viability compared to cells exposed to LED only. SiHa cells (a cell line derived from human cervical cancer cells) were plated in a 384 well plate in 5% FBS media. Cells were treated with 100 ug/mL quinine and 10 ug/mL riboflavin 5’- phosphate for 1 hour. After 1 hour, the quinine and riboflavin 5’-phosphate were washed from the cells. The cells were then exposed to LED at a 17.5 cm distance (equivalent to 0.030 Watts) for 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes, 5 minutes, 2 minutes, or 1 minute. No treatment control cells were only subjected to LED exposure. Cell viability was measured 24 hours and 48 hours after LED exposure using the CellTiter-Glo® assay (Figs. 11-14). 24 hours after LED exposure, cells exposed to quinine and riboflavin 5’-phosphate displayed about 10% viability after LED exposures of 30 minutes or 25 minutes (Fig. 12). In contrast, non-treated cells were greater than 80% viable 24 hours after LED exposures of the same lengths of time (Figure 2). Treated cells had lower viability than non-treated cells 24 hours after 30, 25, 20, 15, 10, or as little as 5 minutes of LED exposure (Fig. 12). Viability was measured by comparison to control cells in separate wells. 48 hours after LED exposure, treated cells were less than 10% viable after LED exposures of 30 or 25 minutes (Fig. 14). Again, non-treated cells had greater than 80% viability 48 hours 323503294.1 30 Attorney Docket No.: A2001-7005WO after LED exposure of the same lengths of time (Fig. 14). Treated cells showed lower viability 48 hours after 30, 25, 20, 15, 10, or 5 minutes of LED exposure compared to non-treated cells. (Fig. 14). Example 7 Dose response of cells to quinine and riboflavin 5’-phosphate combined with LED light exposure This Example demonstrates determination of the IC50 of quinine and riboflavin 5’- phosphate in combination with LED light exposure in vitro in four cell lines. Cell Culture Four different cell lines were used: Ca Ski, DoTc2-4510, SiHa, and Ect1/E6E7. Cells were plated in 384-well tissue culture treated assay plates and allowed to adhere overnight at 37°C and 5% CO2. SiHa and Ca Ski cells were plated at a density of 5,000 cells/well. Ect1/E6E7 and DoTc2- 4510 cells were plated at a density of 7,500 cells/well. Cells were grown in a 1:1 (v:v) mixture of Dulbecco's modified Eagle's medium (Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) and Ham's F12 nutrient mix (Nissui Pharmaceutical Co., Ltd., Tokyo, Japan) containing 5% fetal bovine serum (FBS) (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) or no FBS. Stock Solutions Quinine was solubilized in DMSO at a stock concentration of 100 mg/mL. Riboflavin 5’- phosphate was solubilized in H2O at a stock concentration of 50 mg/mL. Light Exposure Cells were either exposed to no LED, 1 hour of substance incubation followed by LED exposure for 30 minutes, or 1 hour of substance incubation, media replacement, and then LED exposure for 30 minutes. Cell Viability Cell viability was determined using the CellTiter-Glo® assay (Promega). IC50 is defined as the inflection point on the dose response curve (half of the distance between the min and max of the curve fit). NA denotes that the maximum of the curve is below 50% viability, or the IC50 is otherwise unable to be calculated. EC50 of quinine in vitro with and without LED exposure 323503294.1 31 Attorney Docket No.: A2001-7005WO Cells were exposed to 0, 10, 25, 50, 100, 250, or 500 μg/mL quinine with or without LED exposure as described above. Cells were re-treated at 24 hours after initial treatment, including LED exposure. Results are shown in Tables E1, E2, and E3. Table E1. EC50 of quinine in vitro (no LED exposure) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours SiHa >500 μg/mL 139 μg/mL 121 μg/mL Table E2. EC50 of quinine in vitro (LED exposure for 30 minutes) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours Table E3. EC50 of quinine in vitro (LED exposure for 30 minutes after media replacement) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours These results demonstrate that LED exposure lowers the IC50 of quinine in all four tested cell lines. EC50 of riboflavin 5’-phosphate in vitro with and without LED exposure 323503294.1 32 Attorney Docket No.: A2001-7005WO Cells were exposed to 0, 2.5, 5, 15, 30, or 60 μg/mL riboflavin 5’-phosphate with or without LED exposure as described above. Cells were re-treated at 24 hours after initial treatment, including LED exposure. Results are shown in Tables E4, E5, and E6. Table E4. EC50 of riboflavin 5’-phosphate in vitro (no LED exposure) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours SiHa >60 μg/mL >60 μg/mL >60 μg/mL Table E5. EC50 of riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours Table E6. EC50 of riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes after media replacement) Cell line EC50 at 0 hours EC50 at 24 hours EC50 at 48 hours These results demonstrate that LED exposure lowers the IC50 of riboflavin 5’-phosphate in all four tested cell lines. EC50 of combined quinine and riboflavin 5’ phosphate in vitro with and without LED exposure Cells were exposed to 0, 10, 25, 50, 100, 250, or 500 ug/mL quinine and 2.5, 5, 15, 30, or 60 μg/mL riboflavin 5’-phosphate. Cells were re-treated with quinine and riboflavin 5’- 323503294.1 33 Attorney Docket No.: A2001-7005WO phosphate at 24 hours after initial administration, including re-exposure to LED. Results are shown in Tables E7-E15. Tables E7-E9 show the EC50 of cells exposed to quinine and riboflavin 5’-phosphate with no LED exposure. Tables E10-E12 show the EC50 of cells exposed to quinine and riboflavin 5’-phosphate with LED exposure for 30 minutes. Tables E13-E15 show the EC50 of cells exposed to quinine and riboflavin 5’ phosphate with media replacement and then LED exposure for 30 minutes. EC50 is defined as described above. Table E7. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (no LED exposure) at 0 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 2 L L 1 L L L Table E8. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (no LED exposure) at 24 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 323503294.1 34 Attorney Docket No.: A2001-7005WO Table E9. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (no LED exposure) at 48 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 2.5 µg/mL µg/mL 15 µg/mL µg/mL µg/mL Table E10. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes) at 0 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 Table E11. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes) at 24 hours 0 323503294.1 35 Attorney Docket No.: A2001-7005WO CaSki <2.5 µg/ml <2.5 µg/ml <2.5 µg/ml <2.5 µg/ml <2.5 µg/ml DoTc2- <10 µg/ml <10 µg/ml <10 µg/ml <10 µg/ml <10 µg/ml Table E12. EC50 of quinine combined with riboflavin 5 -phosphate in vitro (LED exposure for 30 minutes) at 48 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 25 /mL /mL 15 /mL /mL /mL Table E13. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes after media replacement) at 0 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 323503294.1 36 Attorney Docket No.: A2001-7005WO Table E14. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes after media replacement) at 24 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 2.5 µg/mL µg/mL 15 µg/mL µg/mL µg/mL Table E15. EC50 of quinine combined with riboflavin 5’-phosphate in vitro (LED exposure for 30 minutes after media replacement) at 48 hours Cell line EC50 with EC50 with 5 EC50 with EC50 with 30 EC50 with 60 These results demonstrate that individual and combined actives were potent photosensitizers when exposed to simulated PDT light, resulting in cell eradication at low concentrations. When applied to cells for 1 hour and then washed off prior to illumination, absorbed quinine and riboflavin 5’phosphate retained in the cells induced photodynamic cell death as single agents. When combined, much lower concentrations of both agents caused complete loss of cell viability than when either was given alone. 323503294.1 37 Attorney Docket No.: A2001-7005WO Example 8. Photodynamic Therapy Gel Surgical removal or laser ablation of cervical dysplasia can be painful and can compromise structure of the cervix, with a substantially increased risk of preterm birth. This example describes a less tissue-destructive treatment modality, photodynamic therapy (PDT), which can destroy dysplastic cells while sparing the normal structure and function of the cervix. Photodynamic therapy for treatment of cervical dysplasia involves application of fluorescent photosensitizer compounds to areas in need of treatment, in some embodiments with preferential uptake of the photosensitizer into abnormal or neoplastic cells versus surrounding normal epithelium. After application of the photosensitizer, followed by rinsing or swabbing unabsorbed material from the cervix, application of visible light at an appropriate wavelength and intensity excites electrons in the photosensitizer. The excited photosensitizer molecule interacts with oxygen, generating cytotoxic reactive oxygen species. Atmospheric oxygen is in a relatively stable “triplet” state, referring to the quantum spin states of its electrons. Interaction with a light- activated excited photosensitizer generates singlet oxygen, which is extremely reactive; generation of singlet oxygen within cells can rapidly destroy them with little collateral tissue damage. Selectivity for dysplastic versus normal cells can be achieved via several modes of action; 1) direct application of photosensitizers only to dysplastic areas; 2) preferential uptake of photosensitizers into abnormal cells (exploiting metabolic differences between normal and dysplastic cells); and 3) selective application of light to dysplastic areas while avoiding surrounding normal tissue. This Example describes the use of riboflavin-5-phosphate and quinine, which have desirable profiles for safety and effectiveness as photosensitizers. Both of these agents are fluorescent and have high quantum efficiency for excitation and generation of singlet oxygen that can destroy dysplastic cells when exposed to visible light in the near-UV range, via a PDT light probe, e.g., as described herein. These agents require only uptake into cells, and not slow metabolic transformation, so a much briefer exposure to photosensitizers is sufficient for efficacy. These two photosensitizers provide mutual synergy for destroying cells, based on targeting to different intracellular organelles. Riboflavin per se has low solubility in benign solvents, so riboflavin-5-phosphate (R5P) is used in this Example. This derivative is water-soluble, but requires removal of the phosphate 323503294.1 38 Attorney Docket No.: A2001-7005WO group to promote uptake into cells. Dysplastic cervical epithelial cells express acid phosphatase activity that is not displayed by normal cervical or vaginal epithelium. This enzyme allows for local dephosphorylation of R5P, followed by uptake of riboflavin into cells. Riboflavin transporters are upregulated in cervical dysplasia, further promoting preferential destruction of abnormal cells. Some riboflavin produced by dephosphorylation of R5P will precipitate on dysplastic regions (but can be rinsed off of normal epithelium prior to light activation), providing amplification of PDT activity, and also allowing for a readily visible fluorescent diagnostic for detection of dysplasia in situ. PDT Gel Preparation Ingredients: • Quinine Hydrochloride • Riboflavin-5-phosphate • Glycerol • Propylene Glycol • Hydroxyethylcellulose The solvents of the PDT Gel, glycerol and propylene glycol (PG), were selected based in part on providing adequate solubility of both quinine and R5P, while also being nonaqueous to reduce risk of hydrolysis of the phosphate group on R5P. Furthermore, both glycerol and PG act as “optical clearing agents”, increasing light permeability of mucosal tissue, and these solvents also work well with hydroxyethylcellulose to form a stable gel. For preparation of 20 ml of PDT Gel for co-delivery of quinine and riboflavin to an epithelial surface, the following steps are performed: • 0.5 grams of quinine hydrochloride are dissolved in 10 mL glycerol while heating to 50 degrees C. • 0.1 grams of ribose-5-phosphate are dissolved in 10 ml propylene glycol by heating to 60 degrees C. A higher concentration of R5P could be used, such as up to about 0.2 grams/10 ml. • The two solutions, quinine in glycerol and R5P in PG, are combined • 1 gram of hydroxyethylcellulose (HEC) is added and dispersed in the solution • The mixture is heated to 80 degrees C 323503294.1 39 Attorney Docket No.: A2001-7005WO • The HEC will turn the mixture into a uniform gel over the course of about 24 hours Both quinine and R5P are photosensitive, so the production process can be conducted with reagents protected from light. The gel and its active constituents may be stored at room temperature, protected from light. In some embodiments, the unit dose is about 2 ml. Opaque containers may be used. Vials may also be used, as the PDT Gel may be applied to the cervix with a blunt syringe, medical swab, or other applicator. In some embodiments, a typical treatment volume will be about 1 ml or less. Unless specifically stated otherwise as apparent from the foregoing disclosure, it is appreciated that, throughout the present disclosure, discussions using terms such as “processing,” “computing,” “calculating,” “determining,” “displaying,” or the like, refer to the action and processes of a computer system, or similar electronic computing device, that manipulates and transforms data represented as physical (electronic) quantities within the computer system's registers and memories into other data similarly represented as physical quantities within the computer system memories or registers or other such information storage, transmission or display devices. One or more components may be referred to herein as "configured to," "configurable to," "operable/operative to," "adapted/adaptable," "able to," "conformable/conformed to," etc. Those skilled in the art will recognize that "configured to" can generally encompass active-state components and/or inactive-state components and/or standby-state components, unless context requires otherwise. Those skilled in the art will recognize that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as "open" terms (e.g., the term "including" should be interpreted as "including but not limited to," the term "having" should be interpreted as "having at least," the term "includes" should be interpreted as "includes but is not limited to," etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles 323503294.1 40 Attorney Docket No.: A2001-7005WO "a" or "an" limits any particular claim containing such introduced claim recitation to claims containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "an" (e.g., "a" and/or "an" should typically be interpreted to mean "at least one" or "one or more"); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should typically be interpreted to mean at least the recited number (e.g., the bare recitation of "two recitations," without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to "at least one of A, B, and C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, and C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). In those instances where a convention analogous to "at least one of A, B, or C, etc." is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., "a system having at least one of A, B, or C" would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that typically a disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms unless context dictates otherwise. For example, the phrase "A or B" will be typically understood to include the possibilities of "A" or "B" or "A and B." With respect to the appended claims, those skilled in the art will appreciate that recited operations therein may generally be performed in any order. Also, although various operational flow diagrams are presented in a sequence(s), it should be understood that the various operations may be performed in other orders than those which are illustrated, or may be performed concurrently. Examples of such alternate orderings may include overlapping, interleaved, interrupted, reordered, incremental, preparatory, supplemental, simultaneous, reverse, or other variant orderings, unless context dictates otherwise. Furthermore, terms like "responsive to," 323503294.1 41 Attorney Docket No.: A2001-7005WO "related to," or other past-tense adjectives are generally not intended to exclude such variants, unless context dictates otherwise. It is worthy to note that any reference to "one aspect," "an aspect," "an exemplification," "one exemplification," and the like means that a particular feature, structure, or characteristic described in connection with the aspect is included in at least one aspect. Thus, appearances of the phrases "in one aspect," "in an aspect," "in an exemplification," and "in one exemplification" in various places throughout the specification are not necessarily all referring to the same aspect. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner in one or more aspects. As used herein, the singular form of "a", "an", and "the" include the plural references unless the context clearly dictates otherwise. As used herein, the term "comprising" is not intended to be limiting, but may be a transitional term synonymous with "including," "containing," or "characterized by." The term "comprising" may thereby be inclusive or open-ended and does not exclude additional, unrecited elements or method steps when used in a claim. For instance, in describing a method, "comprising" indicates that the claim is open-ended and allows for additional steps. In describing a device, "comprising" may mean that a named element(s) may be essential for an embodiment or aspect, but other elements may be added and still form a construct within the scope of a claim. In contrast, the transitional phrase "consisting of" excludes any element, step, or ingredient not specified in a claim. This is consistent with the use of the term throughout the specification. As used herein, “treatment”, "treating" and cognates thereof refer to the medical management of a subject with the intent to improve, ameliorate, stabilize, prevent or cure a disease, pathological condition, or disorder. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to preventing, minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder); and supportive treatment (treatment employed to supplement another therapy). As used herein, the term “photosensitizing composition” refers to a composition comprising one or more photosensitizing compound. 323503294.1 42 Attorney Docket No.: A2001-7005WO A “photosensitizing compound,” as used herein, refers to: (i) a compound that produces a reactive oxygen species or toxicity to a cell comprising the compound when activated by a suitable wavelength of light, or (ii) a precursor that is metabolized in a patient’s body into a compound as described in (i). In some embodiments, the photosensitizing composition comprises more than one photosensitizing compound. The photosensitizing compounds can be activated by the same or different wavelengths of light. In some embodiments, the photosensitizing compound is riboflavin-5’-phosphate or quinine. The term “activate” as used herein in the context of light activating a compound from a photosensitizing composition, refers to the light causing the compound to produce a reactive oxygen species or toxicity to a cell comprising the compound. As used herein, an “analog” of a compound refers to a metabolite and/or a metabolic precursor of the compound. For instance, riboflavin-5′-phosphate is an analog of riboflavin. As another example, quinidine is an analog of quinine. Any patent application, patent, non-patent publication, or other disclosure material referred to in this specification and/or listed in any Application Data Sheet is incorporated by reference herein, to the extent that the incorporated materials is not inconsistent herewith. As such, and to the extent necessary, the disclosure as explicitly set forth herein supersedes any conflicting material incorporated herein by reference. Any material, or portion thereof, that is said to be incorporated by reference herein, but which conflicts with existing definitions, statements, or other disclosure material set forth herein will only be incorporated to the extent that no conflict arises between that incorporated material and the existing disclosure material. None is admitted to be prior art. In summary, numerous benefits have been described which result from employing the concepts described herein. The foregoing description of the one or more forms has been presented for purposes of illustration and description. It is not intended to be exhaustive or limiting to the precise form disclosed. Modifications or variations are possible in light of the above teachings. The one or more forms were chosen and described in order to illustrate principles and practical application to thereby enable one of ordinary skill in the art to utilize the various forms and with various modifications as are suited to the particular use contemplated. It is intended that the claims submitted herewith define the overall scope. 323503294.1 43

Claims

Attorney Docket No.: A2001-7005WO CLAIMS 1. A device, comprising: one or more light sources configured to produce one or more wavelengths of light; a component configured to control the one or more light sources; and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 2. A device, comprising: an elongated body having a longitudinal axis extending from a proximal end to a distal end; one or more light sources housed in the elongated body and configured to produce one or more wavelengths of light; and a light guide implemented on the distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 3. A device, comprising: one or more light sources configured to produce one or more wavelengths of light; a component configured to control the one or more light sources; and a treatment probe including a light guide implemented on a distal end, wherein the treatment probe has a length of 15-25 cm, a diameter of 1-2 cm, and wherein the light guide has a tapered extension with a length of 0-40 mm. 4. A device, comprising: an elongated body having a longitudinal axis extending from a proximal end to a distal end, wherein the elongated body has a length of 17-30 cm, a diameter of 1-2.5 cm; one or more light sources housed in the elongated body and configured to produce one or more wavelengths of light; and a light guide implemented on a distal end of the elongated body, wherein the light guide has a tapered extension with a length of 0-40 mm. 323503294.1 44 Attorney Docket No.: A2001-7005WO 5. The device of any of claims 1-4, wherein the one or more light sources include a plurality of light emitting diodes (LEDs) or one or more optical fibers. 6. The device of claim 5, wherein at least a first portion of the LEDs emit light having a wavelength range of 400-700 nm. 7. The device of claim 5, wherein at least a second portion of the LEDs emit light with a peak emission spectrum near 400 nm. 8. The device of claim 5, wherein at least a third portion of the LEDs emit light with a peak emission spectrum near 405 nm. 9. The device of claim 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 390-415 nm, e.g., 395-410 nm, e.g., 400-410 nm. 10. The device of claim 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 440-460 nm, e.g., 445-455 nm, e.g., about 450 nm. 11. The device of claim 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 390-460 nm. 12. The device of claim 5, wherein at least a fourth portion of the LEDs emit light with a peak emission spectrum near 650 nm. 13. The device of claim 5, wherein at least a portion of the LEDs emit light with a peak emission spectrum between 620-660 nm, e.g., 630-655 nm. 14. The device of claim 5, wherein at least a portion of the LEDs are capable of emitting light that is free of or substantially free of ultraviolet light. 323503294.1 45 Attorney Docket No.: A2001-7005WO 15. The device of claim 5, wherein at least a portion of the LEDs are capable of emitting light that is free of or substantially free of red light. 16. The device of claim 5, wherein the plurality of LEDs emit the one or more wavelengths of light contemporaneously. 17. The device of claim 6, wherein the plurality of LEDs emit the one or more wavelengths of light continuously. 18. A system for photodynamic therapy (PDT) comprising the device of any of proceeding claims and a photosensitizing composition. 19. A system for photodynamic therapy (PDT), the system comprising: a photosensitizing composition; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto the cervix. 20. A system for photodynamic therapy (PDT), the system comprising: a photosensitizing composition comprising riboflavin; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject. 21. A system for photodynamic therapy (PDT), the system comprising: 323503294.1 46 Attorney Docket No.: A2001-7005WO a photosensitizing composition comprising quinine; and a PDT device, comprising: one or more light sources configured to produce one or more wavelengths of light that activates the photosensitizing composition, and a treatment probe including a light guide implemented on a distal end, wherein the light guide is configured to direct the one or more wavelengths of light onto a tissue of a subject. 22. The system of any of claims 18-21, further comprising a power source, wherein optionally the power source includes a built-in battery and a charging circuit for supplying power to the one or more light sources. 23. The system of any of claims 18-22, further comprising a module configured to switch operational modes of the one or more light sources. 24. The system of any of claims 18-23, further comprising a module configured to allow a user to adjust a light irradiation intensity of the one or more light sources. 25. The system of any of claims 18-24, wherein the light irradiation intensity includes maximum light energy delivered in each PDT treatment session of 40-160 J/cm2, e.g., 80-120 J/cm2, e.g., 90-110 J/cm2, e.g., approximately 100 J/cm2. 26. The system of any of claims 18-25, wherein the light irradiation is at a fluence rate of approximately 25-300 mW/cm2. 27. The system of any of claims 18-26, wherein the light guide has a length of 0-40 mm. 28. The system of any of claims 18-27, wherein the light guide is made from polymethyl methacrylate. 323503294.1 47 Attorney Docket No.: A2001-7005WO 29. The system of any of claims 18-28, wherein the light guide is made from materials having transparency to the first and the one or more second lights. 30. The system of any of claims 18-29, wherein the light guide is made from materials appropriate for medical use. 31. The system of any of claims 18-30, wherein the light guide is made from materials with high elasticity. 32. The system of any of claims 18-31, further comprising one or more single-use plastic sheathes for the treatment probe. 33. The system of any of claims 18-32, further comprising one or more cervical cups for retention of the photosensitizing composition on the cervix of a patient between application and light treatment. 34. The system of any of claims 18-33, further comprising swabs and sterile saline for removing excess cervical mucus or the photosensitizing composition. 35. A device or system of any of the preceding claims, for use in treating or preventing a cancer or infection in a subject in need thereof. 36. A method of treating or preventing a cancer or infection in a subject in need thereof, the method comprising illuminating the cancer cells, dysplastic cells, or infected area using the device. 37. The method or use of claim 35 or 36, wherein the method comprises illuminating the cervix of the subject using the device. 38. The method or use of claim 35 or 36, wherein the method further comprises applying the photosensitizing composition to the cancer cells, dysplastic cells, or infected area. 323503294.1 48 Attorney Docket No.: A2001-7005WO 39. The method or use of claim 35 or 36, wherein the method further comprises applying the photosensitizing composition to the cervix of the subject. 40. The method or use of any of claims 35-39, which comprises illuminating the affected area with the device for about 1-50, 5-40, or about 10 minutes. 41. A device or system of any of the preceding claims, for use in diagnosing a dysplasia or cancer in a subject in need thereof. 42. A method of detecting a dysplasia, cancer, or infection in a subject in need thereof, the method comprising: applying the pharmaceutical composition of any of claims 43-50 to the cervix of the subject, and illuminating the cervix of the subject using the device of any of claims 1-17, wherein fluorescence above a baseline level indicates the presence of the cancer or infection. 43. A pharmaceutical composition comprising: quinine or an analog thereof; and riboflavin or an analog thereof; wherein the pharmaceutical composition is a gel. 44. The pharmaceutical composition of claim 43, wherein the analog of riboflavin is riboflavin - 5’-phosphate. 45. The pharmaceutical composition of claim 43 or 44, wherein the analog of quinine is quinidine. 46. The pharmaceutical composition of any of claims 43-45, wherein the concentration of the quinine or analog thereof is 0.1 – 25 mg/ml. 323503294.1 49 Attorney Docket No.: A2001-7005WO 47. The pharmaceutical composition of any of claims 43-46, wherein the concentration of the riboflavin or analog thereof is 0.01 - 10 mg/ml. 48. The pharmaceutical composition of any of claims 43-47, further comprising a gelling agent. 49. The pharmaceutical composition of claim 48, wherein the gelling agent is a cellulosic thickener such as hydroxyethylcellulose, hydroxypropylmethylcellulose, or methylcellulose. 50. The pharmaceutical composition of claim 48, wherein the gelling agent is a poly(acrylic acid such as carbomer. 51. The system of any of claims 18-34, wherein the photosensitizing composition comprises quinine or an analog thereof. 52. The system of any of claims 18-34, wherein the photosensitizing composition comprises riboflavin or an analog thereof. 53. The system of any of claims 18-34, wherein the photosensitizing composition is a gel. 54. The system of any of claims 18-34, wherein the photosensitizing composition is a pharmaceutical composition according to any of claims 43-53. 55. The pharmaceutical composition of any of claims 43-54, for use in photosensitizing dysplastic cells or infected cells. 56. A method of using the pharmaceutical composition of any of claims 43-54 for photosensitizing dysplastic cells or infected cells, the method comprising applying the pharmaceutical composition to the dysplastic cells or infected cells. 57. A device, comprising: one or more light sources configured to produce one or more wavelengths of light; 323503294.1 50 Attorney Docket No.: A2001-7005WO a component configured to control the one or more light sources; and a probe including an endoscope implemented on a distal end, wherein the probe and the endoscope are configured to direct the one or more wavelengths of light onto the cervix. 58. The device of claim 57, wherein the endoscope is retractable up to 4 cm. 59. The device of claim 57, wherein the one or more light sources are arranged in concentric circles and each concentric circle is controlled to produce the one or more wavelengths of light independently. 60. The device of claim 57, wherein the probe includes a first portion joined with a second portion via a connection portion, wherein the first portion is for placement the probe into an endocervical canal of a patient, and the second portion connects with a handle portion of the probe. 61. The device of claim 60, wherein the connection portion is made of malleable materials. 62. The device of claim 57, wherein an extension length of the endoscope is controlled by syringe like mechanism or a hydraulic function of the device. 63. The device of claim 57, further comprising image and video sensors configured to provide endoscopic vision of the cervix. 64. The device of claim 57, wherein the endoscope has a diameter up to 7 mm. 65. The device of claim 57, wherein the distal end of the probe has a diameter up to 3 cm. 66. The device of claim 57, wherein the endoscope includes micro LED arrays for emitting the one or more wavelengths of light to surrounding cervical tissues with no treatment light wavelengths into the uterus. 323503294.1 51
PCT/US2025/029555 2024-05-15 2025-05-15 Device, system and method for photodynamic treatment of epithelial dysplasia and neoplasia Pending WO2025240738A1 (en)

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