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WO2015103005A1 - Composés amines amphiphiles et leur utilisation en tant qu'agents thérapeutiques et nanosupports - Google Patents

Composés amines amphiphiles et leur utilisation en tant qu'agents thérapeutiques et nanosupports Download PDF

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WO2015103005A1
WO2015103005A1 PCT/US2014/071937 US2014071937W WO2015103005A1 WO 2015103005 A1 WO2015103005 A1 WO 2015103005A1 US 2014071937 W US2014071937 W US 2014071937W WO 2015103005 A1 WO2015103005 A1 WO 2015103005A1
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cancer
cell
tumor
micelle
compound
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PCT/US2014/071937
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English (en)
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Timothy P. CRIPE
Mark A. CURRIER
Isabella Orienti
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Research Institute At Nationwide Children's Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the present disclosure relates to amphiphilic amine compounds and their use as therapeutic agents and nanocarriers for bioactive molecules.
  • the major aim of cancer therapy should be to achieve maximal tumor cell killing during the first- line treatment, including the elimination of circulating tumor cells and sterilization of the microscopic sites of metastatic foci that often remain after the induction therapy and are responsible for disease relapse.
  • Nanocarriers improve the performance of the passenger drug by allowing for higher payload capacity, prolonged blood circulation times, and increased accumulation in solid tumors, which can result in higher drug concentrations at tumor sites with improved antitumor efficacy and decreased toxicity to normal cells and tissues.
  • lipophilic amines (Kazmi et al., Drug Metab Dispos. 2013, 41(4):897-905) appear particularly interesting because their mechanism of action differs from classical chemo therapeutic agents.
  • the molecular targets of these compounds are mainly located in lysosomes and mitochondria rather than DNA, RNA or receptor tyrosine kinases (RTKs), which often induce resistance through the expression of p- glycoprotein, multidrug resistance-associated proteins or activation of alternative RTK pathways (Salehan et al., supra; Tredan et al., Journal of the National Cancer Institute. 2007, 99(19): 1441-1454).
  • lipophilic amines are predominantly non-ionized and can passively diffuse across the lipid bilayers of the cell and cellular organelle membranes.
  • the amines Upon entering the acidic environment of the lysosomes or mitochondrial matrix, the amines become ionized and are therefore less able to efficiently diffuse out, resulting in pronounced accumulation within these cellular organelles.
  • the amines cause various physiological and morphological perturbations of the lysosomal and mitochondrial apparatus, including inducing cell death (Sun et al., Cancer Res. 1994, 54(6): 1465-71 ; Duvvuri et al., ACS Chem Biol.
  • ROS reactive oxygen species
  • lysosomes are similarly quite specific to tumor cells due to their increase in lysosomal enzymes and deregulation of enzymatic functions compared to normal cells, which provide acidification defects and metabolic perturbations that can damage the lysosomal apparatus in the presence of accumulated lipophilic amines (Wilson et al., Cancer Res. 1989, 49(3):507-10; Ndolo et al., PLoS One. 2012;7(l l):e49366).
  • lipophilic amines As antitumor agents, a major drawback to the use of lipophilic amines as antitumor agents is their significant lipophilicity, which hinders their aqueous solubilization and limits their bioavailability and therapeutic efficacy. For more effective delivery of chemotherapeutics, lipophilic amines endowed with improved aqueous solubilization are needed to provide increased bioavailability and enhanced antitumor efficacy.
  • the present disclosure is directed to amphiphilic amine compounds that behave as antitumor agents with specific affinity and cytotoxic activity for tumor cells.
  • amphiphilic amine compounds can also form micelles that serve as nanocarriers for other bioactive molecules.
  • Figure 1 is a schematic of the assembly of amphiphilic amine compounds into micelles. The disclosure is further directed to methods of using the amphiphilic amine compounds and micelles and compositions containing the compounds to treat hyperproliferative disease, including cancer.
  • the disclosure provides a compound comprising a substituted or unsubstituted hydrophilic fused polycyclic hydrocarbon ring system, wherein the ring system is at least tricyclic, contains at least two nitrogen atoms, and contains an azetidine ring or an aziridine ring.
  • the hydrophilic fused polycyclic hydrocarbon ring system comprises structural formula (I):
  • x and y are individually selected from the group consisting of 0 to 10; z is 0 or 1; and one or more carbon atoms in structural formula (I) is optionally substituted with one or more groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • x is 3, y is 4, and z is 1.
  • x is 3, y is 4, and z is 0.
  • x is 3, y is 5, and z is 1. In another aspect, x is 3, y is 5, and z is 0. In another aspect, x is 3, y is 3, and z is 1. In another aspect, x is 3, y is 3, and z is 0.
  • the compound may further comprise at least one substituted or unsubstituted Cs_2o alkyl group.
  • the compound comprises structural formula (II), (III), or (IV):
  • Ri and R 2 are individually selected from the group consisting of hydrogen and substituted or unsubstituted Cs_ 2 o alkyl, and one or more carbon atoms in structural formula (II), (III), or (IV) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • Ri is H and R 2 is Cs_ 2 o alkyl.
  • Ri is C 5 - 2 o alkyl and R 2 is hydrogen.
  • Ri or R 2 is selected from the group consisting of pentyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl.
  • Ri or R 2 can be tetradecyl.
  • the compound comprises structural formula (V), (VI), or (VII):
  • R 3 is substituted or unsubstituted Cs_2o alkyl, and one or more carbon atoms in structural formula (V), (VI), or (VII) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • R 3 is selected from the group consisting of pentyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl.
  • R 3 can be tetradecyl.
  • the compound is selected from the group consisting of:
  • the disclosure provides a micelle comprising a substituted or unsubstituted hydrophilic fused polycyclic hydrocarbon ring system, wherein the ring system is at least tricyclic, contains at least two nitrogen atoms, and contains an azetidine ring or an aziridine ring.
  • the micelle comprises a hydrophobic hydrocarbon group attached to the hydrophilic fused polycyclic hydrocarbon ring system through a linker.
  • the hydrophobic hydrocarbon group is substituted or unsubstituted Cs_2o alkyl.
  • the hydrophobic fused polycyclic hydrocarbon ring system comprises structural formula (I):
  • x and y are individually selected from the group consisting of 0 to 10; z is 0 or 1; and one or more carbon atoms in structural formula (I) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • x is 3, y is 4, and z is 1.
  • x is 3, y is 4, and z is 0.
  • the micelle further comprises substituted or unsubstituted Cs_2o alkyl.
  • the micelle comprises structural formula (II), (III), or (IV):
  • Ri and R 2 are individually selected from the group consisting of hydrogen and substituted or unsubstituted Cs_ 2 o alkyl, and one or more of the carbon atoms in structural formula (II), (III), or (IV) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • Ri is H and R 2 is Cs_ 2 o alkyl.
  • Ri is C 5 - 2 o alkyl and R 2 is hydrogen.
  • Ri or R 2 is selected from the group consisting of pentyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl.
  • Ri or R 2 can be tetradecyl.
  • the micelle comprises structural formula (V), (VI) or (VII):
  • R 3 is substituted or unsubstituted Cs_2o alkyl, and one or more carbon atoms in structural formula (V), (VI), or (VII) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • R 3 is selected from the group consisting of pentyl, heptyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, and octadecyl.
  • R 3 can be tetradecyl.
  • the micelle comprises a plurality of compounds selected from the group consisting of:
  • the disclosure also provides a composition
  • a composition comprising a compound or micelle comprising a substituted or unsubstituted hydrophilic fused polycyclic hydrocarbon ring system, wherein the ring system: is at least tricyclic, contains at least two nitrogen atoms, and contains an azetidine ring or an aziridine ring.
  • the composition further comprises a pharmaceutically acceptable excipient.
  • the composition further comprises a therapeutic agent encapsulated within the micelle.
  • the therapeutic agent may be selected from the group consisting of antitumor agents, antineoplastic agents, prodrugs, analgesics, anesthetics, analeptics, adrenergic agents, adrenergic blocking agents, adrenolytics, adrenocorticoids, adrenomimetics, anticholinergic agents, anticholinesterases,
  • anticonvulsants alkylating agents, alkaloids, allosteric inhibitors, anabolic steroids, anorexiants, antacids, antidiarrheals, antidotes, antifolics, antipyretics, antirheumatic agents, psychotherapeutic agents, neural blocking agents, anti-inflammatory agents, antihelmintics, antibiotics, anticoagulants, antidepressants, antiepileptics, antibacterials, antifungals, antifibrotic agents, anti-infective agents, anti-parasitic agents, antihistamines, antimuscarinic agents, antimycobacterial agents, antineoplastic agents, antiprotozoal agents, antiviral agents, cardiac drugs, anxiolytic sedatives, beta- adrenoceptor blocking agents, corticosteroids, cough suppressants, dopaminergics, hemostatics, hematological agents, hypnotics, immunological agents, muscarinics, neurological drugs, bioactive peptides, steroid hormone
  • parasympathomimetics prostaglandins, radio-pharmaceuticals, sedatives, stimulants, sympathomimetics, vitamins, xanthines, growth factors, hormones, antiprion agents, and combinations thereof.
  • the therapeutic agent may be an antitumor agent selected from the group consisting of an aromatase inhibitor; an anti-estrogen; an anti-androgen; a gonadorelin agonist; a topoisomerase I inhibitor; a topoisomerase II inhibitor; a microtubule active agent; an alkylating agent; a retinoid, a carontenoid, or a tocopherol; a cyclooxygenase inhibitor; an MMP inhibitor; an mTOR inhibitor; an antimetabolite; a platin compound; a methionine aminopeptidase inhibitor; a bisphosphonate; an antiproliferative antibody; a heparanase inhibitor; an inhibitor of Ras oncogenic isoforms; a telomerase inhibitor; a proteasome inhibitor; a Flt-3 inhibitor; an Hsp90 inhibitor; a kinesin spindle protein inhibitor; a MEK inhibitor; an antitumor antibiotic; a
  • the disclosure provides a method of inhibiting tumor cell growth comprising contacting a cell with a compound, micelle, or composition of the invention, in an amount effective to inhibit growth of the tumor cell.
  • the disclosure provides use of a compound, micelle, or composition of the invention for the preparation of a medicament, wherein the medicament comprises an amount of the compound, micelle, or composition, that is effective for inhibiting growth of a tumor cell.
  • the disclosure provides a composition for use in inhibiting tumor cell growth comprising a compound, micelle, or composition of the invention in an amount effective to inhibit growth of a tumor cell.
  • the disclosure provides a method of treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound, micelle, or composition of the invention to the subject.
  • the disclosure provides use of a compound, micelle, or composition of the invention for the preparation of a medicament, wherein the medicament comprises an amount of the compound, micelle, or composition that is effective for treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder.
  • the disclosure provides a composition for use in treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder comprising a compound, micelle, or composition of the invention in an amount effective to treat or prevent a neoplastic, hyperplastic or hyperproliferative disorder.
  • the hyperproliferative disorder is selected from the group consisting of cancer, benign prostate hyperplasia, colorectal neoplasia, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • cancer benign prostate hyperplasia, colorectal neoplasia, benign soft tissue tumors, bone tumors, brain and spinal tumors
  • the disclosure provides a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound, micelle, or composition described herein to the subject.
  • the disclosure provides use of a compound, micelle, or composition of the invention for the preparation of a medicament, wherein the medicament comprises an amount of the compound, micelle, or composition that is effective for treating cancer.
  • the disclosure provides a composition for use in treating cancer comprising a compound, micelle, or composition of the invention in an amount effective to treat cancer.
  • the cancer is selected from the group consisting of adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell
  • leukemia/lymphoma aggressive NK-cell leukemia, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma,
  • angiomyolipoma angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor
  • B-cell chronic lymphocytic leukemia B-cell prolymphocytic leukemia
  • B-cell lymphoma basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney,
  • craniopharyngioma cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma,
  • dysembryoplastic neuroepithelial tumor dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological mal
  • lymphoma Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangio sarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogeous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non- small cell carcinoma, non- small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma
  • Figure 1 depicts the self-assembly of "RCn” amphiphilic amine compounds into micelles in an aqueous environment.
  • Figure 2 depicts the mass spectrum analysis of the compound 2-tetradecyl-4,8- diazatricyclo [6.5.0.0 1 , 4 ] tridecane (RC ⁇ 6 ) .
  • Figure 3 depicts western blot analysis of caspase 3, 8 and 9 in SH-SY5Y cells treated with 5 ⁇ RC 16 .
  • Figure 3A shows SH-SY5Y cells treated with RC 16 for 2, 8, 12, or 24 hours.
  • Figure 3B shows SH-SY5Y cells treated with RC 16 for 4, 6, 12, 24, or 36 hours.
  • M denotes the marker.
  • H3h and H9h denote HeLa cells treated with 5 ⁇ staurosporine for 3 hours and 9 hours, respectively, as a positive control of apoptosis.
  • S9h denotes SH-SY5Y cells treated with 5 ⁇ staurosporine for 9 hours as a positive control of apoptosis.
  • HPR denotes SH-SY5Y treated with 5 ⁇ fenretinide in ethanol for 24 hours as a positive control of apoptosis.
  • Figure 4 depicts activation of caspases following treatment with RC 16 .
  • Figure 5 depicts levels of reactive oxygen species (ROS) measured in relative fluorescence units (RFU) in SH-SY5Y, A673, and Osteomet cells following treatment with RC 16 for 12 hours or 24 hours. .
  • ROS reactive oxygen species
  • Figure 6 depicts transmission electron microscopy images of tumor and normal cells following treatment with 5 ⁇ RC 16 .
  • Figure 6A depicts SH-SY5Y neuroblastoma cells.
  • Figure 6B depicts normal human fibroblast cells.
  • Figure 7 depicts electron microscopy images of the surface of tumor and normal cells following treatment with 5 ⁇ g/mL RC 16 .
  • Figure 7 A depicts SH-SY5Y cells treated with 5 ⁇ g/mL RC 16 .
  • Figure 7B depicts control (untreated) SH-SY5Y cells.
  • Figure 7C depicts normal human fibroblast (HGF 68) cells treated with 5 ⁇ g/mL RC 16 .
  • Figure 7D depicts untreated normal human fibroblast cells.
  • Figure 8 depicts the cytotoxicity induced by RC 16 in cells with altered sialic acid residues.
  • Figure 8A depicts cytotoxicity in S462TY cells following treatment with 50 mU/mL neuramidase and 3 ⁇ RC 16 (RC16-NE) or RC 16 alone.
  • Figure 8B depicts cytotoxicity in CHLA-20, SK-N-AS, SH-SY5Y, and S462TY cells following treatment with 3 ⁇ RC 16 ,3 ⁇ sialic acid (SA) or a mixture of 3 ⁇ RC 16 and 3 ⁇ sialic acid (Mix).
  • Figure 9 depicts pharmacokinetic data for RC 16 .
  • Figure 9 A depicts the plasma concentration (log ng/mL) versus time (hours) profile for RC 16 after intravenous
  • Figure 9B depicts the plasma concentration (ng/mL) versus time (hours) profile for RC 16 after oral administration.
  • Figure 10 depicts the biodistribution of RC 16 in nude mice bearing CHLA-20 tumors.
  • Figure 10A depicts whole-body imaging of mice at 12, 24, and 48 hours after intravenous injection of fluorescently-labeled RC 16 .
  • Figure 10B depicts the fluorescence intensity in tissues and organs at 24, 48, and 72 hours after the intravenous injection.
  • Figure 11 depicts cytotoxicity in CHLA-20, SK-N-AS, A673, A549, and S462TY tumors in nude mice measured as relative tumor volume (RTV) following intravenous administration of RC 16 and in CHLA-20 cells following oral administration of RC 16 compared to control (tumors in untreated mice; CTR).
  • RTV relative tumor volume
  • Figure 12 depicts body weight in mice following intravenous or oral administration of RC 16 .
  • Figure 12A depicts the body weight of mice following an intravenous injection of RC 16 (Treated) compared to untreated mice (CTR).
  • Figure 12B depicts the body weight of mice following oral administration of RC 16 (Treated) compared to untreated mice (CTR).
  • Figure 13 depicts survival in a metastatic model following treatment with RC 16 and in an untreated control (CTR).
  • Figure 14 depicts electron microscopy images of RC 16 micelles in an aqueous environment.
  • Figure 15 depicts cytotoxic activity of RCie-doxorubicin micelles, free doxorubicin (DOXO), and free RC 16 .
  • Figure 15A depicts the cytotoxic activity of RCie-doxorubicin micelles (top) and free doxorubicin (bottom).
  • Figure 15B depicts the cytotoxic activity of free RC 16 .
  • Figure 16 depicts cytotoxic activity of RC ⁇ -etoposide micelles, free etoposide (ETO), and free RC 16 .
  • Figure 16A depicts the cytotoxic activity of RC ⁇ -etoposide micelles (top) and free etoposide (bottom).
  • Figure 16B depicts the cytotoxic activity of free RC 16 .
  • Figure 17 depicts cytotoxic activity of RCie-paclitaxel micelles, free paclitaxel (PX), and free RC 16 .
  • Figure 17 A depicts the cytotoxic activity of RC ⁇ -paclitaxel micelles (top) and free paclitaxel (bottom).
  • Figure 17B depicts the cytotoxic activity of free RC 16 .
  • amphiphilic amine compounds that have antitumor, e.g., cytotoxic, activity against many different types of hyperproliferative cells, but with lower toxicity to normal tissue compared to other existing drugs.
  • the antitumor activity of the compounds involves alterations in mitochondria and lysosomes.
  • the amphiphilic amine compounds interact with the polysialic acid expressed on the glycoproteins and gangliosides of tumor cell membranes, representing a mechanism of action not present in other antitumor drugs.
  • the amphiphilic amine compounds can be used as therapeutic agents alone and can also serve as nanocarriers for other bioactive molecules.
  • the compounds Due to their amphiphilic character, the compounds can spontaneously self-assemble in aqueous solution, forming micelles which can complex hydrophobic or partially hydrophobic drugs. Complexes of the compounds with antitumor agents such as doxorubicin, etoposide, and paclitaxel showed increased antitumor activity in comparison with the free drugs.
  • antitumor agents such as doxorubicin, etoposide, and paclitaxel showed increased antitumor activity in comparison with the free drugs.
  • anti-antitumor agent or “chemotherapeutic agent” refers to any compound that is toxic with respect to hyperproliferative cells or inhibits the growth or proliferation of hyperproliferative cells.
  • anti-antitumor agent includes
  • chemotherapeutic agents include, but are not limited to, an aromatase inhibitor, an anti-estrogen, an anti-androgen, a gonadorelin agonist, a topoisomerase I inhibitor, a topoisomerase II inhibitor, a microtubule active agent, an alkylating agent, a retinoid, a carotenoid, a tocopherol, a cyclooxygenase inhibitor, an MMP inhibitor, a mTOR inhibitor, an antimetabolite, a platin compound, a methionine aminopeptidase inhibitor, a bisphosphonate, an antiproliferative antibody, a heparanase inhibitor, an inhibitor of Ras oncogenic isoforms, a telomerase inhibitor, a proteasome inhibitor, a compound used in the treatment of hematologic malignancies
  • antitumor agents include, but are not limited to, azacitidine, axathioprine, bevacizumab, bleomycin, capecitabine, carboplatin, chlorabucil, cisplatin, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, epirubicin, etoposide, fenretinide, fluorouracil, gemcitabine, herceptin, idarubicin, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitoxantrone, oxaliplatin, paclitaxel, tafluposide, teniposide, tioguanine, retinoic acid, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, receptor tyrosine kinase inhibitor
  • fused polycyclic hydrocarbon ring system refers to a chemical structure comprising at least two fused hydrocarbon rings.
  • fused means that each ring in the polycyclic ring system shares at least two atoms, i.e., at least one side of the ring, with at least one other ring in the system.
  • a fused polycyclic hydrocarbon ring system may contain three rings (tricyclic), four rings, five rings, six rings, or more.
  • a fused polycyclic hydrocarbon ring system may be saturated or unsaturated.
  • a fused polycyclic hydrocarbon ring system may contain one or more heteroatoms.
  • One or more carbon atoms in the fused polycyclic hydrocarbon ring system may optionally be substituted with one or more groups selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof. Additionally or alternatively, one or more carbon atoms in the fused polycyclic hydrocarbon ring system may optionally be substituted with a linker.
  • substituted with refers to the replacement of one or more hydrogen atoms attached to a carbon atom with one or more of the aforementioned groups.
  • alkyl refers to a straight or branched C 1-2 o hydrocarbon chain, including but not limited to heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nondecyl, eicosyl, and combinations thereof.
  • Cx_y means the alkyl has between "X" and "Y" carbon atoms.
  • An alkyl may be saturated, i.e., contain only single bonds between carbon atoms, or may optionally contain one or more carbon-carbon double and/or carbon-carbon triple bonds.
  • One or more carbon atoms in an alkyl may optionally be substituted with one or more groups selected from the group consisting of halo, hydroxy, oxo, carboxamido, carboxy, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • heteroatom refers to an atom that is not carbon that replaces a carbon atom in the backbone of a chemical structure.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, fluorine, chlorine, bromine, and iodine.
  • the prefix "hetero" before a group indicates that the group contains at least one heteroatom.
  • halo refers to one or more atoms of fluorine, chlorine, bromine, iodine, and combinations thereof.
  • aryl refers to a monocyclic or polycyclic aromatic group.
  • Aryl also refers to bicyclic and tricyclic carbon rings, where one ring is aromatic and the others are saturated, partially unsaturated, or aromatic.
  • cycloalkyl refers to a monocyclic or polycyclic aliphatic ring.
  • micelle refers to an aggregate structure comprising a plurality of amphiphilic molecules oriented to provide the structure with a hydrophobic interior region and a hydrophilic exterior surface.
  • linker refers to a carbon-carbon or carbon-heteroatom bond or other chemical moiety connecting the hydrophilic group to the hydrophobic group on an amphiphilic molecule.
  • a linker may include one or more polymers. Exemplary polymers may be linear or branched and include, but are not limited to, polysaccharides, polypeptides, copolymers, polyethylene glycol (PEG), polyoxyethylene glycol, polypropylene glycol, monomethoxy-polyethylene glycol, dextran, hydroxyethyl starch, cellulose, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymer, polypropylene oxide/ethylene oxide copolymer, polyoxyethylated polyol (e.g., glycerol), polyvinyl alcohol, and combinations and copolymers thereof.
  • PEG polyethylene glycol
  • PEG polyoxyethylene glycol
  • polypropylene glycol monomethoxy-pol
  • a therapeutically effective amount depends on the condition of a subject and the specific compound administered. The term refers to an amount effective to achieve a desired clinical effect. A therapeutically effective amount varies with the nature of the condition being treated, the length of time that activity is desired, and the age and the condition of the subject, and ultimately is determined by the health care provider. In one aspect, a therapeutically effective amount of a compound, micelle, or composition of the invention is an amount effective to inhibit growth of hyperproliferative cells, prevent tumor cell metastasis, and/or result in cell death, e.g., via apoptosis or necrosis.
  • the present disclosure provides a class of amphiphilic amine compounds having antitumor activity.
  • the disclosure also provides micelles formed from a plurality of the amphiphilic amine compounds.
  • the amphiphilic amine compounds self- assemble into micelles having a hydrophilic exterior and a hydrophobic interior when dispersed in an aqueous solution.
  • the micelles comprises a plurality of compounds of the present disclosure oriented such that the hydrophilic fused polycyclic hydrocarbon ring systems form the exterior surface of the micelles and the hydrophobic hydrocarbon groups reside in the interior of the micelles, as shown in Figure 1.
  • the compounds and micelles comprise a substituted or unsubstituted hydrophilic fused polycyclic hydrocarbon ring system, wherein the fused polycyclic hydrocarbon ring system is at least tricyclic, contains at least two nitrogen atoms, and contains an azetidine ring or an aziridine ring.
  • the fused polycyclic hydrocarbon ring system is tricyclic.
  • the fused polycyclic hydrocarbon ring system contains four rings or five rings.
  • the fused polycyclic hydrocarbon ring system contains two nitrogen atoms.
  • the fused polycyclic hydrocarbon ring system contains at least 7 carbon atoms, at least 8 carbon atoms, at least 9 carbon atoms, at least 10 carbon atoms, at least 1 1 carbon atoms, at least 12 carbon atoms, at least 13 carbon atoms, at least 14 carbon atoms, or at least 15 carbon atoms.
  • the fused polycyclic hydrocarbon ring system contains 7 to 10 carbon atoms, 8 to 1 1 carbon atoms, 9 to 12 carbon atoms, 9 to 14 carbon atoms, 10 to
  • one or more carbon atoms in the fused polycyclic ring system is replaced with one or more heteroatoms.
  • one or more carbon atoms in the fused polycyclic hydrocarbon ring system is optionally substituted with one or more groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • amphiphilic amine compounds or micelles of the present disclosure may comprise a substituted or unsubstituted hydrophobic hydrocarbon group.
  • the hydrophobic hydrocarbon group is a straight or branched alkyl chain.
  • the hydrophobic hydrocarbon group is a straight or branched alkyl chain having 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, 10 carbon atoms, 1 1 carbon atoms, 12 carbon atoms, 13 carbon atoms, 14 carbon atoms, 15 carbon atoms, 16 carbon atoms, 17 carbon atoms, 18 carbon atoms, 19 carbon atoms, or 20 carbon atoms.
  • the hydrophobic hydrocarbon group is a straight chain alkyl having 5 to 20 carbon atoms (Cs_2o), 10 to 20 carbon atoms (QO-M), 10 to 15 carbon atoms (Cio-is), 15 to 20 carbon atoms ( ⁇ 15-2 ⁇ ), 7 to 18 carbon atoms (C 7-18 ), 10 to 18 carbon atoms (Cio-is), 12 to 18 carbon atoms (C 12-18 ),
  • the hydrophobic hydrocarbon group has a molecular weight less than 281.
  • the substituted or unsubstituted hydrophilic fused polycyclic hydrocarbon ring system and substituted or unsubstituted hydrophobic hydrocarbon group are attached via a linker.
  • the linker is a carbon-carbon bond or carbon-heteroatom bond (e.g., carbon-nitrogen), i.e., the substituted or unsubstituted hydrophilic fused polycyclic hydrocarbon ring system and substituted or unsubstituted hydrophobic
  • the linker is a polymer, for example, linear or branched polyethylene glycol (PEG), linear or branched polysaccharide, linear or branched polypeptide, or copolymers thereof.
  • PEG polyethylene glycol
  • the linker attaches the hydrophobic hydrocarbon group to the azetidine ring or aziridine ring.
  • the fused polycyclic hydrocarbon ring system comprises structural formula (I):
  • x and y are individually selected from the group consisting of 0 to 10, z is 0 or 1, and one or more carbon atoms in structural formula (I) is optionally substituted with one or more groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • x is 3, y is 4, and z is 1.
  • x is 3, y is 4, and z is 0.
  • x is 3, y is 5, and z is 1.
  • x is 3, y is 5, and z is 0.
  • x is 3, y is 3, and z is 1.
  • x is 3, y is 3, and z is 0.
  • x is 3, y is 3, and z is 1.
  • x is 3, y is 3, and
  • the compounds and micelles of the present disclosure comprise structural formula (II), (III), or (IV):
  • Ri and R 2 are individually selected from the group consisting of hydrogen and substituted or unsubstituted Cs_ 2 o alkyl, and one or more of the carbon atoms in structural formula (II), (III), or (IV) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • Ri is hydrogen
  • R 2 is Cs_ 2 o alkyl.
  • Ri is Cs_ 2 o alkyl
  • R 2 is hydrogen.
  • Ri is Cs_ 2 o alkyl
  • R 2 is C5-20 alkyl that may be the same as or different from Ri.
  • Ri and/or R 2 is selected from the group consisting of heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nondecyl, eicosyl, and combinations thereof.
  • Ri or R 2 is tetradecyl (C14H29).
  • the compounds and micelles of the present disclosure comprise structural formula (V), (VI), or (VII):
  • R 3 is substituted or unsubstituted Cs_2o alkyl, and one or more carbon atoms in structural formula (V), (VI) or (VII) is optionally substituted with one or more side groups individually selected from the group consisting of alkyl, hydroxy, oxo, halo, carboxamido, aryl, carboxy, heteroaryl, cycloalkyl, heterocycloalkyl, alkoxy, amino, azo, nitro, cyano, alkylamino, imino, thio, and combinations thereof.
  • R is selected from the group consisting of heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nondecyl, eicosyl, and combinations thereof.
  • R 3 is tetradecyl.
  • the compounds and micelles of the present disclosure may be made by any suitable method known in the art and those described herein. See, e.g., Brandi et al., Chem Rev. 2008, 108(9):3988-4035.
  • the present disclosure further includes all possible stereoisomers and geometric isomers of the compounds and micelles comprising structural formula (I), (II), (III), (IV), (V), (VI), or (VII).
  • the present invention includes both racemic compounds and optically active isomers.
  • a compound of structural formula (I), (II), (III), (IV), (V), (VI), or (VII) is desired as a single enantiomer, it can be obtained either by resolution of the final product or by stereo specific synthesis from either isomerically pure starting material or use of a chiral auxiliary reagent. Resolution of the final product, an intermediate, or a starting material can be achieved by any suitable method known in the art.
  • the present invention is intended to include all tautomeric forms of the compounds. All combinations of formulas (I) to (VII) are contemplated herein.
  • the disclosure provides, but is not limited to, compounds, micelles, and compositions comprising any of the following structures:
  • compositions comprising the compounds and/or micelles described herein.
  • a composition comprises a compound and/or micelle described herein and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is an aqueous vehicle, carrier, buffer, or diluent.
  • the compound in the composition is in the form of a physiologically acceptable salt, ester, or solvate, which is encompassed by the invention.
  • physiologically acceptable salt refers to any salt that is pharmaceutically acceptable. Some examples of physiologically acceptable salts include acetate, hydrochloride, hydrobromide, sulfate, citrate, tartrate, glycolate, oxalate, and combinations thereof.
  • compositions employed are limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound and/or micelle, and by the route of administration.
  • Physiologically-acceptable carriers are well known in the art.
  • Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders, e.g., lyophilizates, for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468).
  • injectable formulations are further described in, e.g., Pharmaceutics and
  • a composition comprising a compound and/or micelle described herein is, in one aspect, placed within a container, along with packaging material that provides instructions regarding the use of such compositions.
  • such instructions include a tangible expression describing the reagent concentration, as well as, in certain embodiments, relative amounts of excipient ingredients or diluents (e.g., water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition.
  • the present disclosure also provides methods of treatment.
  • the disclosure provides a method of inhibiting tumor cell growth comprising contacting a cell with a compound, micelle, or composition described herein in an amount effective to inhibit growth of the tumor cell.
  • the disclosure provides a method of treating or preventing a neoplastic, hyperplastic or hyperproliferative disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound, micelle, or composition described herein to the subject.
  • the disease to be treated is cancer.
  • treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma
  • prolymphocytic leukemia B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy- associated T-cell lymphoma, esophageal cancer,
  • the present disclosure provides a method of treating a benign hyperproliferative disorder including but not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, meningioma, multiple endocrine neoplasia, nasal polyps, pituitary tumors, prolactinoma, pseudotumor cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, vocal cord nodules, polyps, and cysts, Castleman disease, chronic pilonidal disease, benign prostate hyperplasia, dermatofibroma, pilar cyst, pyogenic granuloma, and juvenile polyposis syndrome.
  • a benign hyperproliferative disorder including but not limited to, benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors,
  • a therapeutically effective amount of a compound, micelle, or composition described herein, typically formulated in accordance with pharmaceutical practice is administered to a subject in need thereof. Whether such a treatment is indicated depends on the individual case and is subject to medical assessment that takes into consideration signs, symptoms, and/or malfunctions that are present, the risks of developing particular signs, symptoms and/or malfunctions, and other factors.
  • a particular administration regimen for a particular subject will depend, in part, upon the compound, micelle, or composition, the amount administered, the route of administration, and the cause and extent of any side effects.
  • the amount administered to a subject should be sufficient to effect the desired response over a reasonable time frame. Dosage typically depends upon the route, timing, and frequency of administration. Accordingly, a clinician titers the dosage and modifies the route of administration to obtain the optimal therapeutic effect, and conventional range-finding techniques are known to those of ordinary skill in the art.
  • the methods of the disclosure comprise administering, e.g., from about 0.1 g/kg up to about 100 mg/kg or more of compound, micelle, or composition, depending on the factors mentioned above.
  • the dosage ranges from 1 g/kg up to about 50 mg/kg; or 5 g/kg up to about 25 mg/kg; or 10 g/kg up to about 10 mg/kg.
  • Some conditions require prolonged treatment, which may or may not entail administering lower doses over multiple administrations.
  • a dose is administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day. The treatment period will depend on the particular condition and may last one day to several days, weeks, months, or years.
  • Suitable methods of administering a physiologically-acceptable composition such as a pharmaceutical composition comprising a compound and/or micelle described herein, are well known in the art. Although more than one route can be used to administer a compound, a particular route can provide a more immediate and more effective reaction than another route. Depending on the circumstances, a pharmaceutical composition comprising the compound and/or micelle is applied or instilled into body cavities, absorbed through the skin or mucous membranes, ingested, inhaled, and/or introduced into circulation.
  • the pharmaceutical composition orally through injection or infusion by intravenous, intratumoral, intraperitoneal, intracerebral (intra-parenchymal), intracerebroventricular, intramuscular, intra-ocular, intraarterial, intraportal, intralesional, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, urethral, vaginal, or rectal means; by controlled, delayed, sustained or otherwise modified release systems; or by implantation devices.
  • drug exposure can be optimized by maintaining constant drug plasma concentrations over time.
  • the composition is administered regionally via intratumoral, administration, intrathecal administration, intracerebral (intra-parenchymal) administration, intracerebroventricular administration, or intraarterial or intravenous administration targeting the region of interest.
  • the composition is administered locally via implantation of a matrix, membrane, sponge, or another appropriate material onto which the desired compound has been absorbed or encapsulated.
  • the device is, in one aspect, implanted into any suitable tissue or organ, and delivery of the desired compound is, for example, via diffusion, timed-release bolus, or continuous administration.
  • a compound, micelle, or composition described herein can be administered in an amount of about 0.005 to about 500 milligrams per dose, about 0.05 to about 250 milligrams per dose, or about 0.5 to about 100 milligrams per dose.
  • the compound, micelle, or composition can be administered, per dose, in an amount of about 0.005, 0.05, 0.5, 5, 10, 20, 30, 40, 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 milligrams, including all doses between 0.005 and 500 milligrams.
  • the above dosages are exemplary of the average case, but there can be individual instances in which higher or lower dosages are merited, and such are within the scope of this invention.
  • a clinician determines the actual dosing regimen that is most suitable for an individual subject, which can vary with the age, weight, condition and response of the particular subject.
  • the compounds and micelles of the present invention may be used in combination with other antitumor therapies.
  • antitumor therapies that can be used in combination with the compounds and micelles include surgery, radiotherapy (e.g., gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), endocrine therapy, biologic response modifiers (e.g., interferon, interleukin, tumor necrosis factor (TNF), hyperthermia and cryotherapy), agents to attenuate any adverse effect (e.g., antiemetics), gene therapy, viruses, and any other chemotherapeutic agent.
  • radiotherapy e.g., gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes
  • endocrine therapy e.g., gamma- radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy
  • amphiphilic amine compounds can complex other bioactive molecules or antitumor agents including chemotherapeutic agents such as doxorubicin, fenretinide, etoposide and/or paclitaxel. This complexation ability is based on the
  • micellar assemblates also referred to as complexes.
  • micellar complexation may modify the drug disposition in the body by preventing an uncontrolled drug distribution and promoting drug accumulation in solid tumors where the discontinuity of the capillaries and the lack of an efficient lymphatic drainage favors the entrapment and retention of
  • nanoparticulate systems such as micelles, liposomes or soluble macromolecules (Torchilin and Lopez-Davila et al., supra).
  • the encapsulation of paclitaxel and etoposide within micelles is desirable because the very low aqueous solubility of these drugs strongly limit their therapeutic potential (Singh et al., Crit Rev The r Drug Carrier Syst. 2009, 26(4):333-72; Ukawala et al., Drug Deliv. 2012, 19(3): 155-67) and the excipients used to improve their solubility may cause serious adverse reactions.
  • Cremophor EL also causes vasodilation, labored breathing, lethargy, hypotension, and leaching of plasticizers, such as diethylhexylpthalate, from the polyvinylchloride infusion bags/sets.
  • micellar complexation of doxorubicin is also advantageous to modify the biodistribution of the drug in addition to increase its solubility.
  • Doxorubicin induces a strong dose-limiting cardiotoxicity (Berthiaume et al., Cell Biol Toxicol. 2007, 23(1): 15-25), and its encapsulation in nanoparticulate carriers such as micelles or liposomes has proven to decrease its distribution to the heart, resulting in a reduction of the cardiotoxic effect (Mohan et al., Mol Pharm. 2010, 7(6): 1959-73; Sun et al., Biomaterials. 2013, 34(28):6818-28; Tardi et al., J Drug Target.
  • the compounds and micelles described herein possess strong cytotoxic activity against a variety of cancer types, but with low toxicity to normal cells. Without intending to be bound by any theory, the effects of the compounds and micelles on mitochondria and lysosomes in tumor cells, as well as their interaction with tumor cell-surface sialic acid, appear to contribute to the antitumor activity.
  • the particular molecular structure of the amphiphilic amine compounds and micelles may account for the multiple mechanisms of action.
  • the nitrogen atoms in the amphiphilic amine compounds and micelles allow for high water solubility, and the fused polycyclic hydrocarbon ring system allows the compound to partition in biological membranes in the presence of the high aqueous solubility.
  • structural formulas (II), (III), (IV), (V), (VI), and (VII) comprise (a) a 3- or 4-membered ring, (b) a 6-membered ring and (c) a 6-, 7- or 8-membered ring condensed in a tricyclic assembly linked to an alkyl tail.
  • the hydrophobic aliphatic cycles surrounding the amine groups in the tricyclic assembly provide a counter-balance to the hydrophilicity increase triggered by the protonation of the amine groups in an aqueous physiological environment, thus allowing the molecules to partition through biological membranes in the presence of positive charges.
  • the compounds and micelles accumulate in mitochondria based on the high negative transmembrane potential of the mitochondrial inner membrane (negative inside), which favors passage of protonated molecules into the matrix, and by the acidic pH of the intermembrane space, due to the export of hydrogen ions from the matrix, which attracts amine molecules from the cytoplasm inside the mitochondria by the presence of an electrochemical gradient through the outer
  • the lysosomes of cancer cells are characterized by an increase in lysosomal enzymes and a deregulation of the enzymatic functions resulting in acidification defects and metabolic perturbations, which may make the lysosomal structure more sensitive to the accumulation of partitionable amines (Wilson et al. and Ndolo et al., supra).
  • the amphiphilic amine compounds and micelles interact with sialic acid.
  • the interaction with sialic acid enables selectivity for tumor cells due to higher levels of the polysialylated glycoproteins and gangliosides on their surface (Seifert et al., Arch Biochem Biophys. 2012, 524(l):56-63; Falconer et al., Curr Cancer Drug Targets. 2012, 12(8):925-39; Cantu et al., Chem Phys Lipids. 2011, 164(8):796-810).
  • the molecular interaction of the compounds and micelles with sialic acid may be attributed to the presence of the 3-membered aziridine ring or 4-membered azetidine ring in the polycyclic assembly of the molecules which makes them very reactive towards the sialic acid residues present as polymers (polysialic acid) on the glycoproteins and gangliosides of the tumor cell membranes.
  • Azetidine rings are known to easily react with nucleophiles undergoing acid catalyzed ring opening reactions (Kenis et al., J Org Chem. 2012;77(14):5982-92; Ghorai et al., J Org Chem.
  • amphiphilic amine compounds or micelles of the present disclosure exert their antitumor activity via the induction of apoptosis or necrosis.
  • Apoptotic cells may be identified by histological markers such as nuclear and cytoplasmic condensation and cellular fragmentation.
  • Necrotic cells may be identified by histological markers such as cellular and organelle swelling, chromatin flocculation, loss of nuclear basophilia, degraded cytoplasmic structure, impaired organelle function, increased membrane permeability, and cytolysis.
  • One mechanism for inducing apoptosis and/or necrosis involves the activation of initiator caspases (e.g., caspase-2, caspase-8, caspase-9, caspase-10), executioner caspases (e.g., caspase-3, caspase-6) and also pro-inflammatory caspases (e.g., caspase-1 and caspase - 13).
  • initiator caspases e.g., caspase-2, caspase-8, caspase-9, caspase-10
  • executioner caspases e.g., caspase-3, caspase-6
  • pro-inflammatory caspases e.g., caspase-1 and caspase - 13
  • Tdt-mediated dUTP nick-end labeling TUNEL
  • ISEL in situ end labeling
  • FACS fluorescence-activated cell sorting
  • ELISA enzyme-linked immunosorbent assays
  • Tumor cell growth also can be analyzed to determine the antitumor activity of the compounds or micelles of the present disclosure.
  • Tumor mass, volume, and/or length can be assessed using methods known in the art such as calipers, ultrasound imaging, computed tomography (CT) imaging, magnetic resonance imaging (MRI), optical imaging (e.g., bioluminescence and/or fluorescence imaging), digital subtraction angiography (DSA), positron emission tomography (PET) imaging and/or other imaging analysis.
  • Tumor cell proliferation can also be analyzed using cellular assays that measure, e.g., DNA synthesis, metabolic activity, antigens associated with cell proliferation, and/or ATP.
  • DLCs Delocalized Lipophilic Cations
  • lysosomotropic drugs such as Delocalized Lipophilic Cations (DLCs) and lysosomotropic drugs.
  • DLCs such as rhodamine, MKT-077 F16 and dequalinium are characterized by the presence of quaternary ammonium ions and amines in highly
  • DLCs hydrophobic molecular structures able to delocalize the positive charge in the molecular backbone.
  • the antitumor activity of DLCs is based on their ability to accumulate into the mitochondria of tumor cells.
  • a major drawback to their use as antitumor drugs is their high lipophilicity, which restrains their aqueous solubilization and thus their
  • Lysosomotropic drugs such as chloroquine and MDL 72527 are amines endowed with hydrophilic/hydrophobic balance suitable for drug partition through the biological membranes and accumulation in lysosomes (Kimura et al., Cancer Res. 2013; 73(l):3-7).
  • chloroquine and MDL 72527 are currently employed as chemosensitizers in tumor treatments in association with other antitumor drugs in the presence of multidrug resistance (Agostinelli et al., Int J Oncol. 2007, 31(3):473-84; Funk et al., Mol Pharm. 2012, 9(5): 1384-95.).
  • the amphiphilic amine compounds and micelles of the present disclosure also provide increased bioavailability, improved tumor specificity, and other advantages that are lacking with currently available antitumor agents.
  • the generalized nature of the effects of the amphiphilic amine compounds and micelles of the present disclosure may have a distinct advantage over drugs that attack specific molecular targets, as it may be more difficult for cells to develop resistance.
  • Cells are able to develop resistance to drugs that bind DNA, RNA or RTKs through the expression of P-glycoprotein, multidrug resistance-associated proteins, activation of alternative RTK pathways, or acquisition of non-binding mutations (Salehan et al. and Tredan et al., supra).
  • Amphiphilic amine compounds 1 to 7 were synthesized in a one-step procedure set out in Scheme 1 and were characterized by 1 H NMR, 13 C NMR, mass spectra, and elemental analysis. Compounds 1 to 7 were synthesized by mixing l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and the appropriate alkyl bromide in the presence of an enoxy catalyzer. All reagents and solvents employed are commercially available (e.g., from Sigma- Aldrich, St. Louis, MO, or Fluka Chemie GmbH, Buchs, Switzerland).
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • Amphiphilic amine compounds (denoted "RC) were synthesized following the procedure in Scheme 1.
  • a mixture of DBU and the appropriate alkene (in a 1:3 mole ratio) in N-methylpyrrolidone was stirred at room temperature for 4 hours in the presence of 2- [2- (ethenyloxy)ethoxy]ethan-l-ol (0.2 M) as a catalyst.
  • the addition of diethylether induced the precipitation of a solid residue that was purified by flash chromatography using a mixture of methanol/water (9: 1) as eluent.
  • the final products were characterized by 1 H NMR, 13 C NMR, mass spectra, and elemental analysis.
  • NMP N-methylpyrrolidone
  • the human pediatric tumor cell lines tested were: neuroblastoma (CHLA-20, SH- SY5Y, SK-N-AS), osteosarcoma (Osteomet/143.98.2), malignant peripheral nerve sheath tumor (S462.TY), rhabdomyosarcoma (A673 and RH41) and lymphoma (Ramos).
  • Cells were plated in 96- well tissue culture plates at a density of 1 x 10 3 cells/well, allowed to attach for 24 hours, and then left untreated or treated with growth medium containing different concentrations of RC compounds dissolved in PBS. After different time periods, the cell vitality was determined by a 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazoliumbromide (MTT) assay, according to the manufacture's instruction (Promega, Madison, WI). Briefly, the cell culture medium was substituted with fresh medium containing 0.5 mg/mL of MTT.
  • MTT 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyl tetrazoliumbromide
  • RC 16 Due to its improved antitumor activity, RC 16 was further evaluated on a set of adult tumor cell lines which were selected for being particularly resistant to the antitumor treatments in clinical use: mammary carcinoma (MDA-MB-231), osteosarcoma (MG-63), colon carcinoma (WiDr) and lung carcinoma (A549).
  • MDA-MB-231 mammary carcinoma
  • MG-63 osteosarcoma
  • WiDr colon carcinoma
  • A549 A murine neuroblastoma (Neuro-2A) cell line was also used.
  • RC 16 Against the adult tumor cells, RC 16 was very active with IC 50 values in the low micromolar range (1 ⁇ to 10 ⁇ , Table 2). In contrast, RC 16 exhibited very low cytotoxicity with respect to normal cells. The IC 50 values for RC 16 for human keratinocytes, human fibroblasts and HUVECs were more than ten-fold higher than those for tumor cells (Table 2).
  • Annexin V binding assay was performed to distinguish and quantitatively determine the percentage of dead, viable, apoptotic and necrotic cells in SH-SY5Y,
  • Osteomet/143.98.2 and A673 cells treated with 5 ⁇ RC 16 for 15 hours and 24 hours.
  • SH-SY5Y, A673 and Osteomet/143.98.2 cells were stained with Annexin V- FITC/7AAD according to the manufacturer's instructions (eBiosciences Inc., San Diego, CA). Briefly, adherent cells were seeded in 6- well plates at a concentration of 4.5 x
  • the data indicated an apoptotic mode of cell death in all the cell lines analyzed and a different rapidity of cell death depending on the cell type. Differences between control and treated cells were statistically significant at any time of treatment (p-value 0.016 versus control).
  • Flow cytometric (FACS) analysis showed that the percentage of cells in apoptosis following treatment with 5 ⁇ RC 16 increased over time with differences among the cell lines SH-SY57, A673, and Osteomet. At 15 hours, the extent of apoptosis was higher in A673 and lower in Osteomet. After 24 hours, all the cells showed about 100% apoptosis.
  • Detection of caspase activity was evaluated by ApoFluor ® Green Apoptosis Detection kits specific for: caspase- 1 and caspase-4; caspase-2, caspase-3 and caspase-7: caspase-6, caspase-8, caspase-9, caspase- 10, and caspase- 13 (MP Biochemicals, Verona, Italy), according to the manufacturer's instructions. Briefly, cells were detached with EDTA and centrifuged at 400 x g for 5 minutes at room temperature. Cell supernatants were removed, and the pellets were resuspended in a buffer containing the appropriate caspase- specific fluorescent probe. After 1 hour of incubation, samples were washed and analyzed by flow cytometry (FACScan, Becton Dickinson, San Jose, CA) equipped with a 15-mW argon ion laser at 488 nm (16).
  • flow cytometry FACScan, Becton Dickinson, San Jose, CA
  • the western blot analysis indicated activation of caspases 3, 8 and 9 after exposure to RC 16 , as shown in Figures 3A and 3B.
  • different commercially available kits for single caspases i.e., caspase-1, caspase-2, caspase-3, caspase-6, caspase-8, caspase-9, caspase- 10, and caspase-13
  • caspase-1, caspase-2, caspase-3, caspase-6, caspase-8, caspase-9, caspase- 10, and caspase-13 were used to measure the increase in fluorescence after 1, 2, 4, 6, 12, 24, and 36 hours in SH-SY5Y cells exposed to RC 16 .
  • all the foregoing caspases were already activated at 4 hours and became more active thereafter in treated tumor cells with respect to controls.
  • caspase-2, caspase-8, caspase- 9, caspase-10) and in apoptosis execution was observed.
  • the proinflammatory caspases (caspase-1 and caspase-13) were also activated.
  • the role of caspases in cell death is mainly related to their ability to induce inflammatory processes in vivo with massive activation of inflammatory cells, thus their contribution to the whole mechanism activating cell death may be observed in vivo.
  • ROS reactive oxygen species
  • Intracellular ROS Assay Kit Cell Biolabs Inc, San Diego, CA
  • cells (1 x 10 5 /mL) were washed twice in PBS and incubated with 5 ⁇ 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) for 1 hour at 37 °C.
  • H2DCFDA 5 ⁇ 2',7'-dichlorodihydrofluorescein diacetate
  • the medium was changed with fresh medium containing 5 ⁇ RC 16 for 15 hours and 24 hours.
  • samples were washed with PBS, and a mixture of medium and cell lysis buffer (1: 1) was added for 5 minutes at 37 °C.
  • the fluorescence was read by a fluorimetric plate reader (Spectra max M2, Molecular Devices, Sunnyvale, CA).
  • the excitation wavelength was 480 nm and the emission wavelength was 530 nm.
  • TEM was also used to verify the formation of micelles in an aqueous environment due to the amphiphilic nature of the RC molecules.
  • An aqueous solution of RCi 6 (20 ⁇ ) was stained with 2% (w/v) phosphotungstic acid for 3 minutes on a copper grid and subsequently visualized under TEM.
  • TEM images were also recorded from SH-SY5Y cells treated with the same RC 16 concentration (20 ⁇ ) according with the previously described procedure for cells.
  • SH-SY5Y cells treated with RC 16 for 24 hours showed a polygonal morphology in which nucleus and nucleolus were well preserved while cytoplasm was characterized by several vacuoles of different diameter, as shown in Figure 6A.
  • damaged mitochondria with no clear cristae were easily detected.
  • Late autophagy vacuoles (lysosome-like vacuoles) with materials at different stage of degradation, damaged rough endoplasmic reticulum (RER) and multilamellar bodies connected with phospholipid degradation were also observed.
  • Normal human fibroblast cells treated with RC 16 at the same concentration and time showed a fibroblastic shape morphology and a well-preserved nucleus, as shown in Figure 6B.
  • hydrophilic/hydrophobic balance of the molecule contributes to the compound' s antitumor activity.
  • Neuraminidase was used to cleave the sialic acid residue from the sialylated glycoproteins and gangliosides of the tumor cell surface.
  • Cells were seeded on 96-well plates at a density of 2 x 10 4 cells/plate and after 24 hours, they were exposed to 50 mU/ml neuraminidase Type VI from Clostridium perfrigens (Sigma- Aldrich) for 3 hours. Cells were washed 3 times with PBS and then treated with RC 16 . The cytotoxicity was evaluated after 24 hours by MTT assay and compared to cells not treated with neuraminidase. A different experiment aimed at testing the same hypothesis was performed by evaluating the
  • stoichiometric amount with respect to RC 16 were seeded on 96-well plates at a density of 2 x 10 4 cells/plate and after 24 hours, they were treated with a mixture of RC 16 and sialic acid (3 ⁇ :3 ⁇ ) and compared with cells treated with pure RC 16 or pure sialic acid at the same concentration (3 ⁇ ) of the mixture. After 24 hours, the cytotoxicity was evaluated by MTT assay.
  • RC 16 micelles accumulated on tumor cell membranes, but not normal cells, as shown in Figures 7A to 7D.
  • the pre-treatment of cells with neuraminidase to decrease the presence of sialic acid on the glycoproteins and gangliosides of the cell surface also decreased the cytotoxic activity of RC 16 , as shown in Figure 8A, supporting the hypothesis of an interaction of RC 16 with the sialic acid residue of the cell membrane as a contribution to its whole mechanism of action.
  • the addition of sialic acid to the culture medium, to interact with RC 16 and decrease its availability towards the sialic acid present on the glycoproteins and gangliosides of the tumor cell surface also decreased the RC 16 cytotoxic activity, as shown in Figure 8B.
  • MTD maximum tolerated dose
  • the MTD of RC 16 by intravenous administration was 4 mg/kg. At the MTD, 100% survival was obtained with no body weight loss with respect to the controls.
  • a biodistribution study was carried out in athymic nude mice bearing CHLA-20 tumors.
  • the mice received intravenous injections of RC 16 labelled with CellVue® Maroon (eBioscience, Inc.) at a mole ratio of dye to RC 16 of 1 : 100 through the tail vein at a dose of 1 mg/kg.
  • IVIS In Vivo Imaging System
  • the mice were then euthanized, and the organs were removed and weighed for quantitative optical imaging performed by the IVIS system with the same filter sets (excitation/emission: 760/800 nm).
  • IVIS images were taken at 12, 24 and 48 hours after intravenous injection of RC 16 labelled with CellVue® Maroon in nude mice bearing CHLA-20 tumors.
  • the images showed an extensive distribution of fluorescence in the whole body at 12 hours and a gradual decrease of distribution at 24 hours and 48 hours with a persistence of fluorescence in the liver and the gastrointestinal system, as shown in Figure 10A.
  • the organs were removed from the euthanized mice at 12 hours, 24 hours and 48 hours after intravenous injection of the labelled RC 16 and were imaged immediately after dissection, as shown in Figure 10B.
  • mice were then randomized into groups of 6 animals for each tumor type.
  • the animals were treated with RC 16 or vehicle (PBS) alone, administered slowly through the tail vein or gavaged in a volume of 200 ⁇ L ⁇ .
  • RC 16 was administered at the dose of 1 mg/kg 3 times a week for 3 weeks or at the dose of 2 mg/kg/day for 3 weeks by gavage.
  • the tumors were monitored for 5 days.
  • the average percentage of body weight change was used as an indicator for tolerability.
  • Toxicity was defined as body weight loss of 20% or more and/or mortality.
  • mice were slowly injected through the tail vein with Neuro 2 A murine neuroblastoma cells (0.2 x 10 6 ) dispersed in PBS. After 5 days from the injection, the mice were treated once with RC 16 injected through the tail vein in a volume of 200 ⁇ ⁇ at doses of 20 ⁇ g or 40 ⁇ g/mouse. After treatment, the animals were monitored for survival.
  • RC 16 micelles were detected by Scanning electron microscopy (SEM). SH-SY5Y cells were seeded on holders for 24 hours, and then the medium was replaced with fresh medium containing 20 ⁇ RC 16 for 1 hour. At the end of the treatment, the samples were washed with PBS, fixed in 2.5% glutaraldehyde, and then dehydrated in an acetone series (70%, 90%, 100%). The dried specimens were sputter-coated with gold and examined by SEM (Hitachi SU-70; Hitachi Instruments, Schaumburg, IL). The aqueous solution of RC 16 (20 ⁇ ) was desiccated at room temperature on the sample holder, coated with gold and examined by SEM.
  • SEM Scanning electron microscopy
  • aqueous solution of RC 16 (10 mM, lmL) was mixed with an ethanol solution of doxorubicin, paclitaxel or etoposide (ImM, 1 mL). After stirring for 12 hours at 25 °C in a sealed container, the mixture was dialyzed through a 5000 Da MW cutoff dialysis membrane against 100 mL of water. The dialysis was carried out for 48 hours by changing the external medium every 8 hours. The internal RC 16 -drug complex was freeze-dried and the solid residue obtained was weighed and spectrophotometrically analysed to establish the percentage of drug content in the final complex. The complexes were also evaluated for their cytotoxicity in CHLA-20 in comparison with the free drugs at the same concentration.
  • RC 16 micelles were able to encapsulate exemplary antitumor drugs.
  • RC compounds comprising hydrophobic straight chain alkyl tail groups containing more than 16 carbons demonstrated less stability as micelles in water due to the increased lipophilicity of the tail chains.
  • the encapsulation efficiency calculated as the weight percentage of drug in the final dried complex, was: doxorubicin (2.3%) (DOXO) > paclitaxel (1.8%) (PTX) > etoposide 1.0%) (ETO).
  • compositions of the present disclosure possess strong cytotoxic activity against cell lines derived from multiple cancer types.
  • RC 16 is characterized by an intermediate alkyl tail length and exhibited the strongest cytotoxic activity among the compounds tested.
  • RC 16 exhibited significant antitumor activity in several cancer models by both intravenous and oral routes.
  • Mechanistic studies suggested that RC 16 binds to sialic acid residues on the cell membrane and induces cell death via mitochondrial and lysosomal damage.
  • the IC 50 of the compound RCi 6 for normal cells was ten-fold higher than for tumor cells, indicating that RC 16 is significantly less toxic to normal cells.
  • RC 16 exhibited significant antitumor effects in vivo using several human xenografts and in a metastatic model of murine neuroblastoma. RC 16 fully suppressed tumor growth by both intravenous and oral administration routes and strongly improved the survival in the metastatic model.
  • RC 16 was also evaluated as a nanocarrier for bioactive molecules.
  • the amphiphilic character of RC 16 provided a spontaneous molecular self-assembling in water with formation of nanomicelles allowing complexation of doxorubicin, etoposide and paclitaxel.
  • the multiagent micelles significantly improved the in vitro antitumor activity of the drugs through enhancement of their solubility in water and improved drug availability.
  • RC 16 and related amphiphilic amine compounds, micelles, and compositions may be useful as antitumor therapies.
  • the present disclosure provides a multimechanistic antitumor drug class that shows promise for cancer therapy.
  • the amphiphilic amine compounds bind to and induce cytotoxicity in tumor cells by several mechanisms of action, with differential effects on normal cells, resulting in a clinically significant therapeutic window. Furthermore, the amphiphilic amine compounds are useful for encapsulating traditional cytotoxic

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Abstract

L'invention concerne des composés amines amphiphiles, des micelles et des compositions les renfermant. L'invention concerne également des méthodes d'utilisation des composés amines amphiphiles pour traiter les maladies hyperprolifératives comme le cancer. L'invention concerne par ailleurs des méthodes d'utilisation des micelles constituées de plusieurs composés amines amphiphiles comme nanosupports pour d'autres molécules bioactives.
PCT/US2014/071937 2014-01-03 2014-12-22 Composés amines amphiphiles et leur utilisation en tant qu'agents thérapeutiques et nanosupports WO2015103005A1 (fr)

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US11123322B2 (en) 2015-06-04 2021-09-21 Crititech, Inc. Taxane particles and their use
US10729673B2 (en) 2015-06-04 2020-08-04 Crititech, Inc. Taxane particles and their use
US10993927B2 (en) 2015-06-04 2021-05-04 Crititech, Inc. Taxane particles and their use
US11033542B2 (en) 2016-04-04 2021-06-15 Crititech, Inc. Methods for solid tumor treatment
US11458133B2 (en) 2016-04-04 2022-10-04 Crititech, Inc. Methods for solid tumor treatment
US10874660B2 (en) 2016-04-04 2020-12-29 CritlTech, Inc. Methods for solid tumor treatment
US10894045B2 (en) 2016-04-04 2021-01-19 Crititech, Inc. Methods for solid tumor treatment
CN110730679A (zh) * 2017-06-09 2020-01-24 克里蒂泰克公司 囊内注射抗肿瘤颗粒治疗上皮囊肿
US12128131B2 (en) 2017-06-09 2024-10-29 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
US11737972B2 (en) 2017-06-09 2023-08-29 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
WO2018227037A1 (fr) * 2017-06-09 2018-12-13 Crititech, Inc. Traitement de kystes épithéliaux par injection intrakystique de particules antinéoplasiques
US11523983B2 (en) 2017-06-09 2022-12-13 Crititech, Inc. Treatment of epithelial cysts by intracystic injection of antineoplastic particles
US11160754B2 (en) 2017-06-14 2021-11-02 Crititech, Inc. Methods for treating lung disorders
US10507181B2 (en) 2017-06-14 2019-12-17 Crititech, Inc. Methods for treating lung disorders
US11583499B2 (en) 2017-10-03 2023-02-21 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
US11918691B2 (en) 2017-10-03 2024-03-05 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
US11058639B2 (en) 2017-10-03 2021-07-13 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
US12329858B2 (en) 2017-10-03 2025-06-17 Crititech, Inc. Local delivery of antineoplastic particles in combination with systemic delivery of immunotherapeutic agents for the treatment of cancer
CN113350281B (zh) * 2020-03-02 2023-08-15 苏州亚盛药业有限公司 载药聚合物胶束及其制剂和制备方法
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