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WO2005120589A2 - Contrast agent comprising alginate and an isotope or paramagnetic ion - Google Patents

Contrast agent comprising alginate and an isotope or paramagnetic ion Download PDF

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Publication number
WO2005120589A2
WO2005120589A2 PCT/NO2005/000205 NO2005000205W WO2005120589A2 WO 2005120589 A2 WO2005120589 A2 WO 2005120589A2 NO 2005000205 W NO2005000205 W NO 2005000205W WO 2005120589 A2 WO2005120589 A2 WO 2005120589A2
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WO
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Prior art keywords
alginate
manganese
delivery system
contrast
ions
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Application number
PCT/NO2005/000205
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French (fr)
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WO2005120589A3 (en
Inventor
Christian Brekken
Yrr MØRCH
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Ntnu Technology Transfer
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Publication of WO2005120589A2 publication Critical patent/WO2005120589A2/en
Publication of WO2005120589A3 publication Critical patent/WO2005120589A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG
    • A61K49/128—Linear polymers, e.g. dextran, inulin, PEG comprising multiple complex or complex-forming groups, being either part of the linear polymeric backbone or being pending groups covalently linked to the linear polymeric backbone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1803—Semi-solid preparations, e.g. ointments, gels, hydrogels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1213—Semi-solid forms, gels, hydrogels, ointments, fats and waxes that are solid at room temperature

Definitions

  • the present invention relates to a contrast agent delivery system useful in magnetic resonance imaging and positron emission tomography, wherein the delivery system comprises cross linked alginate with a structure adjusted for controlled release of said contrast agent. More specifically, the invention relates to a slow release delivery system comprising alginate, wherein the content of ⁇ -gulopyranuronic acid of 40-80%o, and manganese as a cross binding and imaging enhancing agent and optionally other bivalent cross binding ions.
  • Magnetic resonance imaging is a well-known imaging technique and diagnostic tools used in medical settings to produce images of high quality of the inside of a human or animal body and images of compartments of selected cells or microorganisms.
  • MRI uses radiofrequency waves and a strong magnetic field to provide clear and detailed pictures of internal organs and tissues.
  • the technique is used for the diagnostic or monitoring purposes in various pathologic conditions, essentially in all part of the human or animal body, including cancer, stroke, heart and vascular disorders etc.
  • PET is a nuclear medical imagine technique where radioactive isotopes emitting a positron are utilized to provide detailed pictures of organs and tissues.
  • PET it is possible to detect areas of molecular biology detail by utilizing radioisotopes that have different rates of uptake depending on the specific type of tissue involved.
  • PET is used to detect and monitor several disorders, including inter alia cancer, neurological disorders and vascular and heart conditions.
  • Contrast agents adapted for MRI or PET techniques may comprise or constitute an imaging enhancing substances such as paramagnetic ions or isotopes, respectively.
  • Manganese ions are taken up by living cells and might be used to differentiate between living cells and cells that are damaged i.e. have lost their capacity to transport manganese across their cell membrane.
  • manganese and other paramagnetic ions can be cytotoxic and its use in living subjects is limited to certain dose levels when administered systemically, i.e. intravenous injection.
  • chelating compounds For example, by binding manganese to chelating compounds, a physiological acceptable administration of manganese is suggested.
  • the prior art disclose several manganese chelating compounds for use as a contrast agent in MRI technology.
  • US 5,716,898 disclose a contrast medium for MRI using an ⁇ -hydroxy keton containing group as a manganese- chelating compound.
  • US patent application No. 20040101969 describes the use of a liposome encapsulating a compound of interest and a contrast agent such as manganese.
  • US patent application 20020090341 discloses a method for early detection of myocardial ischemia.
  • the method of said patent application utilizes a physiological acceptable manganese complex or salts thereof.
  • US patent No 6,337,064 Bl discloses a manganese-chelating complex salt.
  • the alleged advantages of this complex is claimed to be the high stability of said complex.
  • Mn-DPDP also known as mangafodipir
  • the complex claimed in US 6,337,064 Bl does not dissociates and release manganese, cf. second column, line 8-16.
  • US patent application US2003/0198599 Al relates to fluorinated and paramagnetic polyuronides and proteins useful as imaging probes, diagnostic agents and contrast agents. More specifically, said application relates to polyuronide polymers, such as alginate beads, directed to a receptor, wherein the polyuronide is modified with fluorine containing moiety and/or a paramagnetic ion. The desired images of specific organs or tissues are then alleged to be provided when the paramagnetic polyuronide polymer is taken up by the cells of said organ or tissue.
  • said application list manganese as one of several possible useful paramagnetic ions, the examples mainly focus on alginate beads comprising gadolinium. Furthermore, as will be apparent from the detailed description of the present invention below, it is clear that a polyuronide polymer comprising manganese would not function according to the alleged purpose as claimed in US 2003/0198599 Al. Summary of the invention
  • the present inventors have surprisingly found that alginate gels or spheres with a content of ⁇ -L-gulopyranuronic acid (G) of about 40-80% w/v is useful as a slow release delivery system for contrast- enhancing agents.
  • the contrast-enhancing agent according to the present invention is e.g. manganese.
  • manganese is released after injection or implantation of the delivery system by replacement of suitable monovalent or divalent ions present at the injection or implantation site (Na + , Ca 2+ etc.).
  • the present invention thus provides a contrast agent delivery system for magnetic resonance imaging and positron emission tomography.
  • the present delivery system releases the contrast-enhancing agent in a controlled manner and thus provides detailed and specific images of biological structures, organs or tissues in microorganisms, cell cultures, fish, animals or humans, respectively.
  • the present delivery system provides localized and stationary delivery of contrast- enhancing agents such as paramagnetic ions or isotopes into specific extravascular body compartments by injection or implantation where cellular manganese uptake is desirable at a certain dose and dose-rate; to produce enhanced image contrast in MR (e.g. Mn 2+ ) or PET imaging (e.g. 52 Mn).
  • contrast- enhancing agents such as paramagnetic ions or isotopes into specific extravascular body compartments by injection or implantation where cellular manganese uptake is desirable at a certain dose and dose-rate; to produce enhanced image contrast in MR (e.g. Mn 2+ ) or PET imaging (e.g. 52 Mn).
  • the present invention is a useful tool in medical imaging (diagnosis, monitoring various diseases or disorders and treatment regimes, research etc.). It is based on the association of cross binding and contrast-enhancing agent, i.e. bivalent ions such as manganese with alginates in formation of gels, and the subsequent release of the contrast-enhancing agent from the gels when injected/implanted into physiological compartments.
  • contrast-enhancing agent i.e. bivalent ions such as manganese with alginates in formation of gels
  • the invention provides a slow release manganese delivery system comprising alginate with a ⁇ -gulopyranuronic acid content of 40-80%), and manganese as a cross binding and imaging enhancing agent and optionally other bivalent cross binding ions.
  • the present delivery system may according to another embodiment of the invention comprise other cross binding bivalent ions in addition to the contrast- enhancing agent, e.g. Ba 2+ , Ca 2+ or Sr 2+ '
  • alginate gels with controlled and selected releasing rate of the contrast-enhancing agent is provided.
  • the releasing rate of the contrast- enhancing agent is controlled by preparing alginate gels by manipulating the presence and concentration of other cross binding divalent ions or by manipulating the G-content and the alginate used.
  • the present delivery system may according to another embodiment of the invention be of a size in the range of about 0.15- 1.00 mm. Detailed description of the invention
  • Figure 1 shows the structure of the monomers of alginate.
  • FIG. 3 is a light microscopic image of Mn 2+" alginate spheres with addition of Ba 2+ in the gelling solution (alginate with 65% G, Scale bare is 100 ⁇ m).
  • B -
  • E show Mn 2+ -release from the alginate spheres according to the invention. Vials filled with Mn 2+ -alginate spheres at (B) 1 min, (C) 20 hrs, (D) 40 hrs, and (E) 60 hrs after rinsing the spheres from their incubation solution. Scale bar is 1 cm.
  • PT180 65% G-alginate from Laminaria hyperborea (high G-alginate) - see Example 1 below.
  • Dry sample 4 freeze-dried Mpyr alginate (high M-alginate) - see Example 2 below.
  • Alginate is a true block copolymer composed of homopolymeric regions of M and G (termed M- and G-blocks, respectively), interspersed with regions of alternating structure called MG-blocks ( Figure 2).
  • Alginates are isolated from marine brown algae and are used in the phannaceutical, 10 cosmetic, textile and food industry. The most common uses are based on the polyelectrolytic nature of the alginates, which forms the basis of their gelling properties. The commercially available sodium alginates are water-soluble. When adding such alginates to a solution containing polyvalent ions, for example bivalent alkaline
  • alginate gels having a defined form are produced. This is a result of an ionic cross-linking of several alginate chains. Alginate is able to bind polyvalent cations selectively in the order: Pb > Cu > Cd > Ba > Sr > Ca > Co, Ni, Zn > Mn
  • Alginate's affinity for polyvalent cations depends on the monomer composition and the distribution of G units along the chain.
  • Diaxially linked G-units form binding sites for cations that crosslink G-blocks from different alginate chains.
  • long G-blocks and a high content of G-blocks gives an alginate of high affinity and selectivity for polyvalent
  • the alginate's G content will depend on the source from which the alginate is isolated.
  • the common, commercially available alginates have a G content of 40- 60%.
  • the contents of G of e.g. sodium alginates may be increased by epimerization using mannuronan C-5 epimerases (e.g. AlgE4) which convert M to G, cf. example 4 below. Methods for converting M to G is described in Svanem,
  • a gel can be defined as a cross-linked polymer, which has been swollen in water.
  • the degree of swelling will substantially be detennined by the osmotic potential of the dissociable ions, which at equilibrium is in balance with the cross- linking forces in the gel network.
  • dissociable monovalent ions like Na +
  • the release of the contrast- enhancing agent and the cross-linking ions can be manipulated by varying the type and concentration of gel- forming ions used, as well as by varying the G-content of the alginate.
  • concentration of the cross-binding ions By varying the concentration of the cross-binding ions, a delivery system with a predetennined releasing rate of the enhancing agent, e.g. manganese, is obtained.
  • the enhancing agent e.g. manganese
  • barium and strontium forms stronger alginate gels than calcium.
  • the alginate gels or beads prepared by using Br 2+ and/or Sr 2+ is thus more stable. This result in alginate gels/beads that to a lesser extent swell in physiological solutions and thus slow replacement of ions and slow release of the contrast agent.
  • the delivery system adjusted for the specific desired releasing rate of the contrast-enhancing agent, e.g. manganese.
  • the contrast-enhancing agent e.g. manganese.
  • Br 2+ is specifically preferable when a slow release of the manganese ions is required.
  • Ca 2+ is preferably used as a cross binding agent.
  • the alginates to be used for preparation of gels according to this present invention are highly purified and have a G-content in the area of 40-80%.
  • the alginates and their G-content will be chosen in dependence of the proposed use.
  • the manganese dose and dose-rate can thus also be tailored by adjusting the G-content of the alginate backbone, size and number of spheres, and addition of other divalent ions in the gelling solutions. Alginates with high G content forms gels or beads with stronger binding of manganese. This results in slow release of manganese.
  • alginates with low G content form gels or beads with looser binding of manganese, and gels/beads with a faster release of manganese is obtained compared with alginate gels /beads with higher G-content.
  • gels with the highest mechanical strength are made from alginates with a high content of G and using gelling ions of high selectivity such as Ba 2+ and Sr 2+ .
  • Tissue microenvironments differing in ability to transport manganese away from the alginate capsule (into cells and throughout the extracellular space) will require different doses and dose-rates of manganese to produce maximum MR image quality per unit scan time (high temporal and/or spatial resolution).
  • Furthennore, specific areas for implantation of the delivery device (e.g. in the brain) might limit the size or number of spheres tolerated.
  • the present invention is flexible with regard to this, by allowing for selection of: alginate core composition (G-content), alginate cross binding ion(s), alginate sphere size, injection preparation (wet/dry) and number of alginate spheres injected.
  • alginate spheres differing by backbone composition (G-content),injection preparation (wet/dry), and size are shown in Figure 4.
  • the present delivery system comprising alginate with a G-content of about 40-80% may be manufactured by cross linking the alginate chains and thus by forming alginate gels or alginate spheres cross-linked with one or more suitable cross linking agents.
  • the cross linking agent is also a contrast- enhancing agent, e.g. a paramagnetic ion such as manganese or a manganese isotope for MR or PET imaging.
  • the contrast-enhancing agent is preferably Mn 2+ or 52m Mn.
  • alginate gels cross-linked with Mn 2+ alone or together with other bivalent ions according to methods well known to the person skilled in the art. The following steps may be followed for the preparation of the alginate gel:
  • the concentration range for the alginate solution used in the preparation of the alginate gels is preferably 0.8 - 5% (w/v). Furthermore, this solution is preferably added to a solution of polyvalent gel-fonning cations having a total concentration of 50 mM - 1.2 M. Non-limiting examples of such polyvalent gel-forming cations are Ba 2+ , Ca 2+ or Sr 2+ .
  • a preferred method for preparing an alginate gel according to the present invention is by the following steps:
  • the initial T2* is very much shorter (in for example brain tissue) compared with pure saline solution, in the order of 0.01 seconds.
  • release of manganese will affect TI -relaxation for the most part, to produce shorter TI -relaxation times for nearby tissue water resulting in increased signal in Tl- weighted MR images ( Figure 5).
  • Watanabe T. et al. in Magnetic Resonance in Medicine 46:424-429(2001)
  • Watanabe et al. used a pure MnCl 2 solution injected into the corpus vitreum of laboratory rats to produce MRI contrast enhancement of the optic nerve. This contrast enhancement is specific and has to date only been produced by the introduction of manganese.
  • the controlled delivery system according to the present invention may also comprise conventional phannaceutical acceptable adjuvants, carriers, excipients or diluents well known to the skilled person in the art.
  • the present fonnulation may be prepared as wet formulations suitable for subcutaneous, intramuscular or interstitial injections/implantations, e.g. for intracortical administration.
  • a preferred contrast releasing formulation comprises the delivery system of the invention and saline solution.
  • the contrast agent releasing formulation is a dry formulation. Dry formulations according to the present invention may be prepared by freeze-drying alginate gels/beads. The dry formulation according to the invention is preferably administrated by implantation of the formulation at a desired location.
  • the medical practitioner or clinician of the art may, with the support of the present description, adapt a suitable administration route and contrast releasing condition, e.g. required manganese releasing rate for the specific patient and the purpose of the MR or PET imaging.
  • a suitable administration route and contrast releasing condition e.g. required manganese releasing rate for the specific patient and the purpose of the MR or PET imaging.
  • Alginate spheres were successfully produced from a series of different alginate types (se examples below) ranging in size from 200-1000 mm (Figure 3 A). After rinsing the spheres from their concentrated MnCl 2 incubation solution, a series of TI -weighted MRI scans were performed to detect manganese efflux from the spheres into a 0.9%) NaCl solution (Figure 3B-E). The MR signal intensity dropped as a function of time in an exponential fashion and levelled off after about 30-40 hrs after start of the rinsing procedure (at the current stage, no rigorous analysis has been performed on the kinetics of this process). Plots of the normalized signal intensity of a set of diffe: c t Mn 2+ -alginate spheres are shown in figur * 1.
  • Saturated manganese-containing alginate gels from vials containing high molar manganese concentration were rinsed in 3-6 consecutive steps in 0.9% NaCl medical injection fluid, to remove ions that were not participating in the gel structure.
  • the volume of alginate gel was approximately 1% of the volume of incubation solution and rinsing solution.
  • the final vials containing approximately 1% gel volume fraction in the 0.9% NaCl solution was placed standing in the iso- center of a 2.35 T MR spectrometer for MR imaging ( Figure 3).
  • One transversal image slice was chosen to follow the MR image signal intensity as a function of time after start of the rinsing procedure.
  • the imaging was repeated every 30 minutes for up to 60 hours after start of rinsing.
  • a 1.8%) w/v solution of a highly purified sodium alginate with a G-content of 65%> was dripped in a solution of 1 M MnCl 2 and 1 mM BaCl using an electrostatic bead generator. Beads were instantly formed. The diameter of the beads was approximately 500 ⁇ m. After gelling, the gelling solution was removed using a filter and the beads washed three times in large volumes of 0.9% NaCl. The processed alginate gel micro-beads were further used in in vitro and in vivo experiments, and the results are shown in Figure 4 and 5, respectively.
  • Example 2 Freeze-dried alginate gel beads with Mn 2+ and Ba 2+
  • a 1.8% w/v solution of a sodium alginate with a G-content of 40% (Mpyr) was dripped in a solution of 1 M MnCl 2 and 1 mM BaCl using an electrostatic bead generator. Beads were instantly formed. The diameter of the beads was approximately 200 ⁇ m. After gelling, the gelling solution was removed using a filter and the beads washed two times in large volumes of 0.9%> NaCl. The gel beads were then freeze dried and put in saline solution just before MR imaging. For in vitro results, see figure 4.
  • Example 3 Alginate gel microbeads in Mn 2+ and Ca +
  • a 1.8% w/v solution of a sodium alginate with a G-content of 70% was dripped in a solution of 50 mM CaCl 2 using an electrostatic bead generator. Beads with a diameter of approx. 200 ⁇ m were instantly formed. The beads were then transferred to a solution of 1 M MnCl 2 and left for a few hours for further gelling. The gelling solution was removed using a filter and the beads washed three times in large volumes of 0.9% NaCl.
  • a high-G sodium alginate with 75%> G was prepared by epimerizing an alginate of 65% G using a mannuronan C-5 epimerase (AlgE4) converting M-blocks to MG- blocks.
  • AlgE4 mannuronan C-5 epimerase
  • a 1.8% solution of the epimerized material was dripped in a solution of 1 M MnCl and 1 mM BaCl 2 using an electrostatic bead generator. Beads with a diameter of approx. 200 ⁇ m were instantly fonned.
  • the gelling solution was removed using a filter and the beads washed three times in large volumes of 0.9% NaCl.
  • the results disclosed above thus show that a slow release delivery system according to the present invention may be used for localized and stationary (e.g.

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Abstract

A system for the delivery of contrast agents such as manganese (MR-active Mn2+ or other manganese isotopes) into extravascular body compartments in living subjects (mammals, amphibians, fish etc.) is described. The compound consists of alginate, manganese ions and other stabilizing ions (Ba2+, Ca2+ etc.) in a gel, formed by mixing of alginate and solutions of the ions mentioned above. The primary alginate used in production of the compound can be adjusted in structure (M- and G-block content and sequence), molecular weight and concentration. In addition, the salt solution and concentration can be varied in order to produce alginate gels of variable manganese amount (dose) and local manganese release rate (dose-rate). When injected or implanted into extravascular body compartments manganese ions will be released from the gel by ion exchange with body fluids and passive diffusion. Once released the manganese ions shortens the longitudinal MR relaxation time of water molecules in their vicinity amounting to positive image contrast in T1-weighted MR images. Furthermore, the compound may also act as slow release agent for positron emission tomography scanning, provided the manganese-isotope is emitting positrons (m52mMn).

Description

Novel contrast agent
The present invention relates to a contrast agent delivery system useful in magnetic resonance imaging and positron emission tomography, wherein the delivery system comprises cross linked alginate with a structure adjusted for controlled release of said contrast agent. More specifically, the invention relates to a slow release delivery system comprising alginate, wherein the content of α-gulopyranuronic acid of 40-80%o, and manganese as a cross binding and imaging enhancing agent and optionally other bivalent cross binding ions.
The field of the invention Magnetic resonance imaging (MRI) is a well-known imaging technique and diagnostic tools used in medical settings to produce images of high quality of the inside of a human or animal body and images of compartments of selected cells or microorganisms.
MRI uses radiofrequency waves and a strong magnetic field to provide clear and detailed pictures of internal organs and tissues. The technique is used for the diagnostic or monitoring purposes in various pathologic conditions, essentially in all part of the human or animal body, including cancer, stroke, heart and vascular disorders etc.
On the other hand, PET is a nuclear medical imagine technique where radioactive isotopes emitting a positron are utilized to provide detailed pictures of organs and tissues. With PET, it is possible to detect areas of molecular biology detail by utilizing radioisotopes that have different rates of uptake depending on the specific type of tissue involved. PET is used to detect and monitor several disorders, including inter alia cancer, neurological disorders and vascular and heart conditions. For both techniques, the imaging of the desired organ or tissue of the body is facilitated by the injection of contrast agents. Contrast agents adapted for MRI or PET techniques may comprise or constitute an imaging enhancing substances such as paramagnetic ions or isotopes, respectively. Manganese ions are taken up by living cells and might be used to differentiate between living cells and cells that are damaged i.e. have lost their capacity to transport manganese across their cell membrane. However, manganese and other paramagnetic ions can be cytotoxic and its use in living subjects is limited to certain dose levels when administered systemically, i.e. intravenous injection.
To solve the toxicity problem of the common imaging enhancing ions, one approach has been to develop chelating compounds. For example, by binding manganese to chelating compounds, a physiological acceptable administration of manganese is suggested. The prior art disclose several manganese chelating compounds for use as a contrast agent in MRI technology. For example, US 5,716,898 disclose a contrast medium for MRI using an α-hydroxy keton containing group as a manganese- chelating compound.
US patent application No. 20040101969 describes the use of a liposome encapsulating a compound of interest and a contrast agent such as manganese.
US patent application 20020090341 discloses a method for early detection of myocardial ischemia. The method of said patent application utilizes a physiological acceptable manganese complex or salts thereof.
A clinically approved manganese slow-release medium usable in MRI exists today for clinical use for intravenous administration produced by Amersham Health ASA (trademark: TESLASCAN, active ingredient/manganese binding compound: mangafodipir = manganese bound to ligand dipyridoxyl difosfat = MnDPDP).
In addition, US patent No 6,337,064 Bl discloses a manganese-chelating complex salt. The alleged advantages of this complex is claimed to be the high stability of said complex. Thus, contrary to other chelating agent disclosed in the prior art such as Mn-DPDP (also known as mangafodipir), the complex claimed in US 6,337,064 Bl, does not dissociates and release manganese, cf. second column, line 8-16.
US patent application US2003/0198599 Al relates to fluorinated and paramagnetic polyuronides and proteins useful as imaging probes, diagnostic agents and contrast agents. More specifically, said application relates to polyuronide polymers, such as alginate beads, directed to a receptor, wherein the polyuronide is modified with fluorine containing moiety and/or a paramagnetic ion. The desired images of specific organs or tissues are then alleged to be provided when the paramagnetic polyuronide polymer is taken up by the cells of said organ or tissue. Although said application list manganese as one of several possible useful paramagnetic ions, the examples mainly focus on alginate beads comprising gadolinium. Furthermore, as will be apparent from the detailed description of the present invention below, it is clear that a polyuronide polymer comprising manganese would not function according to the alleged purpose as claimed in US 2003/0198599 Al. Summary of the invention
The present inventors have surprisingly found that alginate gels or spheres with a content of α-L-gulopyranuronic acid (G) of about 40-80% w/v is useful as a slow release delivery system for contrast- enhancing agents. The contrast-enhancing agent according to the present invention is e.g. manganese. According to the present invention, manganese is released after injection or implantation of the delivery system by replacement of suitable monovalent or divalent ions present at the injection or implantation site (Na+, Ca2+ etc.). The present invention thus provides a contrast agent delivery system for magnetic resonance imaging and positron emission tomography. On the contrary to the majority of contrast agents disclosed in the prior art, which aim to provide stable and constant binding of a contrast-enhancing agent such as a paramagnetic ion to a (chelating) compound, the present delivery system releases the contrast-enhancing agent in a controlled manner and thus provides detailed and specific images of biological structures, organs or tissues in microorganisms, cell cultures, fish, animals or humans, respectively.
The present delivery system provides localized and stationary delivery of contrast- enhancing agents such as paramagnetic ions or isotopes into specific extravascular body compartments by injection or implantation where cellular manganese uptake is desirable at a certain dose and dose-rate; to produce enhanced image contrast in MR (e.g. Mn2+) or PET imaging (e.g. 52 Mn).
The present invention is a useful tool in medical imaging (diagnosis, monitoring various diseases or disorders and treatment regimes, research etc.). It is based on the association of cross binding and contrast-enhancing agent, i.e. bivalent ions such as manganese with alginates in formation of gels, and the subsequent release of the contrast-enhancing agent from the gels when injected/implanted into physiological compartments. The findings are supported by detailed in vitro and in vivo experiments described below.
More specifically, the invention provides a slow release manganese delivery system comprising alginate with a α-gulopyranuronic acid content of 40-80%), and manganese as a cross binding and imaging enhancing agent and optionally other bivalent cross binding ions. The present delivery system may according to another embodiment of the invention comprise other cross binding bivalent ions in addition to the contrast- enhancing agent, e.g. Ba2+, Ca2+ or Sr2+'
According to one preferred embodiment of the present invention, alginate gels with controlled and selected releasing rate of the contrast-enhancing agent is provided. According to one embodiment of the invention, the releasing rate of the contrast- enhancing agent is controlled by preparing alginate gels by manipulating the presence and concentration of other cross binding divalent ions or by manipulating the G-content and the alginate used.
The present delivery system may according to another embodiment of the invention be of a size in the range of about 0.15- 1.00 mm. Detailed description of the invention
The present invention will now be described in more detail, with reference to figures and examples, which constitute the preferred embodiments (best mode). However, the preferred embodiments are not to be interpreted as restrictive to the scope of the enclosed claims.
Short description of the figures
Figure 1 shows the structure of the monomers of alginate. Alginate monomers: M = β-D-mannopyranuronic acid and G = α-L-gulopyranuronic acid. Top: Illustration of the Haworth fomiulas. Bottom: The most probable ring confonnation of the alginate residues; Ci. for the M residues, and C4 for the G residues.
Figure 2 shows a piece of an alginate chain with its monomers: M = β-D- mannopyranuronic acid and G = α-L-gulopyranuronic acid.
Figure 3 (A) is a light microscopic image of Mn2+"alginate spheres with addition of Ba2+ in the gelling solution (alginate with 65% G, Scale bare is 100 μm). (B) - (E) show Mn2+ -release from the alginate spheres according to the invention. Vials filled with Mn2+ -alginate spheres at (B) 1 min, (C) 20 hrs, (D) 40 hrs, and (E) 60 hrs after rinsing the spheres from their incubation solution. Scale bar is 1 cm.
Figure 4 is a plot of normalized MR signal intensity in a ROI in the central part of vials containing a range of different alginate speheres with mangnaese as one of the cross-binding ions. The signal was normalized to the initial signal intensity for each experiment separately. Description of the different types of alginates: Mpyr = 40%) G-alginate from Macrocystis pyriferia (high M-alginate) - see Example 2 below.
PT180 = 65% G-alginate from Laminaria hyperborea (high G-alginate) - see Example 1 below.
Dry sample 4 = freeze-dried Mpyr alginate (high M-alginate) - see Example 2 below.
Large beads = PT180 with sphere diameter of ~500 microns- see Example 1 below.
Small beads = PT180 with sphere diameter of ~200 microns- see Example 1 below. Figure 5 show MR images from the same laboratory rat at increasing times after injection of 10-15 Mn2+-alginate spheres into the corpus vitreum. Note the enhancement of the optic nerve from the retina to the contra-lateral superior colliculus. The structure of alginate Alginates are linear binary copolymers of or-L-gulopyranuronic acid (G) and its C-5 epimere, ?-D-mannopyranuronic acid (M) (Figure 1). The relative amount of the monomers as well as their sequential arrangement along 5 the polymer chain differs widely from one alginate to another. Alginate is a true block copolymer composed of homopolymeric regions of M and G (termed M- and G-blocks, respectively), interspersed with regions of alternating structure called MG-blocks (Figure 2). Alginates are isolated from marine brown algae and are used in the phannaceutical, 10 cosmetic, textile and food industry. The most common uses are based on the polyelectrolytic nature of the alginates, which forms the basis of their gelling properties. The commercially available sodium alginates are water-soluble. When adding such alginates to a solution containing polyvalent ions, for example bivalent alkaline
15 earth metal ions such as Ca , Sr , Mn and Ba , alginate gels having a defined form are produced. This is a result of an ionic cross-linking of several alginate chains. Alginate is able to bind polyvalent cations selectively in the order: Pb > Cu > Cd > Ba > Sr > Ca > Co, Ni, Zn > Mn
20 Alginate's affinity for polyvalent cations, and thus its gel forming properties, depends on the monomer composition and the distribution of G units along the chain. Diaxially linked G-units (G-blocks) form binding sites for cations that crosslink G-blocks from different alginate chains. Hence, long G-blocks and a high content of G-blocks gives an alginate of high affinity and selectivity for polyvalent
25 cations. The alginate's G content will depend on the source from which the alginate is isolated. The common, commercially available alginates have a G content of 40- 60%. Furthermore, the contents of G of e.g. sodium alginates may be increased by epimerization using mannuronan C-5 epimerases (e.g. AlgE4) which convert M to G, cf. example 4 below. Methods for converting M to G is described in Svanem,
30. BIG. Skjak-Brask, G. Ertesvag, H. Valla, S. Cloning and expression of three new Azotobacter vinelandii genes closely related to a previously described gene family encoding mannuronan C-5-epimerases. J Bacteriol 1999; 181:68-77 and Ertesvag, H. Høidal, HK. Hals, IK. Rian, A. Doseth, B. Valla, S. A family of modular type mannuronan C-5-epimerase genes controls alginate structure in Azotobacter
35 vinelandii. Mol Microbiol 1995; 16:719-731. A gel can be defined as a cross-linked polymer, which has been swollen in water. In an ionic gel, the degree of swelling will substantially be detennined by the osmotic potential of the dissociable ions, which at equilibrium is in balance with the cross- linking forces in the gel network. By replacing some of the bivalent cross-linking ions in an alginate gel with dissociable monovalent ions (like Na+), the number of cross-links in the gel will be reduced at the same time as the osmotic potential will rise and the gel will swell. The release of the contrast- enhancing agent and the cross-linking ions can be manipulated by varying the type and concentration of gel- forming ions used, as well as by varying the G-content of the alginate. By varying the concentration of the cross-binding ions, a delivery system with a predetennined releasing rate of the enhancing agent, e.g. manganese, is obtained. For example, barium and strontium forms stronger alginate gels than calcium. The alginate gels or beads prepared by using Br2+ and/or Sr2+ is thus more stable. This result in alginate gels/beads that to a lesser extent swell in physiological solutions and thus slow replacement of ions and slow release of the contrast agent. Dependent of the specific need, one may prepare delivery system adjusted for the specific desired releasing rate of the contrast-enhancing agent, e.g. manganese. Furthermore, the use of Br2+ is specifically preferable when a slow release of the manganese ions is required. On the other hand, when a faster release of manganese is required, Ca2+ is preferably used as a cross binding agent.
The alginates to be used for preparation of gels according to this present invention are highly purified and have a G-content in the area of 40-80%. The alginates and their G-content will be chosen in dependence of the proposed use. The manganese dose and dose-rate can thus also be tailored by adjusting the G-content of the alginate backbone, size and number of spheres, and addition of other divalent ions in the gelling solutions. Alginates with high G content forms gels or beads with stronger binding of manganese. This results in slow release of manganese. On the other hand, alginates with low G content form gels or beads with looser binding of manganese, and gels/beads with a faster release of manganese is obtained compared with alginate gels /beads with higher G-content.
Generally, gels with the highest mechanical strength are made from alginates with a high content of G and using gelling ions of high selectivity such as Ba2+ and Sr2+.
Tissue microenvironments differing in ability to transport manganese away from the alginate capsule (into cells and throughout the extracellular space) will require different doses and dose-rates of manganese to produce maximum MR image quality per unit scan time (high temporal and/or spatial resolution). Furthennore, specific areas for implantation of the delivery device (e.g. in the brain) might limit the size or number of spheres tolerated. The present invention is flexible with regard to this, by allowing for selection of: alginate core composition (G-content), alginate cross binding ion(s), alginate sphere size, injection preparation (wet/dry) and number of alginate spheres injected.
Examples of alginate spheres differing by backbone composition (G-content),injection preparation (wet/dry), and size are shown in Figure 4.
Preparation of the delivery system according to the invention
The present delivery system comprising alginate with a G-content of about 40-80% may be manufactured by cross linking the alginate chains and thus by forming alginate gels or alginate spheres cross-linked with one or more suitable cross linking agents. According to the invention, the cross linking agent is also a contrast- enhancing agent, e.g. a paramagnetic ion such as manganese or a manganese isotope for MR or PET imaging. The contrast-enhancing agent is preferably Mn2+ or 52mMn. Upon administration by injection or. implantation, the contrast-enhancing agent will be released from the alginate gel or alginate spheres.
According to one embodiment of the invention, alginate gels cross-linked with Mn2+ alone or together with other bivalent ions according to methods well known to the person skilled in the art. The following steps may be followed for the preparation of the alginate gel:
Addition of an aqueous solution of alginate to an aqueous salt solution of MnCl2 or of Mn2+, optionally together with other polyvalent gel-forming cations, thereby instantly forming a gel.
Washing the gel using a weak salt solution or physiological solution. The concentration range for the alginate solution used in the preparation of the alginate gels is preferably 0.8 - 5% (w/v). Furthermore, this solution is preferably added to a solution of polyvalent gel-fonning cations having a total concentration of 50 mM - 1.2 M. Non-limiting examples of such polyvalent gel-forming cations are Ba2+, Ca2+ or Sr2+. A preferred method for preparing an alginate gel according to the present invention is by the following steps:
Dripping an aqueous solution of Na-alginate of 1.5 - 2% (w/v) to a solution of MnCl2 (0.5 - 1 M) and CaCl2 or BaCl2 (1 - 50 mM) using an electrostatic bead generator (kommentar: sett gjerne inn eksempel pa type generator), thereby generating alginate gel beads of 0.15 - 1 mm in diameter with a narrow size distribution. Washing the gel beads 3-6 times in physiological salt solution to remove excess gelling ions. In vitro and in vivo experiments
The utilisation of the present invention is shown by both in vitro and in vivo experiments.
In vitro, the experiment consisted of studying the effect of manganese leaking out of on the NMR signal from NaCl-solution surrounding the alginate gel spheres (Figure 3 and 4). The NMR signal dropped when using the MRI pulse sequence described above. This drop in NMR signal is primarily due to the effects of manganese on T2* -relaxation (dipolar effects), since the initial T2* in pure NaCl-solution is in the order of 1 second in this setting (Increased Lorentzian NMR linewidth). Manganese will work as a T2* contrast agent in this situation. The results thus show that manganese will be released from the slow release delivery system according to the present invention.
In vivo, the initial T2* is very much shorter (in for example brain tissue) compared with pure saline solution, in the order of 0.01 seconds. Thus, in animal experiments release of manganese will affect TI -relaxation for the most part, to produce shorter TI -relaxation times for nearby tissue water resulting in increased signal in Tl- weighted MR images (Figure 5). In v vø-experiments performed on animals was very similar to those experiments that were performed by Watanabe T. et al. (in Magnetic Resonance in Medicine 46:424-429(2001)), only a few years ago. Watanabe et al. used a pure MnCl2 solution injected into the corpus vitreum of laboratory rats to produce MRI contrast enhancement of the optic nerve. This contrast enhancement is specific and has to date only been produced by the introduction of manganese.
Contrast agent releasing formulations
The controlled delivery system according to the present invention may also comprise conventional phannaceutical acceptable adjuvants, carriers, excipients or diluents well known to the skilled person in the art.
The present fonnulation may be prepared as wet formulations suitable for subcutaneous, intramuscular or interstitial injections/implantations, e.g. for intracortical administration. In one embodiment of the invention, a preferred contrast releasing formulation comprises the delivery system of the invention and saline solution. In another embodiment of the invention, the contrast agent releasing formulation is a dry formulation. Dry formulations according to the present invention may be prepared by freeze-drying alginate gels/beads. The dry formulation according to the invention is preferably administrated by implantation of the formulation at a desired location.
The medical practitioner or clinician of the art may, with the support of the present description, adapt a suitable administration route and contrast releasing condition, e.g. required manganese releasing rate for the specific patient and the purpose of the MR or PET imaging.
EXAMPLES
Production of slow release contrast agent delivery system
Alginate spheres were successfully produced from a series of different alginate types (se examples below) ranging in size from 200-1000 mm (Figure 3 A). After rinsing the spheres from their concentrated MnCl2 incubation solution, a series of TI -weighted MRI scans were performed to detect manganese efflux from the spheres into a 0.9%) NaCl solution (Figure 3B-E). The MR signal intensity dropped as a function of time in an exponential fashion and levelled off after about 30-40 hrs after start of the rinsing procedure (at the current stage, no rigorous analysis has been performed on the kinetics of this process). Plots of the normalized signal intensity of a set of diffe: c t Mn2+-alginate spheres are shown in figur * 1.
Magnetic resonance imaging
In vitro
Saturated manganese-containing alginate gels from vials containing high molar manganese concentration were rinsed in 3-6 consecutive steps in 0.9% NaCl medical injection fluid, to remove ions that were not participating in the gel structure. The volume of alginate gel was approximately 1% of the volume of incubation solution and rinsing solution. The final vials containing approximately 1% gel volume fraction in the 0.9% NaCl solution was placed standing in the iso- center of a 2.35 T MR spectrometer for MR imaging (Figure 3). One transversal image slice was chosen to follow the MR image signal intensity as a function of time after start of the rinsing procedure. The MR imaging pulse sequence was a Tl- weighted spin echo (MSME, based on original ASPECT3000 2D MSME from Bruker AG, Germany) with the following key parameters: FOV=5cmx5cm, Matrix=128xl28, Slice thickness=3mm TR=200ms, TE=10ms, NEX=4 Total acquisition time ~2min. The imaging was repeated every 30 minutes for up to 60 hours after start of rinsing.
In vivo
Two laboratory rats (Sprague-Dawley female, ~200g) were subject to injection of 10-15 alginate gel capsules into the corpus vitrum of the left eye. Released manganese will be taken up by retinal ganglion cells and transported along the axons in the optic nerve (ref. Watanabe T. et al.: Magnetic Resonance in Medicine 46:424-429(2001)). 24 hours after alginate injection, the rats underwent MR imaging using the same MR scanner and a TI -weighted 3D pulse sequence (FLASH, ref Haase A. et al.: Journal of Magnetic Resonance 67:258-266(1986)) with the following key parameters: FOV=:5cmx5cmx2cm, Matrix=256x256x64 (voxel=195mmxl95mmx312mm), TR=15ms, TE=4.2ms, FA=25deg., Total acquisition time=32min. Approval from the appropriate authorities was given with reference to the animal experiments. Animals were anesthetized with 0.05 ml/g b.w. subcutaneous injection of a mixture Hypnorm/Dormicum/sterile water (ratio 1 : 1 :2) during all experimental procedures. Example 1: Alginate gel micro-beads with Mn2+ and Ba2+
A 1.8%) w/v solution of a highly purified sodium alginate with a G-content of 65%> (PT180) was dripped in a solution of 1 M MnCl2 and 1 mM BaCl using an electrostatic bead generator. Beads were instantly formed. The diameter of the beads was approximately 500 μm. After gelling, the gelling solution was removed using a filter and the beads washed three times in large volumes of 0.9% NaCl. The processed alginate gel micro-beads were further used in in vitro and in vivo experiments, and the results are shown in Figure 4 and 5, respectively.
Example 2: Freeze-dried alginate gel beads with Mn2+ and Ba2+
A 1.8% w/v solution of a sodium alginate with a G-content of 40% (Mpyr) was dripped in a solution of 1 M MnCl2 and 1 mM BaCl using an electrostatic bead generator. Beads were instantly formed. The diameter of the beads was approximately 200 μm. After gelling, the gelling solution was removed using a filter and the beads washed two times in large volumes of 0.9%> NaCl. The gel beads were then freeze dried and put in saline solution just before MR imaging. For in vitro results, see figure 4.
Example 3: Alginate gel microbeads in Mn2+ and Ca +
A 1.8% w/v solution of a sodium alginate with a G-content of 70% was dripped in a solution of 50 mM CaCl2 using an electrostatic bead generator. Beads with a diameter of approx. 200 μm were instantly formed. The beads were then transferred to a solution of 1 M MnCl2 and left for a few hours for further gelling. The gelling solution was removed using a filter and the beads washed three times in large volumes of 0.9% NaCl.
Example 4: Alginate gel beads of epimerized high-G alginate
A high-G sodium alginate with 75%> G was prepared by epimerizing an alginate of 65% G using a mannuronan C-5 epimerase (AlgE4) converting M-blocks to MG- blocks. A 1.8% solution of the epimerized material was dripped in a solution of 1 M MnCl and 1 mM BaCl2 using an electrostatic bead generator. Beads with a diameter of approx. 200 μm were instantly fonned. The gelling solution was removed using a filter and the beads washed three times in large volumes of 0.9% NaCl. The results disclosed above thus show that a slow release delivery system according to the present invention may be used for localized and stationary (e.g. limited) slow delivery of manganese at anatomical locations in situ, to follow evolution of for example ruptures and lesions of the central nervous system (CNS). In conclusion, a novel contrast- enhancing delivering system for use in medical imaging has been presented. The nature of this invention implies the possibility to design tailor-made formulations for a number of applications.

Claims

1. Controlled contrast agent delivery system comprising alginate, wherein the content of the monomer α-L-gulopyranuronic acid in the alginate is about 40-80%>, and wherein the alginate is cross linked with an agent being both an contrast- enhancing agent and cross linking agent, and wherein said agent is released upon administration.
2. Controlled delivery system according to claim 1, wherein the cross binding and contrast- enhancing agent is an isotope or a paramagnetic ion.
3. Controlled delivery system according to claim 2, wherein the paramagnetic ion is Mn2+.
4. Controlled system according to claim2, wherein the isotope is 52mMn.
5. Controlled delivery system according to any of the claims 1-4, wherein the additional cross binding agents are present.
6. Controlled delivery system according to claim 5, wherein said additional cross binding agent are bivalent ions, preferably Ba2+, Ca2+ or Sr2+'
7. Controlled delivery system any of the claims 1-6, wherein the content of α-L- gulopyranuronic acid is above 60% (w/v), such as above 65% (w/v), 70% (w/v), 75% (w/v).
8. Controlled delivery system according to any of the claims 1-6, wherein the content of α-L-gulopyranuronic acid is about 65%>-80% (w/v), such as about 70%> (w/v) - 80% (w/v), or 75% (w/v) -80% (w/v).
9. Controlled delivery system according to any of the claims 1-8, wherein the contrast-enhancing agent is released after administration by injection or implantation.
10. Controlled delivery system according to any of the claims 1-9, wherein the alginate is in form of alginate beads, preferably with a size ranging from about 0.15-1.00 mm.
11. Contrast agent releasing formulation, wherein the fonnulation comprises the delivery system according to any of the claims 1-10 and optionally pharmaceutical acceptable excipients, carriers, adjuvants and/or diluents,
12. Formulation according to claim 11, wherein the fonnulation comprises saline solution.
13. Fonnulation according to claim 11 , wherein the alginate is freeze-dried.
14. Formulation according to any of the claims 11-12, wherein the fonnulation is administered by injection/implantation, e.g. by subcutaneous, intramuscular or interstitial injection/implantation.
15. Formulation according to claim 11 and claim 13, wherein the formulation is administered by implantation.
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* Cited by examiner, † Cited by third party
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US20130183246A1 (en) * 2010-10-01 2013-07-18 The Johns Hopkins University Systems and methods for high-throughput microfluidic bead production
CN115844813A (en) * 2022-12-30 2023-03-28 合肥工业大学 Glycerol-coated manganese ion homogeneous cross-linked sodium alginate slow-release hydrogel capable of loading chemotherapeutic drugs and preparation method and application thereof
WO2024138568A1 (en) * 2022-12-29 2024-07-04 Wenzhou Institute, University Of Chinese Academy Of Sciences Contrast agent for magnetic resonance imaging

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NO845059L (en) * 1984-12-17 1986-06-18 Sintef Inst For Marin Biokjemi PROCEDURE FOR PREPARING ALGINATES WITH CHANGED PHYSICAL PROPERTIES AND USING THESE ALGINATES.
WO1993010440A1 (en) * 1991-11-19 1993-05-27 Unger Evan C Gel particle contrast media for improved diagnostic imaging
US20030100830A1 (en) * 2001-11-27 2003-05-29 Sheng-Ping Zhong Implantable or insertable medical devices visible under magnetic resonance imaging
AU2003234709A1 (en) * 2002-04-11 2003-10-27 Carbomer Fluorinated or paramagnetic alginate polymer, annexin paramagnetic conjugate, and their use as contrasting agent in mri

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130183246A1 (en) * 2010-10-01 2013-07-18 The Johns Hopkins University Systems and methods for high-throughput microfluidic bead production
US9156189B2 (en) * 2010-10-01 2015-10-13 The Johns Hopkins University Systems and methods for high-throughput microfluidic bead production
WO2024138568A1 (en) * 2022-12-29 2024-07-04 Wenzhou Institute, University Of Chinese Academy Of Sciences Contrast agent for magnetic resonance imaging
CN115844813A (en) * 2022-12-30 2023-03-28 合肥工业大学 Glycerol-coated manganese ion homogeneous cross-linked sodium alginate slow-release hydrogel capable of loading chemotherapeutic drugs and preparation method and application thereof

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