WO2000066091A1 - Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres - Google Patents

Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres Download PDF

Info

Publication number
WO2000066091A1
WO2000066091A1 PCT/AU2000/000406 AU0000406W WO0066091A1 WO 2000066091 A1 WO2000066091 A1 WO 2000066091A1 AU 0000406 W AU0000406 W AU 0000406W WO 0066091 A1 WO0066091 A1 WO 0066091A1
Authority
WO
WIPO (PCT)
Prior art keywords
folate
polymer
complex
pyridyldithio
complex according
Prior art date
Application number
PCT/AU2000/000406
Other languages
English (en)
Inventor
Gregory John Russell-Jones
John Fergus Mcewan
Original Assignee
Biotech Australia Pty Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biotech Australia Pty Limited filed Critical Biotech Australia Pty Limited
Priority to AU40943/00A priority Critical patent/AU4094300A/en
Priority to JP2000614977A priority patent/JP2002543111A/ja
Priority to CA002372841A priority patent/CA2372841A1/fr
Priority to EP00920286A priority patent/EP1206252A4/fr
Publication of WO2000066091A1 publication Critical patent/WO2000066091A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • 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
    • A61K47/54—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 compound
    • A61K47/55—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/551—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 compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
    • 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
    • A61K47/58—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 by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B11/00—Preparation of cellulose ethers
    • C08B11/20—Post-etherification treatments of chemical or physical type, e.g. mixed etherification in two steps, including purification
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-(meth)acryloylmorpholine
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C08F251/02—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof on to cellulose or derivatives thereof

Definitions

  • the invention relates to the delivery of drug, peptide and protein pharmaceuticals using the folate-mediated uptake system. More particularly the invention relates to the amplification of drug/pharmaceutical delivery with the folate uptake system using a folate-polymer complex. The invention also relates to processes for preparing the complexes, pharmaceutical compositions containing same, methods of treatment involving the complexes and uses of the complexes in the manufacture of medicaments.
  • Folic acid enters cells either through a carrier protein, termed the reduced folate carrier, or via receptor-mediated endocytosis facilitated by the folate receptor.
  • the folate receptor is significantly over-expressed on a large fraction of human cancer cells including ovarian, breast, lung, endometrial, renal, colon, and cancers of myeloid hematopoietic cells.
  • FR- ⁇ is upregulated in malignant tissues of epithelial origin such as ovarian carcinoma, while FR- ⁇ is overexpressed in malignant tissues of nonepithelial origin. While the FR have been detected in normal tissues involved in the retention and uptake of the vitamin, these tissues are in protected sites and generally not accessible following blood-borne delivery of folate conjugates. Thus there is expression in the choroid plexus, the intestinal brush border apical membrane surface and the proximal tubules of the kidney. In the latter case the receptor probably functions to scavenge excreted folate, and as such would not be accessible to large molecule weight folate complexes.
  • Folate-mediated tumor targeting has been exploited to date for delivery of the following molecules and molecular complexes (i) protein toxins, (ii) low-molecular- weight chemotherapeutic agents, (iii) radio-imaging agents (iv) MRI contrast agents, (v) radiotherapeutic agents, (vi) liposomes with entrapped drugs, (vii) genes, (viii) antisense oligonucleotides, (ix) ribozymes, and (x) immunotherapeutic agents.
  • the dose deliverable is small, i.e. one molecule of drug for each molecule of folate, and that the majority of the fo late-drug complexes are very small and as such are excreted in the kidneys and re-absorbed in the proximal tubules, thus leading to undesirable accumulation of folate-drug complexes in the kidney.
  • this invention provides a new set of drug/pharmaceutical-polymer conjugates, to which a folate molecule, or analogue thereof, has been conjugated.
  • These folate-polymer-drug conjugates are suitable for parenteral delivery to tumors as they can utilise the aforementioned folate receptor system for uptake binding and uptake, and have the added advantage of increasing the amount of pharmaceutical agent which can be delivered via the folate uptake mechanism, as well as minimising or avoiding targeting to the kidneys by virtue of their size.
  • a polymer complex having the general formula: (folate-Q) n -P-(Q'-A) m wherein, folate, or an analogue thereof, is a targeting molecule which will bind to a natural folate receptor, preferably a surface folate receptor on a tumor or cancer cell; n, the molar substitution ration of folate in the complex, is in the range from 1.0 to
  • P is a pharmaceutically acceptable polymer
  • A is a pharmaceutically active substance
  • m the molar substitution ratio of A in the complex, is in the range from 1.0 to 1000, preferably from 2 to 200, more preferably from 10 to 100;
  • Q and Q' are independently a covalent bond, or a spacer compound linking folate, P and A by covalent bonds.
  • the polymer complexes of the invention may comprise more than one active substance linked to the polymer, which in turn is linked to at least one targeting molecule which is a folic acid molecule, or analogue thereof, wherein the ability of the targeting molecule to undergo the binding reactions necessary for uptake and transport of folate in a vertebrate host and the activity of the active substance(s) are substantially maintained, following conjugation or following biological release of the active substance from the polymer.
  • a process for the production of a polymer complex of the invention incorporating one or more active substances comprises one or more of the following steps: a) reacting the active substance with the polymer to form said complex; b) chemically modifying the active substance to provide at least one functional group capable of forming a chemical linkage, and reacting the active substance and polymer to form said complex; c) chemically modifying the folate or folate analogue targeting molecule (herein after referred to as TM) to provide at least one functional group capable of forming a chemical linkage and reacting the TM and polymer to form said complex; d) chemically modifying the active substance and the polymer to provide functional groups capable of forming a chemical linkage, and reacting the active substance and polymer to form said complex; e) reacting the active substance with at least one cross-linking agent and reacting the active substance of polymer to form said complex; f) reacting the TM with at least one cross-linking agent
  • the invention further provides a method for the modification of a polymeric support to introduce functional groups capable of reacting either directly with the active substance or with a chemically-modified form of the active substance.
  • the resulting polymer-active substance intermediate contains one or more molecules of the active substance, said intermediate being suitable for coupling to the TM to give a complex capable of amplified delivery of the active substance.
  • a pharmaceutical composition which comprises a polymer complex of the present invention in association with a pharmaceutically acceptable carrier, excipient, diluent and/or adjuvant.
  • a method for the treatment, prophylaxis or amelioration of disease in particular a tumor or cancer cell in a vertebrate host, which method comprises administering to said host a therapeutically effective amount of a polymer complex or composition of the present invention.
  • a polymer complex of the invention in the preparation of a medicament for the treatment, prophylaxis or amelioration of disease, preferably cancer.
  • a method of delivering an active substance to a tumor or cancer cell comprising contacting said tumor or cancer cell with a polymer complex of the invention.
  • the method of delivering the active substance may be achieved in vivo by administering the polymer complex to a host, preferably a vertebrate host, of said tumor or cancer cell.
  • the polymer complex of the invention has coupled to it one or more molecules of one or more active substances to be delivered, the polymer being coupled to the TM to give a complex capable of amplified delivery of the active substances.
  • Figure 1 represents the biodistribution of folate derivatized HMPA and CMC polymers in the presence and absence of the excess folate.
  • the recovery of various folate-polymer complexes from Balb/C mice injected with hybridoma tumor cells are compared by plotting the percentage of recovered injected counts.
  • the data shows that the level of polymer uptake by liver and tumor cells can be enhanced by folate derivatization of the polymers.
  • the polymer complexes of the present invention have been especially targeted to tumors and cancer cells using folic acid or analogues thereof as the targeting moiety. Once the drug-polymer has reached its target tissue the complex is endocytosed by the target cell and the pendant drug may be released by the action of lysosomal enzymes, by cleavage of a disulfide linked drug by intracellular glutathione or otherwise. While it is possible that these complexes could be used for oral delivery of the drug to the circulatory or lymphatic drainage system in general, the products of this invention and a co-pending nanoparticle delivery invention (Australian Provisional Patent Application No. PQ0146 entitled "Amplification of Folate-Mediated Targeting to Tumor Cells using Nanoparticles" filed on 4 May 1999 and incorporated herein in its entirety by reference) preferably relate to targeting the active substances to tumor/cancer cells.
  • the target molecules utilised in the invention are folate molecules or analogues thereof, which possess binding activity for the folic acid receptor, and in particular to surface folate receptors on tumor cells.
  • Analogues contemplated herein include, but are not limited to, modification to the ring structure, functional groups or side chains of the folic acid molecule including the additional removal of protecting groups and salts and complexes thereof derived from any source such as being chemically synthesised or identified by screening process such as natural product screening provided that the analogue possesses some binding activity for the folic acid receptor.
  • the polymer, P, of the present invention can be any pharmaceutically acceptable polymer.
  • the polymer is able to attach to at least one folate molecule and to at least one, but preferably a multiplicity of active substance molecules.
  • Suitable polymers for substitution with folate and modification according to the invention include but are not limited to poly[N-(2-hydroxypropyl)-methacrylamide], dextran, chondroitan sulfate, water soluble polyurethanes formed by covalent linkage of PEG with lysine, poly(glutamic acid), poly(hydroxypropyl glutamine) and branched chain polypeptides formed by the dual modification of the ⁇ and ⁇ -amino groups of lysine during the peptide synthesis, as well as dendrimers and PEG- dendrimers.
  • Such polymers may have multiple amino-termini, to which can be conjugated a plurality of the pharmaceutical or drug to be delivered.
  • the polymers can also be formed with multiple cystines, to provide free thiols, or multiple glutamates or aspartates, to provide free carboxyls for conjugation using suitable carbodiimides.
  • the polymer can contain multiple histidines or tyrosines for conjugation.
  • Other suitable polymers include those having the sequence of [(NH2-X)l6 _ Lys -Lys4-Y4-
  • the linkage to the polymer, or the polymer to which the pharmaceutical is linked should be biodegradable.
  • biodegradable polymers include dextran and its derivatives, and amino acid polymers such as poly-lysine, poly-glutamic acid.
  • Non-biodegradable polymers may also be employed in the present invention and include poly[N-(2-hydroxypropyl)-methacrylamide], to which is attached biodegradable side chains such as those containing ester linkages, or amino acid sequences cleavable within lysosomal vacuoles i.e. Gly-Phe-Leu-Gly (Rihova, B. and J. Kopecek., 1985 Biological properties of targetable poly[N-(2-hydroxypropyl)- methacrylamide] -antibody complexes. J. Control Rel., 2 :289-310).
  • amino acid spacers cleavable by intracellular proteases include Gly-Phe-Ala; Gly-Phe-Ala-Gly; Gly-Phe-Tyr-Ala; and Gly-Phe-Tyr-Ala-Ala [Rejmanova, P., Obereigner, B., and Kopecek, J., 1981 Makromol. Chem. 182 : 1899-1915].
  • folate as used herein is to be considered in its broadest context and refers to the carboxylic acid anion of folic acid and, where not stated, the counter cation may be any suitable cation including pharmaceutically acceptable cations and may also include a proton, i.e. folic acid.
  • the term "folate” may be taken to include reference to analogues of the folate molecule, such as methotrexate, and preferably where the analogue possesses some binding activity for the folic acid receptor.
  • Folate is most easily covalently attached to a ligand, or the polymer, via either its ⁇ or ⁇ - carboxylic acid moiety. It has been shown, however, that the ⁇ -carboxyl derivatives have low avidity for the folate receptor, whereas the ⁇ -carboxyl derivatives have similar affinity to native folate. Other functional groups may be employed as required.
  • the linkage joining the pharmaceutical, or the folate to the polymer is a disulfide bond. In a further embodiment of the invention the linkage joining the pharmaceutical, or the folate to the polymer is an ester linkage. In yet another embodiment of the invention the linkage joining the pharmaceutical or the folate to the polymer is a ⁇ -glutamyl- ⁇ -lysine bond. In yet another embodiment of the invention the linkage joining the pharmaceutical or the folate to the polymer is a diazo-linkage.
  • the spacer compounds Q and Q' are optional. When they are absent the TM folate, and/or the active substance A are linked to polymer P by a direct covalent bond. They are introduced either to improve the folate receptor affinity of the folate complex or to overcome problems in the coupling of the carrier, folate, and/or the active substance A arising from unfavourable steric interactions between the folate and A with the polymer P, or to increase the bioactivity of A in the complex.
  • the spacer compounds may also act as linking agents, being bi-functional compounds with selected functional groups on each end to react with suitable functional groups located on the polymer, and also on the folate targeting molecule and/or on the pharmaceutically active substances.
  • Suitable extended spacers for the conjugation of the pharmaceutical or folate to the polymer matrix preferably have from 1 to 50 atoms in its backbone.
  • Such diradical spacers may be optionally substituted and contain within the chain double bonds, triple bonds, aryl groups and/or hetero atoms.
  • the spacer compounds Q or Q' comprise optionally substituted saturated or unsaturated, branched or linear, C 1 . 50 alkylene, cycloalkylene or aromatic group, optionally with one or more carbons within the chain being replaced with N, O or S, and wherein the optional substituents are selected from carbonyl, carboxy, hydroxy, amino and other groups.
  • the extended spacers include: disuccinimidyl suberate (DSS), bw(sulfosuccinimidyl) suberate (BSS), ethylene glycolbz ' -y(succinimidylsuccinate) (EGS), ethylene glycolbts(sulfosuccinimidylsuccinate) (Sulfo-EGS), p-amino- phenylacetic acid, dithiobts(succinimidylpropionate) (DSP), 3,3'- dithiobt-?(sulfosuccinimidylpropionate) (DTSSP), disuccinimidyl tartarate (DST), disulfosuccinimidyl tartarate (Sulfo-DST), bw[2-(succinimidyloxycarbonyloxy)- ethylene]sulfone (BSOCOES), bw[2-(sulfos),
  • Suitable cross-linking agents for use in the preparation of thiol-cleavable biodegradable linkers include N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP), iminothiolane, sulfosuccinimidyl 6-[3-(2-pyridyldithio) propionamido] hexanoate (Sulfo-LC-SPDP), succinimidyl 6-[3-(2-pyridyldithio) propionamido] hexanoate (LC- SPDP), sulfosuccinimidyl 6-[ ⁇ -methyl- ⁇ -(2-pyridyldithio) toluamido]hexanoate (Sulfo-LC-SMPT), l,4-di[3'-(2'-pyridyldithio)propionamido]butane (DPDPB), 4- succinimidy
  • the active substance to be delivered is preferably a hormone, drug, prodrug, toxin, pharmaceutically active protein, immunogen, or D ⁇ A or R ⁇ A analogue.
  • Suitable toxins include, but are not limited to, ricin, abrin, diphtheria toxin, modecin, tetanus toxin, mycotoxins, mellitin, ⁇ -amanitin, pokeweed antiviral protein, ribosome inhibiting proteins, especially those of wheat, barley, corn, rye, gelonin and maytansinoid.
  • Suitable cytotoxic agents include, but are not limited to alkylating agents such as chlorambucil, cyclophosphamide, melphalan, cyclopropane; anthracycline antitumor antibiotics such as doxorubicin, daunomycin, adriamycin, mitomycin C, 2-(hydroxymethyl)anthraquinone; antimetabolites such as methotrexate, dichloromethatrexate: cisplatin, carboplatin, and metallopeptides containing platinum, copper, vanadium, iron, cobalt, gold, cadmium, zinc and nickel.
  • alkylating agents such as chlorambucil, cyclophosphamide, melphalan, cyclopropane
  • anthracycline antitumor antibiotics such as doxorubicin, daunomycin, adriamycin, mitomycin C, 2-(hydroxymethyl)anthraquinone
  • agents include DON, thymidine, pentamethylmelarnin, dianhydrogalactitol, 5-Methyl-THF, anguidine, maytansine, neocarzinostatin, chlorozotocin, AZQ, 2'deoxycoformycin, PALA, AD-32, r ⁇ -AMSA and misonidazole.
  • active substances which may be delivered by the folate polymers of the invention include but are not limited to hormones and bioactive peptides and polypeptides, antibiotics, antipyretics, analgesics and antiinflammatory drugs, expectorants, sedatives, muscle relaxants, antiepileptics, antiulcer drugs, antidepressants, antiallergic drugs, cardiotonic drugs, antiarrythmic agents, vasodilators, antihypertensives, anticoagulants and haemostatic agents as known in the art.
  • treatment and prophylaxis are to be considered in its broadest context.
  • the term “treatment” does not necessarily imply that a host is treated until total recovery.
  • “prophylaxis” does not necessarily mean that the subject will not eventually contract a disease condition.
  • treatment and prophylaxis include amelioration of the symptoms of a particular condition or preventing or otherwise reducing the risk of developing a particular condition.
  • the term “prophylaxis” may be considered as reducing the severity of onset of a particular condition. “Treatment” may also reduce the severity of an existing condition.
  • the subject of the treatment or prophylaxis is preferably a mammal such as but not limited to human, primate, livestock animal (e.g.
  • sheep, cow, horse, donkey, pig) companion animal e.g. dog, cat
  • laboratory test animal e.g. mouse, rabbit, rat, guinea pig, hamster
  • captive wild animal e.g. fox, deer
  • the mammal is a human or primate. Most preferably the mammal is a human.
  • the agents herein defined may be coadministered with one or more other compounds or molecules.
  • the polymer complex of the invention may be administered in combination with folate nanoparticle complexes, other chemotherapeutic agents or other ameliorative active substances.
  • administered in combination is meant simultaneous administration in the same formulation or in two different formulations via the same or different routes or sequential administration by the same or different routes.
  • sequential administration is meant a time difference of from seconds, minutes, hours or days between the administration of the formulations.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as licithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants.
  • the preventions of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimersal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilisation.
  • dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.
  • the active ingredients When the active ingredients are suitably protected they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, gels, pastes, viscous colloidal dispersions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 1% by weight of active compound.
  • compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions in such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 0.1 ⁇ g and 2000 mg of active compound.
  • the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
  • the tablets, troches, pills, capsules and the like may also contain the following: A binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; buffering agents such as sodium bicarbonate to neutralise or buffer stomach acid; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • buffering agents such as sodium bicarbonate to neutralise or buffer
  • any material may be present as coatings or to otherwise modify the physical form of the dosage unit.
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired.
  • Administration of the agent in the form of a pharmaceutical composition may be performed by any convenient means.
  • the agent of the pharmaceutical composition is contemplated to exhibit therapeutic activity when administered in an amount which depends on the particular case. Variation depends for example, on the human or animal and the agent chosen. Dosage regimes may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily, weekly, monthly or other suitable time intervals or the dose may be proportionally reduced as indicated by the exigencies of the situation.
  • the agent may be administered in any suitable manner.
  • Routes of administration include, but are not limited to, respiratorally, intratracheally, nasopharyngeally, intravenously, intraperitoneally, subcutaneously, intracranially, intradermally, intramuscularly, intraoccularly, intrathecally, intracereberally, intranasally, infusion, orally, rectally, via IV drip, patch and implant.
  • suitable routes are via injection into vessels which supply the tumour or diseased organs.
  • Peptides may also be installed into cavities for example the pleural or peritoneal cavity or injected directly into tumour tissues.
  • His4-Glu4-Lys2-Lys]-Gly5-Cys-COOH was synthesized on an Applied Biosystems peptide synthesiser. More precisely the structure can be represented as follows:
  • toxins which could be used for formation of folate-MLP-toxin conjugates, including momordin, Pseudomonas exotoxin A, ricin and abrin.
  • a general method for the formation of folate-MLP-toxin conjugates is described below.
  • Conjugates are prepared in which the covalent linker contains a biodegradable disulfide bond, which would be reduced in vivo, presumably by intracellular glutathione in the tumor cell, thereby releasing the active substance after transport from the serum into the tumor cell. Briefly, MLPl or MLP2 was reacted with ⁇ - succinimidyl 3-(2-pyridyldithio)propionate (SPDP).
  • SPDP ⁇ - succinimidyl 3-(2-pyridyldithio)propionate
  • the dithiopyridyl-MLP (DTP- MLP) product was purified by RP-HPLC.
  • a free thiol was introduced onto the toxin by a two step procedure in which the toxin was firstly reacted with SPDP, after which the thiopyridyl group was reduced with mercapto-ethanol.
  • the product was purified by RP-HPLC.
  • free thiol was introduced into the toxin directly by reaction with iminothiolane.
  • the thiolated product (SH-HN + toxin) was purified by RP-HPLC.
  • HPMA copolymers Two N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers were synthesised as polymer backbones for the incorporation and derivatization with cytotoxic drugs and folate.
  • HPMA-GFALG A biodegradable polymer (HPMA-GFALG) was synthesised by the free radical copolymerisation of HPMA with N- methacryloylglycylphenylalanylleucylglycine p-nitrophenol ester by the method of Rejmanova and co-workers [Rejmanova,P., Obereigner, B., and Kopecek, J., 1981 Makromol. Chem. 182 : 1899-1915].
  • ricin A chain and folate were reacted with a ten molar excess of a mixture of aminohexyl-folate and Dithiopyridyldodecylsuberyl-hexylamine (1:10 mole:mole) overnight. Unreacted nitrophenyl esters were subjected to aminolysis by the addition of l-amino-2-propanol.
  • the modified polymers were purified by chromatography on Sepharose 6B. A solution of the dithiopyridyldodecylsuberylhexyl modified folate- substituted polymers was dissolved in 2.5% acetic acid and reacted with ricin A chain.
  • HPMA copolymer An N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer was synthesised as a polymer backbone for the incorporation and derivatization with both the cytotoxic drug, daunomycin and folate.
  • a biodegradable polymer (HPMA-GFLG) was synthesised by the free radical copolymerisation of HPMA with N- methacryloylglycylphenylleucinylglycine p-nitrophenol ester by the method of Rejmanova and co-workers [Rejmanova,P., Obereigner, B., and Kopecek, J., 1981 Makromol. Chem. 182 : 1899-1915].
  • daunomycin and folate were reacted with a ten molar excess of a mixture of aminohexyl-folate and daunomycin (1 :10 mole:mole) overnight. Unreacted nitrophenyl esters were subjected to aminolysis by the addition of l-amino-2- propanol. The modified polymers were purified by chromatography on Sepharose 6B.
  • Bolton-Hunter reagent was dissolved at 1 mg/ml in DMSO.
  • the amino-derivatized polymer was dissolved at 5 mg/ml in DMSO or DW containing 25 ⁇ l/ml DIEA.
  • a 3 ⁇ l aliquot of Bolton-Hunter was added to 20 ⁇ l of the polymer solution. The reaction was allowed to proceed for 3 hours. Unreacted Bolton-Hunter was extracted with DCM (5 x 100 ⁇ l) after addition of 50 ⁇ l water.
  • 125 I (1 ⁇ l) was added to the derivatized polymer, followed by the addition of 4 ⁇ l Chloramine-T dissolved @ 20 mg/ml in PBS. The reaction proceeded for 15 sees, at which time the radioactive polymer was purified on PD10 column which had been equilibrated with 2.5% AcOH.
  • Example 8 Alternative Method of Preparation of Hydroxypropyl methacrylamide (HPMA) 1 - Amino-2-propanol (58 g) was dissolved in acetonitrile (225 ml). The solution was cooled to -10 °C using an ethanol/dry ice bath. Methacryloyl chloride (40 g) in acetonitrile (170 ml) was added dropwise with vigorous stirring from a pressure equalising dropping funnel. The mixture was then allowed to warm slowly to room temperature overnight. The hydrochloride salt of l-amino-2-propanol was removed by filtration through Celite filter aid. The solvent was removed at reduced pressure with a bath temperature of 50 °C. The product was isolated by dissolving in methanol and precipitation using acetone. The product was then dissolved in DW and dialysed extensively against DW.
  • HPMA Hydroxypropyl methacrylamide
  • HPMA (4.0 g) was dissolved in DMSO (100 ml). A 1.5 ml aliquot of DIEA was added followed by 1.26 g of solid CDI (l,l'-carbonyldiimidazole). The HPMA was activated for 45 min, whereupon an excess of 1 ,6-diaminohexane (4.0 g) was added. The reaction proceeded for 2 h, at which time the product was dialysed to remove unreacted amines. The final product was lyophilised.
  • CMC low viscosity
  • NHS 150 mg dissolved @ 100 mg/ml in acetone
  • 300 mg dry ED AC 300 mg dry ED AC
  • the CMC was reacted for 15 minutes, whereupon 5 ml 1 M diaminohexane pH 9.5 was added and allowed to react O/WE.
  • the product was dialysed exhaustively against DW. The product was then filter sterilised.
  • Example 12 Preparation of methotrexate-GFLG-HPMA-Folate Methotrexate-GFLG-OH (FW 828, 36 mg, 3 x folate) was dissolved in DMSO (5 ml). DIEA (20 ⁇ L) was added, followed by TSTU (35 mg). The methotrexate was activated for 10 min. The polymer (100 mg) (Aminohexyl-HPMA or FA-hexyl- HPMA) dissolved in DMSO (15 ml) was added to the activated Drug-GFLG-acid solution and reacted 60 min. The product was dialysed extensively to ensure removal of unreacted acid and lyophilised.
  • Methotrexate-GFLG-OH (FW 828, 36 mg, 3 x folate) was dissolved in DMSO (5 ml). DIEA (20 ⁇ L) was added, followed by TSTU (35 mg). The methotrexate was activated for 10 min. The polymer (100 mg) (Aminohexyl-CMC or FA-hexyl-CMC) dissolved in DMSO (15 ml) was added to the activated Drug-GFLG-acid solution and reacted 60 min. The product was dialysed extensively to ensure removal of unreacted acid and lyophilised.
  • Chlorambucil-GFLG-OH (FW 678, 29 mg, 3 x folate) was dissolved in DMSO (5 ml). DIEA (20 ⁇ L) was added, followed by TSTU (35 mg). The chlorambucil was activated for 10 min. The polymer (100 mg) (Aminohexyl-HPMA or FA-hexyl- HPMA) dissolved in DMSO (15 ml) was added to the activated Drug-GFLG-acid solution and reacted 60 min. The product was dialysed extensively to ensure removal of unreacted acid and lyophilised.
  • Chlorambucil-GFLG-OH (FW 678, 29 mg, 3 x folate) was dissolved in DMSO (5 ml). DIEA (20 ⁇ L) was added, followed by TSTU (35 mg). The chlorambucil was activated for 10 min. The polymer (100 mg) (Aminohexyl-CMC or FA-hexyl-CMC) dissolved in DMSO (15 ml) was added to the activated Drug-GFLG-acid solution and reacted 60 min. The product was dialysed extensively to ensure removal of unreacted acid and lyophilised.
  • Example 17 Preparation of Daunomycin-GLFG-HPMA-folate HPMA-hexylaminosuccinic acid (35 mg) was dissolved in DMSO (2.0 ml). TSTU (18 mg) was added and activated for 10 min. H N-GFLG-Daunomycin (FW 938, 3 x folate, 4.4 mg) was added and allowed to react for 5 min. For targeted polymers 6- aminohexyl FA (3 mg, designed to give 20% loading) was added and reacted for 1 h. The product was dialysed to remove unconjugated reagents. The final product was concentrated using an AMICON positive pressure stirred cell with 1 OK membrane.
  • MTX-GFLG-OH (FW 828, 25 mg) was dissolved in DMSO (2 ml). TEA (5 ⁇ l) was added, followed by TSTU (15 mg, 1.2 equiv.). The reaction was allowed to proceed for 10 min, after which 13 mg MLP Polymer dissolved in DMSO (0.5 ml) was added and reacted for 60 min.
  • TSTU 15 mg, 1.2 equiv.
  • folate substituted-polymers were substituted with 125 I-labelled Bolton- Hunter reagent. Control polymers were prepared without folate.
  • Balb/C mice were injected subcutaneously with 2x10 6 hybridoma tumour cells. Two weeks after tumour injection, the radio-iodinated polymers were injected intravenously into the mice. At various time-points the mice were bled from the retro- orbital plexus, euthanased and their tissues removed for determination of radioactivity. Data is presented as the percentage of injected counts that were injected in the mice.
  • the data shows that the level of polymer uptake by liver and tumour cells can be enhanced by folate derivatization of the polymers.
  • the present invention provides a simple and novel technique for the amplification of the folate uptake system thus enabling the amplified delivery of a wide range of active agents to tumor and cancer cells in particular.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Materials Engineering (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Dermatology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'administration de médicaments, de produits pharmaceutiques à base de peptides et de protéines à l'aide du système d'absorption induit par les folates. Plus particulièrement, l'invention a pour objet l'amplification de l'administration de médicaments/produits pharmaceutiques, le système d'absorption des folates utilisant un complexe folate-polymère. L'invention a également pour objet des procédés de préparation des complexes, des compositions pharmaceutiques à base de ces derniers, des procédés de traitement impliquant les complexes et l'utilisation de ces complexes dans la fabrication de médicaments.
PCT/AU2000/000406 1999-05-04 2000-05-04 Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres WO2000066091A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU40943/00A AU4094300A (en) 1999-05-04 2000-05-04 Amplification of folate-mediated targeting to tumor cells using polymers
JP2000614977A JP2002543111A (ja) 1999-05-04 2000-05-04 ポリマーを使用する葉酸で仲介された腫瘍細胞へのターゲッティングの増幅
CA002372841A CA2372841A1 (fr) 1999-05-04 2000-05-04 Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres
EP00920286A EP1206252A4 (fr) 1999-05-04 2000-05-04 Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPQ0147A AUPQ014799A0 (en) 1999-05-04 1999-05-04 Amplification of folate-mediated targeting to tumor cells using polymers
AUPQ0147 1999-05-04

Publications (1)

Publication Number Publication Date
WO2000066091A1 true WO2000066091A1 (fr) 2000-11-09

Family

ID=3814354

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2000/000406 WO2000066091A1 (fr) 1999-05-04 2000-05-04 Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres

Country Status (5)

Country Link
EP (1) EP1206252A4 (fr)
JP (1) JP2002543111A (fr)
AU (2) AUPQ014799A0 (fr)
CA (1) CA2372841A1 (fr)
WO (1) WO2000066091A1 (fr)

Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1504010A1 (fr) * 2002-05-15 2005-02-09 Endocyte, Inc. Conjugues vitamine-mitomycine
JP2005523878A (ja) * 2001-09-28 2005-08-11 パーデュー・リサーチ・ファウンデーション リガンド・免疫原物質複合体を用いた処置方法
EP1578450A1 (fr) * 2002-11-21 2005-09-28 Access Pharmaceuticals Australia Pty Ltd Amplification du ciblage medie par la biotine
EP1592457A2 (fr) * 2003-01-27 2005-11-09 Endocyte, Inc. Conjugues de delivrance de medicaments de liaison au recepteur de vitamines
WO2006060044A1 (fr) * 2004-08-02 2006-06-08 Allergan, Inc. Composes de toxine presentant des caracteristiques ameliorees de translocation membranaire
WO2007080114A2 (fr) * 2006-01-11 2007-07-19 Biotech Igg Ab Conjugué de macromolecule
WO2007022494A3 (fr) * 2005-08-19 2007-09-07 Endocyte Inc Conjugues de ligand multi medicament
WO2007140298A1 (fr) * 2006-05-25 2007-12-06 Bristol-Myers Squibb Company Conjugués d'analogues d'aziridinyl-épothilone et compositions pharmaceutiques les incluant
WO2009133545A2 (fr) * 2008-04-30 2009-11-05 Ben Gurion University Of The Negev Research And Development Authority Systèmes d’administration vasculaire
US20100104626A1 (en) * 2007-02-16 2010-04-29 Endocyte, Inc. Methods and compositions for treating and diagnosing kidney disease
EP2210616A1 (fr) * 2009-01-21 2010-07-28 Centre National de la Recherche Scientifique Nanoparticules furtives polyvalentes pour une utilisation biomédicale
US7872145B2 (en) 2006-05-25 2011-01-18 Bristol-Mysers Squibb Company Aziridinyl-epothilone compounds
EP2349274A1 (fr) * 2008-09-17 2011-08-03 Endocyte, Inc. Conjugués d'antifolates liant le récepteur de folate
US8143415B2 (en) 2007-05-25 2012-03-27 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
US20120253021A1 (en) * 2011-03-29 2012-10-04 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US8846110B2 (en) 2009-10-13 2014-09-30 Rexahn Pharmaceuticals, Inc. Polymeric systems for the delivery of anticancer drugs
US8933205B2 (en) 2005-08-24 2015-01-13 Immunogen, Inc. Process for preparing purified drug conjugates
US9090563B2 (en) 2004-07-23 2015-07-28 Endocyte, Inc. Bivalent linkers and conjugates thereof
US9138484B2 (en) 2007-06-25 2015-09-22 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US9187521B2 (en) 2007-10-25 2015-11-17 Endocyte, Inc. Tubulysins and processes for preparing
US9376500B2 (en) 2009-06-03 2016-06-28 Immunogen, Inc. Conjugation methods
CN105849568A (zh) * 2013-11-14 2016-08-10 恩多塞特公司 用于正电子发射断层术的化合物
US9434610B2 (en) 2008-10-07 2016-09-06 Rexahn Pharmaceuticals, Inc. HPMA—docetaxel conjugates and uses therefore
US9505747B2 (en) 2012-03-29 2016-11-29 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
US9555139B2 (en) 2007-03-14 2017-01-31 Endocyte, Inc. Binding ligand linked drug delivery conjugates of tubulysins
CN106619571A (zh) * 2017-01-03 2017-05-10 西南交通大学 一种提高细胞内吞和细胞核靶向的聚合物纳米载体及其制备方法
US9662402B2 (en) 2012-10-16 2017-05-30 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
US10035817B2 (en) 2012-10-04 2018-07-31 Immunogen, Inc. Method of purifying cell-binding agent-cytotoxic agent conjugates with a PVDF membrane
US10046054B2 (en) 2007-08-17 2018-08-14 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US10111966B2 (en) 2016-06-17 2018-10-30 Magenta Therapeutics, Inc. Methods for the depletion of CD117+ cells
US10398791B2 (en) 2013-10-18 2019-09-03 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US10434185B2 (en) 2017-01-20 2019-10-08 Magenta Therapeutics, Inc. Compositions and methods for the depletion of CD137+ cells
US10557128B2 (en) 2010-02-25 2020-02-11 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10898596B2 (en) 2015-01-07 2021-01-26 Endocyte, Inc. Conjugates for imaging
US10912840B2 (en) 2012-11-15 2021-02-09 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
CN112533640A (zh) * 2018-05-04 2021-03-19 双亥生命科学株式会社 利用基于蜂毒肽的细胞凋亡诱导肽的m2型肿瘤相关巨噬细胞的靶向

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE427948T1 (de) 2001-04-24 2009-04-15 Purdue Research Foundation Folat-mimetika und deren folatrezeptorbindende konjugate
JP5289935B2 (ja) 2005-03-16 2013-09-11 エンドサイト，インコーポレイテッド プテロイン酸およびその結合体の合成と精製
US20080279782A1 (en) * 2007-05-09 2008-11-13 Nitto Denko Corporation Polymers conjugated with platinum drugs
CA3095644A1 (fr) * 2018-03-29 2019-10-03 Nof Corporation Conjugue de polyethylene glycol degradable
CN112608398B (zh) * 2020-11-30 2022-04-22 西安交通大学 一种共载阿霉素和铂类药物的还原/pH敏感型多糖基纳米前药及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010038A1 (fr) * 1994-09-28 1996-04-04 Apollon, Inc. Complexes moleculaires multifonctionnels pour transfert de genes vers des cellules
WO1997025067A2 (fr) * 1996-01-06 1997-07-17 Danbiosyst Uk Limited Polymeres

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2044663A1 (fr) * 1990-07-12 1992-01-13 Makoto Tanaka Complexes antifongiques a base de polyene hydrodispersable
US5449720A (en) * 1993-05-24 1995-09-12 Biotech Australia Pty Limited Amplification of the VB12 uptake system using polymers
TW520297B (en) * 1996-10-11 2003-02-11 Sequus Pharm Inc Fusogenic liposome composition and method
WO2000035422A2 (fr) * 1998-12-18 2000-06-22 Hadasit Medical Research Services & Development Ltd. Procede d'administration d'un compose a des cellules resistant a plusieurs medicaments

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996010038A1 (fr) * 1994-09-28 1996-04-04 Apollon, Inc. Complexes moleculaires multifonctionnels pour transfert de genes vers des cellules
WO1997025067A2 (fr) * 1996-01-06 1997-07-17 Danbiosyst Uk Limited Polymeres

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GINOBBI P. ET AL.: "Folic acid-polylysine carrier improves efficacy of c-myc antisense oligodeoxynucleotides on human melanoma (M14) cells", ANTICANCER RESEARCH, vol. 17, 1997, pages 29 - 36, XP002954079 *
See also references of EP1206252A4 *
WEINER E.C. ET AL.: "Targeting dendrimer-chelates to tumors and tumor cells expressing the high-affinity folate receptor", INVESTIGATIVE RADIOLOGY, vol. 32, no. 12, December 1997 (1997-12-01), pages 748 - 754, XP002954080 *

Cited By (98)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005523878A (ja) * 2001-09-28 2005-08-11 パーデュー・リサーチ・ファウンデーション リガンド・免疫原物質複合体を用いた処置方法
EP2060272A3 (fr) * 2002-05-15 2009-05-27 Endocyte, Inc. Conjugués vitamine-mitomycine
EP1504010A1 (fr) * 2002-05-15 2005-02-09 Endocyte, Inc. Conjugues vitamine-mitomycine
EP1504010A4 (fr) * 2002-05-15 2007-03-28 Endocyte Inc Conjugues vitamine-mitomycine
EP1578450A1 (fr) * 2002-11-21 2005-09-28 Access Pharmaceuticals Australia Pty Ltd Amplification du ciblage medie par la biotine
EP1578450A4 (fr) * 2002-11-21 2009-06-17 Access Pharmaceuticals Austral Amplification du ciblage medie par la biotine
EP1592457A2 (fr) * 2003-01-27 2005-11-09 Endocyte, Inc. Conjugues de delivrance de medicaments de liaison au recepteur de vitamines
EP1592457A4 (fr) * 2003-01-27 2010-09-08 Endocyte Inc Conjugues de delivrance de medicaments de liaison au recepteur de vitamines
EP2517729A3 (fr) * 2003-01-27 2013-01-02 Endocyte, Inc. Conjugués d'administration de médicaments à liaison au récepteur de vitamines
EP2529758A3 (fr) * 2003-01-27 2013-01-02 Endocyte, Inc. Conjugués d'administration de médicaments à liaison au récepteur de vitamines
US9550734B2 (en) 2004-07-23 2017-01-24 Endocyte, Inc. Bivalent linkers and conjugates thereof
US9090563B2 (en) 2004-07-23 2015-07-28 Endocyte, Inc. Bivalent linkers and conjugates thereof
US10647676B2 (en) 2004-07-23 2020-05-12 Endocyte, Inc. Bivalent linkers and conjugates thereof
WO2006060044A1 (fr) * 2004-08-02 2006-06-08 Allergan, Inc. Composes de toxine presentant des caracteristiques ameliorees de translocation membranaire
RU2470668C2 (ru) * 2005-08-19 2012-12-27 Эндосайт, Инк. Конъюгаты лиганда с несколькими лекарственными средствами
EP2374480A3 (fr) * 2005-08-19 2013-05-01 Endocyte, Inc. Conjugués de ligands multi-médicaments
WO2007022494A3 (fr) * 2005-08-19 2007-09-07 Endocyte Inc Conjugues de ligand multi medicament
CN103893778A (zh) * 2005-08-19 2014-07-02 恩多塞特公司 多药物配体缀合物
US9789204B2 (en) 2005-08-24 2017-10-17 Immunogen, Inc. Process for preparing purified drug conjugates
US11471536B2 (en) 2005-08-24 2022-10-18 Immunogen, Inc. Process for preparing purified drug conjugates
US8933205B2 (en) 2005-08-24 2015-01-13 Immunogen, Inc. Process for preparing purified drug conjugates
WO2007080114A3 (fr) * 2006-01-11 2008-03-27 Biotech Igg Ab Conjugué de macromolecule
WO2007080114A2 (fr) * 2006-01-11 2007-07-19 Biotech Igg Ab Conjugué de macromolecule
USRE42930E1 (en) 2006-05-25 2011-11-15 Bristol-Myers Squibb Company Aziridinyl-epothilone compounds
WO2007140298A1 (fr) * 2006-05-25 2007-12-06 Bristol-Myers Squibb Company Conjugués d'analogues d'aziridinyl-épothilone et compositions pharmaceutiques les incluant
US7872145B2 (en) 2006-05-25 2011-01-18 Bristol-Mysers Squibb Company Aziridinyl-epothilone compounds
US20100104626A1 (en) * 2007-02-16 2010-04-29 Endocyte, Inc. Methods and compositions for treating and diagnosing kidney disease
US9555139B2 (en) 2007-03-14 2017-01-31 Endocyte, Inc. Binding ligand linked drug delivery conjugates of tubulysins
US8299266B2 (en) 2007-05-25 2012-10-30 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
US8143415B2 (en) 2007-05-25 2012-03-27 Bristol-Myers Squibb Company Processes for making epothilone compounds and analogs
US10738086B2 (en) 2007-06-25 2020-08-11 Endocyte Inc. Conjugates containing hydrophilic spacer linkers
US9877965B2 (en) 2007-06-25 2018-01-30 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
US9138484B2 (en) 2007-06-25 2015-09-22 Endocyte, Inc. Conjugates containing hydrophilic spacer linkers
US10500204B2 (en) 2007-06-25 2019-12-10 Endocyte, Inc. Vitamin receptor drug delivery conjugates for treating inflammation
US10624969B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11083710B2 (en) 2007-08-17 2021-08-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10517956B2 (en) 2007-08-17 2019-12-31 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11717514B2 (en) 2007-08-17 2023-08-08 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10517957B2 (en) 2007-08-17 2019-12-31 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10485878B2 (en) 2007-08-17 2019-11-26 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624970B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10624971B2 (en) 2007-08-17 2020-04-21 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11369590B2 (en) 2007-08-17 2022-06-28 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11318121B2 (en) 2007-08-17 2022-05-03 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10406240B2 (en) 2007-08-17 2019-09-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US11298341B2 (en) 2007-08-17 2022-04-12 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10646581B2 (en) 2007-08-17 2020-05-12 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10046054B2 (en) 2007-08-17 2018-08-14 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10828282B2 (en) 2007-08-17 2020-11-10 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US9187521B2 (en) 2007-10-25 2015-11-17 Endocyte, Inc. Tubulysins and processes for preparing
US9745341B2 (en) 2007-10-25 2017-08-29 Endocyte, Inc. Tubulysins and processes for preparing
WO2009133545A3 (fr) * 2008-04-30 2010-12-02 Ben Gurion University Of The Negev Research And Development Authority Systèmes d’administration vasculaire
WO2009133545A2 (fr) * 2008-04-30 2009-11-05 Ben Gurion University Of The Negev Research And Development Authority Systèmes d’administration vasculaire
EP2349274A4 (fr) * 2008-09-17 2014-12-17 Endocyte Inc Conjugués d'antifolates liant le récepteur de folate
EP2349274A1 (fr) * 2008-09-17 2011-08-03 Endocyte, Inc. Conjugués d'antifolates liant le récepteur de folate
US10363250B2 (en) 2008-09-17 2019-07-30 Endocyte, Inc. Folate receptor binding conjugates of antifolates
US11219622B2 (en) 2008-09-17 2022-01-11 Endocyte, Inc. Folate receptor binding conjugates of antifolates
US9434610B2 (en) 2008-10-07 2016-09-06 Rexahn Pharmaceuticals, Inc. HPMA—docetaxel conjugates and uses therefore
EP2210616A1 (fr) * 2009-01-21 2010-07-28 Centre National de la Recherche Scientifique Nanoparticules furtives polyvalentes pour une utilisation biomédicale
WO2010084157A3 (fr) * 2009-01-21 2010-11-04 Centre National De La Recherche Scientifique (Cnrs) Nanoparticules furtives multifonctionnelles pour usage biomédical
US10815309B2 (en) 2009-06-03 2020-10-27 Immunogen, Inc. Methods for preparing antibody-drug conjugates
US10233257B2 (en) 2009-06-03 2019-03-19 Immunogen, Inc. Methods for preparing antibody-drug conjugates
US11498979B2 (en) 2009-06-03 2022-11-15 Immunogen, Inc. Methods for preparing a purified maytansinoid conjugate in a solution
US9771432B2 (en) 2009-06-03 2017-09-26 Immunogen, Inc. Conjugation methods
US9376500B2 (en) 2009-06-03 2016-06-28 Immunogen, Inc. Conjugation methods
US8846110B2 (en) 2009-10-13 2014-09-30 Rexahn Pharmaceuticals, Inc. Polymeric systems for the delivery of anticancer drugs
US11155800B2 (en) 2010-02-25 2021-10-26 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US10557128B2 (en) 2010-02-25 2020-02-11 Purdue Research Foundation PSMA binding ligand-linker conjugates and methods for using
US20120253021A1 (en) * 2011-03-29 2012-10-04 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US9914748B2 (en) 2011-03-29 2018-03-13 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
AU2020217301B2 (en) * 2011-03-29 2023-10-19 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US11744900B2 (en) 2011-03-29 2023-09-05 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US10435432B2 (en) 2011-03-29 2019-10-08 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
AU2012236398B2 (en) * 2011-03-29 2016-02-11 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US9428543B2 (en) * 2011-03-29 2016-08-30 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US20140309406A1 (en) * 2011-03-29 2014-10-16 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US8795673B2 (en) * 2011-03-29 2014-08-05 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US11090390B2 (en) 2011-03-29 2021-08-17 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
AU2016202832B2 (en) * 2011-03-29 2018-05-10 Immunogen, Inc. Preparation of maytansinoid antibody conjugates by a one-step process
US10765756B2 (en) 2012-02-24 2020-09-08 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US10080805B2 (en) 2012-02-24 2018-09-25 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US11344623B2 (en) 2012-02-24 2022-05-31 Purdue Research Foundation Cholecystokinin B receptor targeting for imaging and therapy
US9505747B2 (en) 2012-03-29 2016-11-29 Endocyte, Inc. Processes for preparing tubulysin derivatives and conjugates thereof
US10035817B2 (en) 2012-10-04 2018-07-31 Immunogen, Inc. Method of purifying cell-binding agent-cytotoxic agent conjugates with a PVDF membrane
US9662402B2 (en) 2012-10-16 2017-05-30 Endocyte, Inc. Drug delivery conjugates containing unnatural amino acids and methods for using
US10912840B2 (en) 2012-11-15 2021-02-09 Endocyte, Inc. Conjugates for treating diseases caused by PSMA expressing cells
US10471160B2 (en) 2013-10-18 2019-11-12 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
US11951190B2 (en) 2013-10-18 2024-04-09 Novartis Ag Use of labeled inhibitors of prostate specific membrane antigen (PSMA), as agents for the treatment of prostate cancer
US11045564B2 (en) 2013-10-18 2021-06-29 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA) as agents for the treatment of prostate cancer
US11931430B2 (en) 2013-10-18 2024-03-19 Novartis Ag Labeled inhibitors of prostate specific membrane antigen (PSMA) as agents for the treatment of prostate cancer
US10398791B2 (en) 2013-10-18 2019-09-03 Deutsches Krebsforschungszentrum Labeled inhibitors of prostate specific membrane antigen (PSMA), their use as imaging agents and pharmaceutical agents for the treatment of prostate cancer
CN105849568A (zh) * 2013-11-14 2016-08-10 恩多塞特公司 用于正电子发射断层术的化合物
US10898596B2 (en) 2015-01-07 2021-01-26 Endocyte, Inc. Conjugates for imaging
US10111966B2 (en) 2016-06-17 2018-10-30 Magenta Therapeutics, Inc. Methods for the depletion of CD117+ cells
CN106619571A (zh) * 2017-01-03 2017-05-10 西南交通大学 一种提高细胞内吞和细胞核靶向的聚合物纳米载体及其制备方法
US10434185B2 (en) 2017-01-20 2019-10-08 Magenta Therapeutics, Inc. Compositions and methods for the depletion of CD137+ cells
US10576161B2 (en) 2017-01-20 2020-03-03 Magenta Therapeutics, Inc. Compositions and methods for the depletion of CD137+ cells
CN112533640A (zh) * 2018-05-04 2021-03-19 双亥生命科学株式会社 利用基于蜂毒肽的细胞凋亡诱导肽的m2型肿瘤相关巨噬细胞的靶向

Also Published As

Publication number Publication date
AUPQ014799A0 (en) 1999-05-27
EP1206252A1 (fr) 2002-05-22
AU4094300A (en) 2000-11-17
JP2002543111A (ja) 2002-12-17
EP1206252A4 (fr) 2005-02-16
CA2372841A1 (fr) 2000-11-09

Similar Documents

Publication Publication Date Title
EP1206252A1 (fr) Amplification du ciblage des cellules tumorales, induit par les folates a l'aide de polymeres
AU723392B2 (en) Drug complex
WO2000074721A1 (fr) Vitamine pour therapie a double ciblage
AU723442B2 (en) Method for preparing drug complex
Ulbrich et al. Antibody-targeted polymer–doxorubicin conjugates with pH-controlled activation
US20060127310A1 (en) Amplification of biotin-mediated targeting
EP0640622B1 (fr) Derive de polysaccharide et vehicule de medicament
US7041818B2 (en) DDS compound and method for measurement thereof
JPH08510262A (ja) Ｇｃｓｆ及びｅｐｏ用ビタミンｂ▲下１▼▲下２▼介在経口デリバリーシステム
US20090306004A1 (en) Grafted macromolecular conjugates of doxorubicin with anticancer activity and method of their preparation
US7919076B2 (en) PH-sensitive polymeric conjugates of an anthracycline cancerostatic drug for targeted therapy
US20050220754A1 (en) Vitamin directed targeting therapy
JPH1192405A (ja) 薬物複合体
US20030103934A1 (en) Drugs having long-term retention in target tissue
JP2003504312A (ja) 生物学的に活性な材料
Chytil et al. Structural design and synthesis of polymer prodrugs
Hudecz et al. Drug targeting by macromolecules without recognition unit?
AU2004201277A1 (en) Amplification of folate-mediated targeting to tumor cells using polymers
JP5189243B2 (ja) 薬物複合体および薬物送達用担体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
ENP Entry into the national phase

Ref document number: 2000 614977

Country of ref document: JP

Kind code of ref document: A

Ref document number: 2372841

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2372841

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2000920286

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 2000920286

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 2000920286

Country of ref document: EP