EP1912676A2 - Conjugue de polymere comportant un lieur cyclitol - Google Patents

Conjugue de polymere comportant un lieur cyclitol

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Publication number
EP1912676A2
EP1912676A2 EP06800487A EP06800487A EP1912676A2 EP 1912676 A2 EP1912676 A2 EP 1912676A2 EP 06800487 A EP06800487 A EP 06800487A EP 06800487 A EP06800487 A EP 06800487A EP 1912676 A2 EP1912676 A2 EP 1912676A2
Authority
EP
European Patent Office
Prior art keywords
group
compound
polymer
conjugate
biologically active
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06800487A
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German (de)
English (en)
Inventor
David I. Turner
Perry Calias
Gary P. Cook
David T. Shima
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
(OSI) EYETECH Inc
Original Assignee
(OSI) EYETECH Inc
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Publication of EP1912676A2 publication Critical patent/EP1912676A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to conjugates comprising a polymer, a biologically active molecule and carbocyclic group linking the polymer to the biologically active molecule.
  • Conjugating biologically active molecules with polymers, high molecular weight non- immunogenic and lipophilic compounds has been described to improve in vivo profiles of the biologically active molecules.
  • Biologically active molecules, modified with polymers, high molecular weight non-immunogdnic and lipophilic compounds exhibit reduced immunogenicity/antigenicity and.improved pharmacokinetic properties such as stability compared to unmodified versions 1 *:
  • U.S. Patent No. 6,011,020 discloses conjugating a high molecular weight non-immunogenic compound to an aptamer for improving the aptamer' s in vivo circulation half-life.
  • Activated polymers have been reacted with biologically active molecules having nucleophilic functional groups that serve as attachment sites.
  • Polyalkylene glycols such as polyethylene glycol (PEG) are among the most widely used polymers.
  • PEG polyethylene glycol
  • U.S. Patent No. 4,179,337 describes early models of coupling PEG to peptides or polypeptides.
  • U.S. Patent No. 5,122,614 discloses that PEG molecules activated with a N-succinimide carbonate functional group can be attached under aqueous, basic conditions by a urethane linkage to an amine group of a polypeptide.
  • U.S. Patent No. 5,932,462 describes activated multi-armed PEG molecules and multi-armed PEG conjugates.
  • the multi-armed PEG conjugates contain two linear PEG units attached to a multi-functional central moiety such as lysine as the linker between PEG'chains and a biologically active molecule.
  • the invention relates to ⁇ conjugate comprising a polymer, a biologically active molecule and cyclitol linking the polymer to the biologically active molecule.
  • the invention also relates to an activated polymer composition
  • an activated polymer composition comprising a polymer, an active functional group and a cyclitol linking the polymer to the active functional group.
  • the invention also relates to methods of forming a conjugate comprising a polymer, a biologically active molecule and cyclitol linking the polymer to the biologically active molecule.
  • the invention relates to a compound having the formula:
  • a 1 is a biologically active moiety or an active functional group
  • Ri a , Ri b , Ri c , Ri d and R 1 e are each independently selected from the group consisting of -OH, -NH 2 , and -X 2 -L 2 -A 2 ;
  • a 2 is selected from the group consisting of a hydrogen, a polymer, a biologically active moiety and an active functional group;
  • Li and L 2 are each independently selected from the group consisting of a bond and a spacer moiety
  • Xi and X 2 are each independently selected from the group consisting of -O-, -S- and
  • R 2 is selected from the group consisting of a hydrogen and a lower alkyl group.
  • Cyclitols are versatile multifunctional moieties allowing the attachment of up to five polymers onto to a broad spectrum of biologically- active molecules through a single linker unit. Cyclitols are also robust moieties that provide conjugates with a hydrolytically stable linkage.
  • Figure 1 is a schematic representation of a synthesis of an aptamer conjugate comprising two PEG moieties and an inositol linker.
  • Figure 2 is a schematic representation of a synthesis of a trifunctional inositol linking agent.
  • Figure 3 is a schematic representation of a synthesis of an aptamer conjugate comprising two PEG moieties and an inositol linker.
  • Figure 4 is a graphical representation of the results of a VEGFR-I (FIt-I) inhibition assay using a PEGylated VEGF antagonist aptamer having an inositol linker (compound 1), pegaptanib (Mad), and a 5 '-5' capped anti-VEGF aptamer (MacII).
  • compound 1 PEGylated VEGF antagonist aptamer having an inositol linker
  • McII 5 '-5' capped anti-VEGF aptamer
  • Figure 5 is a schematic representation of the chemical structure of a PEGylated VEGF antagonist aptamer having an inositol linker (compound 1).
  • Figure 6 is a schematic representation of the chemical structure of a PEGylated VEGF antagonist aptamer having an inositol linker (compound 10).
  • the invention relates to a conjugate comprising a polymer, a biologically active molecule and cyclitol linking the polymer to the biologically active molecule.
  • the invention also relates to an activated polymer composition
  • an activated polymer composition comprising a polymer, an active functional group and a cyclitol linking the polymer to the active functional group.
  • composition has the formula:
  • A] is a biologically active moiety or an active functional group
  • Ri a , Ri b , Rio Ri d and R] e are each independently selected from the group consisting of
  • a 2 is selected from the group consisting of a hydrogen, a polymer, a biologically active moiety and an active functional group;
  • Li and L 2 are each independently selected from the group consisting of a bond and a spacer moiety
  • Xi and X 2 are each independently selected from the group consisting of -O-, -S- and
  • R 2 is selected from the group consisting of a hydrogen and a lower alkyl group.
  • Ai is a biologically active moiety. In another embodiment, Ai is a nucleic acid. In another embodiment, Ai is an aptamer. In another embodiment, Ai is an anti-VEGF aptamer.
  • Ai is an active functional group. In another embodiment Ai is an electrophilic functional group. In another embodiment Ai is an active functional group comprising a carboxylic acid, carboxylic acid halide, carboxylic acid chloride, halogen, N-succinimide carbonate, succinimidyl ester, 1-benzotriazolylcarbonate ester, N-hydroxymaleimidyl ester, vinyl sulfone, azalactone, cyclic amide thione carbonyl, imidazole carbonyl, isocyanate or isothiocyanate.
  • At least one of Ri a , Ru,, Rio Rid and Rie is -X 2 -L 2 -A 2 .
  • at least two of Ri a , Rib, Ri c , Rid and Rj e are independently -X 2 -L 2 -A 2 .
  • at least three of R la , R ⁇ , R lc , Ri d and R le are independently -X 2 -L 2 -A 2 .
  • at least four of Ri a , Ru » Ri & Ri d and R 1 e are independently -X 2 -L 2 -A 2 .
  • each of Rj a , Rn 3 , Ri 0 , Rw and Rj e are independently -X 2 -L 2 -A 2 .
  • a 2 is a polymer. In a another embodiment, at least one A 2 is a polymer. In another embodiment, A 2 is a biologically active moiety. In another embodiment, A 2 is an active functional group. !
  • Li arid L 2 are, each independently a spacer moiety represented by the formula:
  • Li and L 2 are each independently a spacer moiety represented by a formula selected form the group consisting of:
  • Xi, X 2 , X 3 , X 4 and X 5 are each independently selected from the group consisting of -O- and -NHr!
  • X 1 , X 2 , X3, X 4 and X5 are each -O-.
  • the conjugate has a formula selected from the group consisting of:
  • D is a biologically active moiety
  • POLY is a polymer; each X 3 , X 4 and X 5 are each independently selected from the group consisting of -O-, -S- and -NR 2 -;
  • R 2 is selected from the group consisting of a hydrogen and a lower alkyl group
  • n 0 or 1 ;
  • n is an integer from 0 to 10.
  • D is a nucleic acid. In another embodiment, D is an aptamer. In another embodiment, D is an anti-VEGF aptamer.
  • the conjugate has a formula selected from the group consisting of:
  • the activated polymer composition has a formula selected from the group consisting of:
  • G is a leaving group
  • POLY is a polymer; i each X 3 , X 4 and X5 are each independently selected from the group consisting of -O- ,
  • R 2 is selected from the group consisting of a hydrogen and a lower alkyl group
  • n 0 or 1 ;
  • n is an integer from 0 to 10.
  • G is a leaving group selected from the group consisting of a halide, chloride, N-succinimide, i'-benzotriazole, N-hydroxymaleimide, azalactone, cyclic amide thione and imidazole.
  • POLY is a high molecular weight polymer.
  • POLY is a polymer selected from the group consisting of polyether polyols, polysaccharides, polyesters, high molecular weight polyoxyalkylene, polyamides, polyurethanes, polysiloxanes, polyacrylates, polyols, polyvinylpyrrolidones, polyvinyl alcohols, polyanhydrides, carboxymethyl celluloses, other cellulose derivatives, chitosan, polyaldehydes and polyethers.
  • POLY is a polyalkylene glycol.
  • POLY is a polyethylene glycol (PEG).
  • POLY is a PEG having a molecular weight from 5 kDa to 10O kDa. In another embodiment, POLY is a PEG having a molecular weight of about 20 kDa.
  • each X ⁇ , X 4 and X 5 are each independently selected from the group consisting of -O-, and -NH-. '
  • n is an integer from 0-6. In another embodiment, n is 5.
  • each polymer can be the same or different.
  • each biologically active molecule can be the same or different.
  • a "cyclitol”, as referred to herein, is a cycloalkane comprising a hydroxyl group on one or more ring atoms.
  • T. Hudlicky et al. provide a compilation of known cyclitols and their derivatives ⁇ Cyclitols and Their Derivatives: A Handbook of Physical, Spectral and Synthetic Data, T. Hudlicky and M. Cebulak, Wiley, John & Sons, Incorporated, 1993; which is incorporated herein by reference in its entirety).
  • the cyclitol is a 6-membered cycloalkane.
  • the cyclitol is a 5-membered cycloalkane.
  • cyclitols are tri-, tetra-, penta- and hexa-hydroxy cyclohexanes.
  • Cyclitol derivatives optionally comprise substituents including, but not limited to, alkyl, amino, thio, carbonyl or halogen substituents.
  • the cyclitol is an inositol.
  • Inositols include, but are not limited to myo-inositol, D-c/z/r ⁇ -inositol, L-c/zzV ⁇ -inositol, mwc ⁇ -ihositol, scyllo-inositol, ⁇ /fo-inositol, e/?/-inositol, ciy-inositol and «e ⁇ -inositol.
  • myo-inositol D-c/z/r ⁇ -inositol
  • L-c/zzV ⁇ -inositol L-c/zzV ⁇ -inositol
  • mwc ⁇ -ihositol mwc ⁇ -ihositol
  • scyllo-inositol ⁇ /fo-inositol
  • e/?/-inositol c
  • Activated polymers are polymers that comprise active functional groups. Activated polymers can be used to couple with a biologically active molecule to form a conjugate.
  • an “active functional group” as referred to herein, is a functional group that can react readily with electrophilic or nucleophilic groups on other molecules.
  • active ester would include those esters, such as N- hydroxysuccinimidyl carboxylate ester, that react readily with nucleophilic groups such as amines.
  • active esters include, but are not limited to, N-hydroxymaleimide carboxylate esters and 1-benzotriazolylcarbonate esters.
  • Active functional groups j may comprise a leaving group.
  • suitable leaving groups include, but are not limited to, halides, N-hydroxy-succinimides, N-succinimides, 1-benzotriazols, N-hydroxymaleimides, cyclic amide thiones and imidazoles.
  • active functional groups include, but are not limited to, primary amines, alcohols, hydrazine and hydrazide functional groups, acylhydrazides, carbazates* semicarbazates, and thiocarbazates.
  • spacer refers to a moiety that covalently links the cyclitol together with the polymer, biologically active moiety or active functional group.
  • the spacer is represented by the formula:
  • n O to 10
  • m is 0 or 1
  • p is 0 or 1
  • q is O or 1
  • r is O to 10.
  • the spacer is represented by a formula selected form the group consisting of:
  • n, p and r are as described above.
  • a “lower alkyl group” is a C 1 -C 8 straight chain or branched hydrocarbon or a C 3 -C 8 cyclic hydrocarbon.
  • Examples of lower alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups.
  • hydrolytically stable or “non-hydrolyzable” bond or linkage is used herein to refer to bonds or linkages that are substantially stable in water or substantially do not react with water.
  • a hydrolytically stable linkage does not react under aqueous conditions for an extended period of time.
  • a hydrolytically stable linkage may exist under aqueous conditions indefinitely.
  • physiologically stable bond or linkage is used herein to refer to bonds or linkages that are substantially stable against in vivo cleavage or hydrolysis, but may be also stable in the presence of other in vitro agents.
  • a physiologically stable bond or linkage is hydrolytically stable and is stable to physiological processes in a cell, an organ, the skin, a membrane or elsewhere within the body of a patient.
  • a physiologically stable linkage may exist under physiological conditions indefinitely.
  • any bond or linkage will have reasonable stability under aqueous or physiological conditions
  • the use of selectively hydrolyzable bonds or linkages is contemplated.
  • Selectively hydrolyzable bonds or linkages still have reasonable stability in the circulation.
  • "Selectively hydrolyzable" bonds or linkages include all linkages that are releasable, cleavable or hydrolyzable only or preferentially under certain conditions.
  • selectively hydrolyzable bonds include but are not limited to disulfide and trisulfide bonds and acid-labile bonds.
  • a “biologically active molecule”, “biologically active moiety” or “biologically active agent” can be any substance which can affect any physical or biochemical properties of a biological organism, including but not limited to, viruses, bacteria, fimgi, plants, animals, and humans.
  • Biologically active molecules can include any substance intended for diagnosis, cure mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals.
  • Examples of biologically active molecules include, but are not limited to, nucleic acids, nucleosides, oligonucleotides, aptamers, peptides, proteins, enzymes, small molecule drugs, dyes, lipids, cells, viruses, liposomes, microparticles and micelles.
  • Classes of biologically active agents that are suitable for use with the invention include, but are not limited to, antibiotics, fungicides, anti-viral agents, anti-inflammatory agents, anti-tumor agents, cardiovascular agents, anti-anxiety agents, hormones, growth factors, steroidal agents, and the like.
  • treating is meant the medical management of a patient with the intent that a cure, amelioration, stasis or prevention of a disease, pathological condition, or disorder will result.
  • This term includes active treatment, that is, treatment directed specifically toward improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventive treatment, that is, treatment directed to prevention of the disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder.
  • palliative treatment that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder
  • preventive treatment that is, treatment directed to prevention of the disease, pathological condition, or disorder
  • supportive treatment that is, treatment employed to supplement another specific therapy directed toward the improvement of the disease, pathological condition, or disorder.
  • treating also includes symptomatic treatment, that is, treatment directed toward constitutional symptoms of the disease, pathological condition, or disorder.
  • the method of the invention provides a means for suppressing or treating an ocular neovascular disorder.
  • ocular neovascular disorders amenable to treatment or suppression by the method of the invention include ischemic retinopathy, iris neovascularization, intraocular neovascularization, age-related macular degeneration, corneal neovascularization, retinal neovascularization, choroidal neovascularization, retinopathy of prematurity, retinal vein occlusion, diabetic retinal ischemia, diabetic macular edema, or proliferative diabetic retinopathy.
  • the method of the invention provides a means for suppressing or treating psoriasis or rheumatoid arthritis in a patient in need thereof or a patient diagnosed with or at risk for developing such a disorder.
  • Neovascularization and angiogenesis refer to the generation of new blood vessels into cells, tissue, or organs.
  • the control of angiogenesis is typically altered in certain disease states and, in many cases, the pathological damage associated with the disease is related to altered, unregulated, or uncontrolled angiogenesis.
  • Persistent, unregulated angiogenesis occurs in a multiplicity of disease states, including those characterized by the abnormal growth by endothelial cells, and supports the pathological damage seen in these conditions including leakage and permeability of blood vessels.
  • ocular neovascular disorder is meant a disorder characterized by altered or unregulated angiogenesis in the eye of a patient.
  • Exemplary ocular neovascular disorders include optic disc neovascularization, iris neovascularization, retinal neovascularization, choroidal neovascularization, corneal neovascularization, vitreal neovascularization, glaucoma, pannus, pterygium, macular edema, diabetic retinopathy, diabetic macular edema, vascular retinopathy, retinal degeneration, uveitis, inflammatory diseases of the retina, and proliferative vitreoretinopathy.
  • anti-VEGF agents that inhibit the activity or production of VEGF, including aptamers and VEGF antibodies, are available and can be used in the methods of the present invention.
  • Particular anti-VEGF agents are nucleic acid ligands of VEGF, such as those described in U.S. Patent Nos. 6,168,778; 6,147,204; 6,051,698; 6,011,020; 5,958,691; 5, 817,785; 5,811,533; 5,696,249; 5,683,867; 5,670,637; and 5,475,096, hereby incorporated in their entirety by reference.
  • One particular anti-VEGF agent is pegaptanib sodium.
  • Classes of biologically active agents include anti-infectives including, without limitation, antibiotics, antivirals, and antifungals; analgesics; antiallergenic agents; mast cell stabilizers; steroidal and non-steroidal anti-inflammatory agents; decongestants; anti- glaucoma agents including, without limitation, adrenergics, beta-adrenergic blocking agents, alpha-adrenergic blocking agonists, parasympathomimetic agents, cholinesterase inhibitors, carbonic anhydrase inhibitors, and protaglandins; antioxidants; nutritional supplements; angiogenesis inhibitors; antimetabolites; fibrinolytics; wound modulating agents; neuroprotective drugs; angiostatic steroids; mydriatics; cyclopegic mydriatics; miotics; vasoconstrictors; vasodilators; anticlotting agents; anticancer agents; immunomodulatory agents; VEGF antagonists; immunosuppresant agents; and combinations and prodrugs thereof
  • bio logically' active agents include, but are not limited to, nucleic acids, nucleosides, oligonucleotides, antisense oligonucleotides, RNA, DNA, siRNA, RNAi, aptamers, antibodies, peptides, proteins, enzymes, fusion proteins, porphyrins, and small molecule drugs.
  • antibodies include, but are not limited to, VEGF antibodies bevacizumab (Avastin ® ) and ranizumab (LucentisTM); Genentech, San Francisco, CA.
  • aptamers include, but are not limited to, pegaptanib (Macugen®; (OSI) Eyetech, Inc., New York, NY).
  • steroids include, but are not limited to, anecortave acetate (Retaane®; Alcon, Inc., Fort W ⁇ £th, TX).
  • fusion proteins include, but are not limited to, VEGF TrapTM (Regeneron Pharmaceuticals, Inc. Tarrytown, NY).
  • RNAi include, but are not limited to, Direct RNAiTM (AInylam Pharmaceuticals, Cambridge, MA).
  • compositions of the present invention may be administered by any suitable means that results in a concentration that is effective for the treatment of a neovascular disorder.
  • Each composition for example, may be admixed with a suitable carrier substance, and is generally present in an amount of 1-95% by weight of the total weight of the composition.
  • the composition may be provided in a dosage form that is suitable for ophthalmic, oral, parenteral (e.g., intravenous, intramuscular, subcutaneous), rectal, transdermal, nasal, or inhalant administration.
  • the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointihents, creams, plasters, delivery devices, suppositories, enemas, injectables, implants, sprays,, or aerosols.
  • the pharmaceutical compositions containing a single antagonist or two or more antagonists may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A.R. Gennaro, 2000, Lippincott Williams & Wilkins, Philadelphia, PA. and Encyclopedia of Pharmaceutical Technology, eds., J. Swarbrick and J. C. Boylan, 1988-2002, Marcel Dekker, New York).
  • the anti-VEGF agent is provided in a controlled release formulation.
  • controlled release microparticles are described in US Patent Provisional Application Serial No. 60/796,071 which is hereby incorporated by reference in its entirety.
  • the controlled release formulation comprises a biocompatible, biodegradable polymer selected from the group consisting of lactide polymers, lactide/glycolide copolymers, or polyoxyethylene-polyoxypropylene copolymers.
  • a formulation of the invention may be used in the treatment of any eye disease.
  • a formulation of the invention may also be used to direct an anti-VEGF agent to a particular eye tissue, e.g., the retina or the choroid.
  • the anti-VEGF agent or combination of biologically active agents will be chosen based on the disease, disorder, or condition being treated.
  • other compounds may be included for secondary effects, for example, an antibiotic to prevent microbial growth.
  • the amount and frequency of the dosage will depend on the disease, disorder, or condition being treated and the biologically active agent employed. One skilled in the art can make this determination.
  • oligomer refers to a polymer whose molecular weight is too low to be considered a polymer. Oligomers typically have molecular weights in the hundreds, but polymers typically have molecular weights in the thousands or higher.
  • oligonucleotide refers to an oligomer or polymer of nucleotide or nucleoside monomers consisting of naturally occurring bases, sugars and inter-sugar (backbone) linkages.
  • the term also includes modified or substituted oligomers comprising non-naturally occurring monomers or portions thereof, which function similarly. Incorporation of substituted oligomers is based on factors including enhanced cellular uptake, or increased nuclease resistance and are chosen as is known in the art. The entire oligonucleotide or only portions thereof may contain the substituted oligomers.
  • aptamer means any polynucleotide, or salt thereof, having selective binding affinity for a non-polynucleotide molecule via non-covalent physical interactions.
  • An aptamer can be a polynucleotide that binds to a ligand in a manner analogous to the binding of an antibody to its epitope.
  • the target molecule can be any molecule of interest.
  • An example'of a non-polynucleotide molecule is a protein.
  • An aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein.
  • Anti-VEGF aptamers or "VEGF aptamers” are meant to encompass polynucleotide aptamers that bind to, and inhibit the activity of, VEGF.
  • Such anti-VEGF aptamers may be RNA aptamers, DNA aptamers or aptamers having a mixed (i.e., both RNA and DNA) composition.
  • aptamers can be identified using known methods. For example, Systematic Evolution of Ligands ! by Exponential enrichment, or SELEX, methods can be used as described in U.S. Patent Nos. 5,475,096 and 5,270,163, each of which are incorporated herein by reference in its entirety.
  • Anti-VEGF aptamers include the sequences described in U.S.
  • the sequences can be modified to include 5'-5' and/or 3'-3' inverted caps. (See Adamis, A.P. et ah, published application No. WO 2005/014814, which is hereby incorporated by reference in its entirety).
  • Suitable anti-VEGF aptamer sequences of the invention include the nucleotide sequence GAAGAAUUGG (SEQ ID NO: 1); or the nucleotide sequence UUGGACGC (SEQ ID NO: 2); or the nucleotide sequence GUGAAUGC (SEQ ID NO: 3).
  • anti-VEGF aptamers examples include, but are not limited to:
  • An anti-VEGF aptamer having the sequence: CGGAAUCAGUGAAUGCUUA'UACAUCCG (SEQ ID NO: 4, described in U.S. Patent No. 6,051,698, incorporated hereSri by reference in its entirety).
  • Each C, G, A, and U represents, respectively, the naturally-occurring nucleotides cytidine, guanidine, adenine, and uridine, or modified nucleotides corresponding thereto; and preferably
  • PEGylated aptamer having the structure:
  • G m represents 2'-methoxyguanylic acid
  • a m represents 2'-methoxyadenylic acid
  • C f represents 2'-fluorocytidylic acid
  • U f represents 2'-fluorouridylic acid
  • a r represents riboadenylic acid
  • T d represents deoxyribothymidylic acid.
  • polymers of the invention include, but are not limited to, poly ether polyols (such as polyethylene glycol), polysaccharides (such as carboxymethyl celluloses, other cellulose derivatives, glycosaminoglycans, hyaluronans, and alginates), polyesters, high molecular weight polyoxyalkylene ethers (such as PLURONIC ® ) polyamides, polyurethanes, polysiloxanes, polyacrylates, polyols, polyvinylpyrrolidones, polyvinyl alcohols, polyanhydrides, chitosan, polyaldehydes or polyethers.
  • poly ether polyols such as polyethylene glycol
  • polysaccharides such as carboxymethyl celluloses, other cellulose derivatives, glycosaminoglycans, hyaluronans, and alginates
  • polyesters such as polyethylene glycol
  • high molecular weight polyoxyalkylene ethers such as PLURON
  • the polymers of the present invention are water soluble. In another embodiment the polymers are non-peptidic polymers. In another embodiment the polymers are non-nucleic acid polymers. In another embodiment the polymers are high molecular weight steric groups.
  • the polymer is a polyether polyol. In one embodiment, the polymer is a polyalkylene glycol. In one embodiment, the polymer is a polyethylene glycol (PEG). The PEG may have a free hydroxyl group or may be alkylated. In one embodiment, the terminal end of the PEG not bound to the linker, cyclitol, active functional group or biologically active compound has a methoxy group. A PEG comprising a terminal methoxy group may be referred to as "mPEG". In another embodiment, the polyalkylene glycol is poly(propylene glycol) (“PPG”) and copolymers thereof (e.g. copolymers of ethylene glycol and propylene glycol), terpolymers thereof, mixtures thereof, and the like.
  • PPG poly(propylene glycol)
  • copolymers thereof e.g. copolymers of ethylene glycol and propylene glycol
  • polyethylene glycol refers to any polymer of general formula H(O0j ⁇ 2 CH 2 ) z OH.
  • n is greater than 3.
  • n is from about 4 to about 4000.
  • n is from about 20 to about 2000.
  • n is about 450.
  • PEG has a molecular weight of from about 800 Daltons (Da) to about 100,000 Da.
  • the polyethylene glycol is a 20 kDa PEG, 40 kDa PEG, or 80 kDa PEG.
  • the average relative molecular mass of a polyethylene glycol is sometimes indicated by a suffixed number.
  • a PEG having a molecular weight of 4000 daltons (Da) may be referred to as "polyethylene glycol 4000").
  • a PEG-conjugated product may be referred to as a PEGylated product.
  • PEG polyethylene glycol in any of its forms, including bifunctional PEG, multi-armed PEG, forked PEG, branched PEG and pendent PEG (i.e. PEG or related polymers having one or more functional groups pendent to the polymer backbone.
  • PEG has several advantages. PEG is typically clear, colorless, odorless, soluble in water, stable to heat, inert to many chemical agents, does not hydrolyze or deteriorate, and is generally non-toxic. PEG is considered to be biocompatible. For example, PEG is capable of co-existence with living tissues or organisms without causing harm. More specifically, PEG is substantially non-immunogenic. For example, PEG does not tend to produce an immune response in the body. When attached to a molecule having some desirable function in the body, such as a biologically active agent, the PEG tends to mask the agent and can reduce or eliminate any immune response so that an organism can tolerate the presence of the agent. PEG conjugates tend not to produce a substantial immune response or cause clotting or other undesirable effects. Furthermore, the addition of soluble, high molecular weight steric groups, such as PEG, may improve the antagonist properties of an aptamer (see U.S. Application Serial No. 11/105,279, which is hereby incorporated by reference in its entirety).
  • the polymer is a polysaccharide.
  • polysaccharides include but are not limited to, dextran, cellulqse, chitqsan, polyglucosamine and derivatives thereof.
  • the reducing end of a polysaccharide is available for coupling to an amine group of a molecule by the Schiff-Base chemistry in conjugation.
  • Polysaccharides may be attached to an amine such as an amino substituted cyclitol or an amine terminus of a biologically active compound by reductive animation;
  • the polymer is dextran.
  • the dextran can be a straight chain or branched dextran.
  • the dextran is a carboxymethyl dextran (CMDex).
  • the polymer is a cellulose derivative. In another embodiment the polymer is a carboxymethyl cellulose (CMC).
  • CMC carboxymethyl cellulose
  • title polymer is a polyaldehyde.
  • the polyaldehyde group may be either synthetically derived or obtained by oxidation of an oligosaccharide.
  • the polymer is an alginate.
  • the alginate group is an anionic alginate group that is provided as a salt with a cationic counter- ion, such as sodium or calcium.
  • the polymer is a polyester.
  • the polyester group may be a co-block polymeric polyesteric group.
  • the polymer is a polylactic acid (PLA) or a polylactide-co- glycolide (PLGA).
  • PVA polylactic acid
  • PLGA polylactide-co- glycolide
  • Suitable PLGA groups and method s for conjugating PLGA groups are found in J.H. Jeong et al., Bioconjugate Chemistry 2001, 12, 917-923; J.E. Oh et al., Journal of Controlled Release 1999, 57, 269-280 and J.E. Oh et al., US Patent No. 6,589,548; the contents of each are hereby incorporated by reference in their entirety.
  • the polymer is a, biologically active molecule.
  • the polymer is a nucleic acid, nucleoside, oligonucleotide, aptamer, peptides or protein.
  • the polymer is a glycosaminoglycan, a hyaluronan, a hyaluronic acid (HA), an alginate, a high molecular weight polyoxyalkylene ether, a PLURONIC ® (a block copolymer based on ethylene oxide and propylene oxide), a polyamide, a polyurethane, a polysiloxane, a polyacrylate, a polyvinylpyrrolidone, a polyvinyl alcohol, a polyanhydride, a polyether, a polycaprolactone or a polypeptide.
  • the polymer is a dendron.
  • the dendron may be composed of any combination of monomer and surface modifications. Examples of useful monomers include, but are not limited to, polyamidoamine (PAMAM). Examples of useful surface modification groups include, but are not limited to, cationic ammonium, N-acyl, and N-carboxymethyl group.
  • the dendron may be polyanionic, polycationic, hydrophobic or hydrophilic. In one particular embodiment, the dendron has about 1 to about 256 surface modification groups. In another particular embodiment, the dendron has about 4, 8, 16, 32, 64 or 128 surface modification groups.
  • dendron refers to a molecule representing half of a dendrimer structure.
  • a dendron is typically constructed on one half of a dendrimer core or by cleavage of a dendrimer core after construction of the dendrimer.
  • the dendron may be composed of any combination of monomer and surface modifications. Examples of useful monomers include, but are not limited to, polyamidoamine (PAMAM). Examples of useful surface modifications include, but are not limited to, cationic ammonium, 7V-acyl, and N-carboxymethyl modifications. Alternate surface modifications allow for vastly different properties.
  • the dendron may be polyanionic, polycationic, hydrophobic or hydrophilic.
  • the dendron may be rationally tailored such that the precise number of monomers and surface modification groups are determined by the generation of the dendron (Gl, G2, G3, G4, G5, and G6 possessing 4, 8, 16, 32, 64, and 128 groups respectively).
  • Examples of dendron and dendrimer conjugation techniques are found in US Patent No. 5,714,166 and US Patent Application Publication Nos. 2005/0009988 and 2002/0123609; which are hereby incorporated by reference in their entirety.
  • the construction of a dendron- biologically active molecule conjugate with 1 : 1 stoichiometry may be accomplished by reduction of the disulfide in a dendrimer that contains a cystamine core.
  • the cyclitol moiety itself serves as the core for a dendron.
  • the soluble, high molecular weight steric group is bovine serum albumin (BSA).
  • BSA bovine serum albumin
  • the polymer backbone can be linear or branched.
  • Branched polymer backbones are generally known in the art.
  • a branched polymer has a central branch core moiety and a plurality of linear polymer chains linked to the central branch core.
  • PEG is commonly used in branched forms that can be prepared by addition of ethylene oxide to various polyols, such as glycerol, glycerol oligomers, pentaerythritol and sorbitol.
  • the central branch moiety can also be derived from several mino acids, such as lysine.
  • the branched poly(ethylene glycol) can be represented in general form as W(-PEG-OH) X in which W is derived from a core moiety, such as glycerol, glycerol oligomers, or pentaerythritol, and x represents the number of arms.
  • W is derived from a core moiety, such as glycerol, glycerol oligomers, or pentaerythritol, and x represents the number of arms.
  • Polymers of the present invention can have a molecular weight of from about 800 Da to about 3,000,000 Da. In one embodiment the polymers have a molecular weight of from about 20 kilodaltons (kDa) to about 1000 kDa. In another embodiment the polymers have a molecular weight from about 5 kDa to about 100 kDa. In one particular embodiment, the polymers have a molecular weight of about 20 kDa. In another particular embodiment, the polymers have a molecular weight of about 40 kDa. In another particular embodiment, the polymers have a molecular weigl ⁇ t of about 80 kDa. r ⁇ ; ⁇ , ⁇
  • the polymers of the invention may be conjugated to nucleic acids. Conjugation of the polymer to a nucleic acid may be through the 5' end of the nucleic acid, the 3 ' end of the nucleic acid, or any position along the nucleic acid sequence between the 5' and 3' ends.
  • suitable internal nucleic acid sequence positions for joining to the polymer include an exocyclic amino group on a base, a 5-position of a pyrimidine nucleotide, an 8-position of a purine nucleotide, a hydroxyl group of a phosphate, or a hydroxyl group of a ribose group of the nucleic acid sequence.
  • the terminal activating group or the cyclitol can also include a spacer moiety.
  • the spacer moiety can be located proximal to the polyalkylene oxide or proximal to the terminal activating group.
  • the spacer moiety may be a heteroalkyl, alkoxy or alkyl group containing up to and including 18 carbon atoms or even an additional polymer chain.
  • the spacer moieties can be added using standard synthesis techniques.
  • pharmaceutically acceptable salt refers to non-toxic acid addition salts and alkaline earth metal salts of the compounds of the present invention.
  • the salts can be prepared in situ during the final isolation and purification of such compounds, or separately by reacting the free base or acid functions with a suitable organic acid or base, for example.
  • Representative acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, palmatate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, glucoheptonate, lactobionate, lauryl sulfate salts and the like.
  • Representative alkali and alkaline earth metal salts include, but are not limited to sodium, calcium, potassium and magnesium salts.
  • the invention also relates to methods of forming a conjugate comprising a polymer, a biologically active molecule and a cyclitol linking the polymer to the biologically active molecule.
  • An inositol may be prepared such that the positions that will bear PEG chains may be functionalized selectively.
  • Conduritols may be used as precursors to the inositol fragment. Synthesis of conduritols are described in Balci, Pure App. Chem. 1997, 69, 97-104; Sutbeyaz et ah, J. Chem. Soc. Chem. Commun. 1988, 1330-1331 and references therein; each of which are hereby incorporated by reference in their entirety.
  • a two-step, one-pot synthesis of 1 was accomplished with in-situ activation of compound 3 with an excess of N,N,N,N'-Tetramethyl-0-(N-succinimidyl)uronium tetrafluoroborate (TSU) followed by addition of aptamer.
  • TSU N,N,N,N'-Tetramethyl-0-(N-succinimidyl)uronium tetrafluoroborate
  • inositol linker 2 and inositol activated polymer 3 are shown in Figure 2 and Examples 1-2.
  • Alkylation of myo-inositol-l,3,5-orthoformate gives compound 5.
  • An element of symmetry in 5 allows for a simplified confirmation of regiochemistry by ⁇ MR and ultimately precludes the formation of diastereomeric products upon conjugation to an optically active API. Removal of the silyl protecting group from 5 gave intermediate 6.
  • the desired linker 2 is then prepared upon sequential deprotection of 7. This was accomplished by first refluxing in 0.1M methanolic HCl for 15min then refluxing in 0.4M methanolic hydrazine for 60min.
  • a receptor binding assay for determining the ability of the VEGF aptamer conjugates of the present invention to inhibit VEGF binding to VEGF-Rl is described in Example 6. Results of the assay are shown in Example 7.
  • the ability of inositol-linked VEGF aptamer conjugate 1 to inhibit VEGF binding to VEGF-Rl was compared to that of pegaptanib (Mad) and 5 ' -5 ' capped anti-VEGF aptamer, EYE002 (MacII).
  • the inositol linked PEG-VEGF aptamer conjugate demonstrated activity that is indistinguishable from that of the pegaptanib.
  • Example 1 serve to illustrate certain useful embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. Alternative materials and methods can be utilized to obtain similar results.
  • Example 1 serve to illustrate certain useful embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. Alternative materials and methods can be utilized to obtain similar results.
  • Example 1 serve to illustrate certain useful embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. Alternative materials and methods can be utilized to obtain similar results.
  • Compound 2 was prepared from the commercially available /wyo-inositol-1,3,5- orthoformate using the procedure as described in Carbohydrate Research 2000, 325, 313-320.
  • the resulting pellet was re-dissolved in 4mL of DCM and again precipitated with 36mL OfEt 2 O and centrifuged (5min at 1000 x g) to pellet the PEG species.
  • the PEG species were further dried in vacuo then purified on SEC (Shodex KW-804, isocratic 100% PBS as eluent).
  • SEC Shodex KW-804, isocratic 100% PBS as eluent.
  • the 4OkDa fraction was lyophilized to a white powder and analyzed by MALDI-MS.
  • Compound 1 was purified using an analytical HPLC (C- 18, Hamilton PRP-I) using method "RPHPLC_lmLmin_Pl3 ⁇ " (Solvent A: 1OmM Ammonium Acetate, Solvent B: Acetonitrile). Two lOO ⁇ L injections were done on the same column. The material that eluted at 25.6 minutes in each run was pooled, concentrated, then lyophilized to a white powder. This powder was re-dissolved in 50 ⁇ L of PBS and the concentration of aptamer was determined by a Beer's law calculation (260nm) and confirmed against a standard curve of pegaptanib injections on the HPLC.
  • This mixture of PEG species was dissolved in anhydrous DMSO (1OmL) and DCC (100. mg) was added. The solution was stirred 14h under an argon atmosphere and at room temperature. PEG species were again precipitated by the addition of diethyl ether (9OmL) and isolated on a Buchner funnel. The PEG adducts were dissolved in acetonitrile (8mL) then added to a solution of an anti-VEGF aptamer containing an amino terminus (250mg) in borate buffer (6mL, 10OmM, pH 8.5) then shaken for 14h. The resulting solution was concentrated then diluted to 9mL in deionized water.
  • each well is first; coated with 2 picomole (300 nanograms (ng)) of anti-human IgGl Fc fragment-specific antibody in 100 microliter ( ⁇ L) of PBS at 4°C overnight. The next day, further protein binding in each well is blocked by washing with 300 ⁇ L of Super Block blocking buffer at room temperature for 3 times, 5 minutes each. Each well is then washed with 300 ⁇ L of binding buffer (PBS with 1 mM calcium chloride, 1 mM magnesium chloride, 0.01% HSA, PH 7.4) at room temperature twice.
  • binding buffer PBS with 1 mM calcium chloride, 1 mM magnesium chloride, 0.01% HSA, PH 7.4
  • KDR/Fc 0.25 picomole (85 ng) of the chimeric receptor in 100 ⁇ L of binding buffer is added into the first 11 wells, whereas the twelfth well receive 0.5 picomole (118 ng) of human ICAM- IJFc chimera protein as the background control well.
  • Flt-l/Fc 0.125 picomole (30.8 ng) of the chimeric receptor in 100 ⁇ L of binding buffer each is added into the first 11 wells, whereas the background control well (#12) receive 0.5 picomole (118 ng) of human ICAM- 1/Fc chimera protein.
  • 0.2 picomole (48 ng) of the chimeric receptor in 100 ⁇ l of binding buffer is added to all 12 wells.
  • the chimeric receptors and human ICAM- 1/Fc protein are captured onto th ⁇ 'well by binding to the immobilized anti-human IgGi Fc fragment-specific antibody in ea ⁇ h well at room temperature for 2 to 3 hour.
  • Each well is washed with 300 ⁇ L of binding buffer at room temperature to remove the free chimeric receptors and human ICAM- 1/Fc protein.
  • a set of 10 five-fold dilutions of the Pegaptanib (tube #1 to #10) ranging from 1 ⁇ M (or 2 ⁇ M) to 0.512 picomolar (pM) (or 1.024 pM) are each mixed with about 0.01 ⁇ Ci of 125 I- VEGFi 65 in binding buffer (PBS with 1 mM calcium chloride, 1 mM Magnesium Chloride, 0.01% HSA, pH 7.4) in non-stick 1.5 mL microfuge tubes, in a total 100 ⁇ L final volume each.
  • binding buffer PBS with 1 mM calcium chloride, 1 mM Magnesium Chloride, 0.01% HSA, pH 7.4
  • All 12 tubes are incubated at 37°C (for KDR and FIt-I) or at room temperature (for neuropilin-1) for 15 to 20 min to allow the binding of Pegaptanib to VEGF to reach equilibrium.
  • the 100 ⁇ L binding mix from each tube is then applied to the corresponding well on the receptor-coated Isoplate.
  • the plate is incubated at 37°C (for KDR and FIt-I) or at room temperature (for neuropilin-1) for 2 to 3 hours to allow equilibrium binding to occur.
  • the plate is washed 4 times with 300 ⁇ L/well of binding buffer with (for KDR and neuropilin-1) or without (for FIt-I) 0.05% Tween 20, at room temperature.
  • the plate is air dried for about 10 min, and about 200 ⁇ l of scintillation fluid is added to each well. The radioactivity of each well is determined by scintillation counting.
  • polyethylene glycol 40,000 MW 40 kDa PEG is used at identical molar concentration to replace the Pegaptanib in the binding assay, following all the steps described iabove for Pegaptanib.
  • the 125 I-VEGFi 65 :receptor binding ratios in the wells are calculated as: number of counts retained on the wells (#1 to #11) minus the background (well #12) divided by the maximum binding (positive control, well #11) minus the background (well #12).
  • the resulting binding ratios at different pegaptanib concentrations are analyzed by using nonlinear regression with the GraphPad PRISM program (one site competition), and the resulting curve is used to determine the half-maximum inhibition (IC 50 ) of pegaptanib in inhibiting the receptor binding to VEGF 165 .
  • Data from the experimental negative control using PEG are analyzed by the same method.
  • VEGF-Rl (FIt-I) was compared to that of lysine-linked VEGF aptamer conjugates and non- sterically enhanced VEGF aptamer conjugates.
  • MacII has an IC 50 of 0.375 nM.
  • the results indicate that the inositol-linked VEGF aptamer conjugate (1) is as effective as the lysine-linked VEGF aptamer conjugate, Pegaptanib (EYE-001, Mad), while both the inositol and lysine-linked VEGF aptamer conjugates are much more effective in inhibiting VEGF binding than are non-enhanced VEGF aptamers such as EYE-002 (MacII).

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Abstract

On utilise à cet effet un guide pour guider un dispositif d'ablation d'un tissu du sein. Le dispositif d'ablation peut être muni d'un élément de recueil des tissus amovible pouvant être extrait indépendamment du dispositif d'ablation.
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CA2867381C (fr) 2012-03-16 2016-09-20 The Johns Hopkins University Formulations a liberation controlee pour l'administration d'inhibiteurs du hif-1
CN104394891B (zh) * 2012-03-16 2019-04-16 约翰霍普金斯大学 用于递送活性剂的非线性多嵌段共聚物-药物结合物
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