WO2001036002A1 - Conjugues de copolymere hpma et d'ellipticine - Google Patents

Conjugues de copolymere hpma et d'ellipticine Download PDF

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WO2001036002A1
WO2001036002A1 PCT/US1999/027167 US9927167W WO0136002A1 WO 2001036002 A1 WO2001036002 A1 WO 2001036002A1 US 9927167 W US9927167 W US 9927167W WO 0136002 A1 WO0136002 A1 WO 0136002A1
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polymer
bioactive
group
heterocycle
ape
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PCT/US1999/027167
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English (en)
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Frances Searle
Stephanie Gac-Breton
Ruth Duncan
Stephen Brocchini
David Newman
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School Of Pharmacy, University Of London
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Priority to PCT/US1999/027167 priority Critical patent/WO2001036002A1/fr
Priority to AU18204/00A priority patent/AU1820400A/en
Publication of WO2001036002A1 publication Critical patent/WO2001036002A1/fr

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    • 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

Definitions

  • the present invention is concerned with drug targeting using polymer- bioactive conjugates, novel conjugates and the production thereof.
  • EPR enhanced permeability and retention
  • Polymer therapeutics are taken up into a cell by pinocytosis where the drug is liberated in the lysosome.
  • the lysosomal pH is 5.5 compared to 7.4 in circulating blood, and lysosomes contain a vast array of hydrolytic enzymes including proteases, esterases, glycosidases, phosphates and nucleases.
  • drugs have been conjugated to polymers using conjugation linkers that degrade in the lysosome while remaining intact in the bloodstream. Since many drugs are not pharmacologically active while conjugated to a polymer, this results in drastically reduced toxicity compared to the free drug in circulation.
  • the relatively harsh environment of the lysosome has thus inspired the development of conjugation linkers that degrade only in the lysosome to release the drug (“lysosomotropic drug delivery").
  • linkages have been used to covalently bind a drug to the polymeric carrier.
  • linkages include amide, ester, hydrazide, urethane, carbonate, imine, thioether, azo and carbon-carbon bonds.
  • peptidyl linkers designed to be stable in the bloodstream, but degradable by lysosomal enzymes and thus able to release the drug intracellularly, have been investigated.
  • Peptide linkers have been shown to mediate lysosomotropic drug delivery. It has become apparent that one of the methods of control of the rate and location of drug release from pendent chain polymers is favourably effected when a drug is bound to the polymer backbone via a peptidyl side- chain.
  • tetracyclic compounds have shown antitumour activity. Particularly promising compounds include ellipticine and derivatives thereof, 9-azaellipticines and derivatives thereof, pazellipticine, ditercalinium and intoplicine.
  • l o The alkaloid ellipticine below, 5, 11 -dimethyl-6H-pyrido(4,3- b)carbazole, is a potent cytotoxic agent whose mechanism of action has been attributed variously to direct intercalation into DNA, to modification of topoisomerase activity or to alkylation of cellular DNA or other macromolecules. Alkylation may be mediated through formation of the 9-
  • ester derivatives of the 9-hydroxy ellipticine derivatives are described.
  • the acyl moiety may be of an amino acid and hence include primary amine substituents.
  • ellipticine derivatives have alkylaminocarboxyl substituents at the 1 -carbon atom.
  • the alkyl group has an amine group substituent.
  • Such compounds include ditercalinium and intoplicine.
  • Intoplicine has an aminoalkyl amine substituent whilst ditercalinium is a pyridinium compound in which the quaternising alkyl group is substituted by a N-nitrogen heterocycle.
  • This invention comprises novel polymer and copolymer conjugates of a bioactive heterocyclic compound, the general structure of which is represented by the structure (I)
  • each of R 1 to R 9 are selected from the group consisting of QP, hydrogen, hydroxyl, -CONH 2l cyano amino, halogen, glycosyl, (di)alkyl amino, C 1-4 alkoxy, C ⁇ alkyl, - C 12 alkenyl, C 6 - C 30, aryl, C 7 - C 30 aralkyl, C 7 . 30 alkaryl, C 3 - C 30 cycloalkyl, C 2 ⁇ alkanoyloxy and C 7 .
  • aralkanoyloxy groups any of which alkyl or aryl groups may be unsubstituted or substituted with a group selected from the the group consisting of carboxy, amine (including (di)alkyl amino) acyl, acyloxy, acylamino, alkoxy, hydroxy;
  • R and R 2 or R 1 and R 3 may together with the carbon atoms to which they are joined form an aromatic 6-membered substituted or unsubstituted carbocyclic or heterocyclic ring or, if Y is carbon, R 6 and R 8 , or R 8 and R 9 may, together with the carbon atoms to which they are joined, form an aromatic carbocyclic or heterocyclic 6-membered ring, provided there is at least one 6 membered nitrogen-containing heteroaromatic ring in the molecule, and provided that one and only one of R 1 to R 9 is -QP, Q is a linker group and P is a polymer having a molecular weight in the range
  • the components of the polymeric backbone may comprise acrylic polymers, alkene polymers, urethane polymers, amide polymers, polyimines, polysaccharides and ester polymers.
  • the polymer is synthetic rather than being a natural polymer or derivative thereof.
  • the backbone components comprise derivatised polyethyleneglycol and poly(hydroxyalkyl(alk)acrylamide), most preferably amine derivatised polyethyleneglycol or hydroxypropyl(meth)acrylamide-methacrylic acid copolymer or derivative thereof.
  • a preferred molecular weight range is 15 to 40 kD.
  • R 4 , R 6 , R 9 , and R 7 are preferably selected from the group consisting of hydrogen, hydroxyl, and C, - C 12 alkyl, more preferably hydrogen, methyl, ethyl, propyl and butyl, most preferably hydrogen or methyl.
  • Y is carbon it is preferred for R 6 and R 7 each to be methyl
  • R 1 is preferably hydrogen, hydroxy or acyloxy (preferably C 2-6 -alkanoyloxy)
  • R 2 and R 3 are preferably hydrogen.
  • R s comprises a group selected from the group consisting of hydrogen, C C 6 alkyl but is most preferably QP.
  • the bioactive heterocycle utilised in the present invention may be attached to the polymeric backbone via any of the groups R 1 -R 9 i.e. any of R 1 to R 9 may represent QP.
  • the bioactive heterocycle is attached to the polymeric backbone via QP.
  • QP for example, may comprise a cleavable peptide linkage most preferably a peptide linkage capable of being cleaved by preselected cellular enzymes, for instance, those found in lysosomes of cancerous cells.
  • an acid hydrolysable linker could comprise an ester or amide linkage and be for instance, a cis-aconityl linkage.
  • the linker group may comprise a structure selected from the group consisting of
  • R 10 -R 12 are selected from the group consisting of, C,-C 12 alkanediyl, C 2 . 12 alkenylene and C 6 -C 18 arylene.
  • bioactive heterocycles of the present invention include the following structures, ( ⁇ )-(v):
  • R 13 -R 51 are selected from the respective groups listed above as being represented by R 1 .
  • a particularly preferred heterocycle has structure
  • R 18 and R 19 are preferably both methyl.
  • R 13 is preferably hydrogen, hydroxyl, alkoxy or alkanoyloxy.
  • R 14 , R 15 , R 16 , R 20 , R 21 , and R 22 are preferably each hydrogen, and R 17 is preferably QP as defined hereinbefore.
  • R 23 is preferably hydroxy or alkoxy, preferably methoxy.
  • R 24 to R 26 and R 28 to R 32 are preferably all hydrogen, R 27 is preferably QP.
  • R 36 is preferably hydrogen.
  • R 33 to R 35 , R 37 and R 39 to R 41 are preferably hydrogen.
  • R 38 is preferably hydrogen or substituted C 2-4 alkyl amino, for instance (N, N- dialkylamino)alkyl amino, such as 3-(N, N-dimethylamino)propylamino, and R 37 is preferably QP.
  • R 48 is preferably hydroxyl or C 1-4 alkoxy.
  • R 44 is preferably hydrogen or substituted C 2-4 alkyl amino, such as (3-N, N-dimethylamino)propyl amino.
  • R 45 is preferably QP.
  • the bioactive heterocycle utilised in the present invention is attached to the polymeric backbone via the 5-membered ring nitrogen of any of structures ( ⁇ )-(v), or by R 44 of structure (V) and R 3 or R 20 of structure (n), in other words preferably R 17 , R 27 , R 37 , R 45 , R 44 , R 13 , or R 20 is QP.
  • a further embodiment of the present invention provides a method of synthesis of a copolymer conjugate (I) by reacting a reactive polymer (vi)
  • R 70 comprises an amino group, an amino C ⁇ -alkyl group, a carboxylic group or a hydroxyl group or a mixture thereof.
  • U preferably comprises an activated leaving group such as p-nitrophenol, tosyl, I, Br and is most preferably joined to a terminal carbonyl group of L.
  • R 70 and LU react to form a peptide bond and displace U.
  • R 70 preferably is a primary or secondary amino group (where it is joined to a ring carbon) or an aminoalkyl group and LU is preferably a group -R 71 -COU.
  • Preferred leaving groups U are p-nitrophenyl or R 71 is a divalent group, preferably having at least 6 up to about 50 atoms in the chain between the bonds joining it to P and the carbonyl group. Most preferably R 71 is an oligopeptide group.
  • Suitable water-soluble reactive polymers (vi) having functional pendent moieties -LU of a suitable molar content are readily available and, for instance, are of the type used to form polymer therapeutics as described above.
  • HPMA copolymers with methacrylic acid with pendent oligopeptide groups joined via peptide bonds to the methacrylic acid with activated carboxylic terminal groups such as paranitrophenyl derivatives.
  • the heterocyclic compound of the formula (vn) is used in a suitable amount to give the desired degree of derivatisation of the polymer. Where 100% derivatisation is desired the heterocyclic compound is used in stoichiometnc amounts or higher for complete reaction of all -LU groups. Where less than complete derivatisation of those groups takes place, residual reactive groups -LU are generally blocked, after the reaction with heterocyclic compound, to deactivate the groups.
  • Blocking reagents suitability comprises the same group as the functional group of R 70 , ie., a primary or secondary amino group.
  • R 70 is an amino group
  • compounds in which R 70 is an aminoalkyl group have been desribed in EP-A- 0209511 , FR-A-2527209 and US-A-4310667, the substituent being on a ring nitrogen of the pyridinium ring
  • amino alkylaminocarbonyl substituents at the 1 -carbon atom are described in EP-A-0591058.
  • derivatives with primary amine groups available for reaction with activated carboxylic compounds P(R 71 COU)m are amino acid esters of 9- hydroxylated ellipticine.
  • linker preferably comprises at least one cleavable peptide bond.
  • linker is an enzyme cleavable oligopeptide group preferably comprising sufficient amino acid units to allow specific binding and cleavage by a selected cellular enzyme.
  • the linker is at least two amino acids long, more preferably at least three amino acids long.
  • a further embodiment of the invention is the provision of a method of selectively degrading a polymer-bioactive heterocycle conjugate as defined herein before, comprising the steps of: a) introducing the polymer-bioactive heterocycle conjugate to a lysosomal environment, b) cleaving said polymer.
  • Yet a further embodiment of the invention is the provision of method for releasing a bioactive heterocycle comprising the steps of a) introducing the polymer-bioactive heterocycle conjugate to a lysosomal environment, b) cleaving the bioactive agent from the polymer by acid or enzymic hydrolysis,
  • the present invention also envisages the production of compositions and pharmaceutical compositions comprising the polymer-heterocyclic bioactive agent conjugate of the present invention.
  • bioactive heterocyclic agents utilised in the present invention are (ix) and (x), shown below
  • R 52 is selected from the group consisting of hydrogen, hydroxy, C ⁇ alkoxy or C 2-12 acyloxy, most preferably hydrogen or hydroxy.
  • R 53 , R 56 , R 60 and R 57 are selected from the group consisting of hydrogen, alkylaminoalkane-1 , 2-diyl, dialkylaminoalkane-1 , 2-diyl, aminoalkane-1 , 2- diyl, alkoxy and hydroxy, preferably aminoalkane-1 , 2-diyl, most preferably aminoethyl, aminopropyl, aminobutyl, aminopentyl and aminohexyl.
  • R 54 , R 55 , R 58 and R 59 are selected from the group consisting of H, C, - C 12 alkyl, C 6 - C 12 aryl, C, - C 12 aralkyl, C 6 - C 12 cycloalkylene, preferably C, - C 6 alkyl, most preferably methyl.
  • heterocyclic group is 6-(aminoalkyl)-ellipticine, most preferably 6-(3- aminopropyl)-ellipticine (APE) shown below
  • the polymeric backbone comprises a hydroxyalkyl(alk)acrylamide methacrylamide copolymer, most preferably a copolymer of hydroxypropyl(meth)acrylamide copolymer (HPMA).
  • HPMA hydroxypropyl(meth)acrylamide copolymer
  • a can be in the range of 0.01 -100 and b can be in the range 0-99.99. a is preferably in the range of 0.04-20 and b is preferably in the range 80-99.96.
  • L is an oligopeptide group containing between 2 and 10 peptide moieties, most preferably 3 or 4.
  • the preferred embodiment L is a Gly-Phe-Leu-Gly- linkage.
  • U is an ONp group, wherein Np is a p- nitrophenyl group.
  • the HPMA copolymer GFLG-ONp polymer preferably has the structure (xn)
  • c and d are as defined for a and b above.
  • c is in the range 0.3 to 15 and d is in the range of 99.7 to 85.
  • heterocyclic bioactive agent conjugate may rely for its localisation at a solid tumour primarily upon EPR, it may be desirable to attach ligands allowing active targeting.
  • the conjugate of polymer and bioactive agent moiety preferably has a molecular weight in the range 100 D to 800 kD, more preferably in the range 15 kD to 40 kD.
  • 6-(3-aminopropyl)-ellipticine is linked to a copolymer via pendent, lysosomally labile peptide side-chains.
  • the bioactive agent is linked to the polymer using aminolysis of carboxyterminal p-nitrophenyl ester groups (Ulbrich et al., 1996 11 ).
  • the APE can be loaded in the required quantity, preferably in the range 10-100% of available peptide linker.
  • the unloaded linkers can be blocked using an agent such as 1-amino-2-propanol or further derivatized.
  • the preparation of the polymer-bioactive agent conjugate takes place via a 2 step process as shown in Scheme 1 below.
  • the initial step is the addition of APE.2HCI, in a specifically selected equivalence ratio, to a polymer having the structure (xn) as defined above. This results in a striclty defined proportion of the total available peptide linkers being loaded with APE.
  • the second step involves blocking or further derivatization of the remaining unloaded reactive pendent oligo peptide groups with 1-amino-2-propanol.
  • the N-C bond that is created when ONp is displaced is the bond that is cleaved by the cellular proteinases.
  • HPMA copolymer-aminopropylellipticine displays considerably increased solubility in aqueous solution compared to free drug, and obviates the hemolytic effects of low molecular weight ellipticine, believed to be due to charge-dependent association of the ellipticine with phospholipids in cell membranes, as determined for red cell ghosts (Lee, 1976 12 ).
  • the polymeric backbone comprises derivatised polyethyleneglycol, most formed preferably from amine derivatised polyethyleneglycol by reaction with amino acids or oligopeptide with reactive side chains.
  • the derivatised polyethyleneglycol comprises a structure comprising a repeating unit selected from the group consisting of
  • R 72 and R 73 , R 74 and R 75 , and R 76 and R 77 is a group LU as defined above and the remaining groups R 72 to R 77 are selected from, hydrogen, C, ⁇ alkyl, C ⁇ aryl, C 7 . 13 alkaryl and C 7 . 13 aralkyl groups, any of which may be unsubstituted or substituted by amine, hydroxyl, alkoxy, acyl, acyloxy, acylamino, aminocarbonyl, carboxylic, or oligopeptide groups.
  • Figure 1 is the HPLC profile of an HPMA-GFLG-APE conjugate after hydrolysis by HCI, (described in Example 5).
  • Figure 2 shows size exclusion chromatograms of HPMA-GFLG (A), HPMA-GFLG-APE (B) and methanol (C), as described in Example 6;
  • FIG 3 shows the results of Example 8, the key for which is
  • FIGS 4 and 5 show the result of Example 9.
  • the key to Figure 4 is as follows:
  • 6-(3-aminopropyl)-ellipticine, APE.2HCI was obtained from the National Cancer Institute, Washington, U.S. A and prepared by the following method: Ellipticine (xni) was treated with sodium hydride (NaH) (20% excess) and bromopropylphthalimide (20% excess) in dimethyl formamide containing 1 equivalent of hexamethylphosphoric triamide (HMPT) at room temperature for 6.5 hours. This afforded the phthalimidopropylellipticine derivative (xiv), m.p. 225-230° (yield 64%).
  • An analogous method can be used to produce the 9-methoxy-6-(3- aminopropyl)-ellipticine derivative.
  • HPMA-Gly-Phe-Leu-Gly-p-nitrophenol ester (5mol%) (1g) was dissolved with stirring in dry dimethyl formamide (25ml). 6-(3-aminopropyl)- ellipticine dichloride, APE.2HCI (84mg, 0.75 equivalent) was dissolved in dry dimethyl sulphoxide (17ml). For the 1 % pHPMA-GFLG-ONp the proportions of the starting polymer and APE were adapted appropriately. The solutions were mixed, a small aliquot of each (5-1 O ⁇ l) being retained for thin-layer chromatography.
  • a dilute solution of dry triethylamine in dry dimethyl formamide (1 :100 v.v, 9.3ml, 3:1 equivalents to APE.2HCI) was prepared for addition in aliquots (500 ⁇ l at 5min. intervals) to the reaction mixture. After each addition, with swirling, samples (10 ⁇ l) were taken into a 1ml cuvette containing Dulbecco's phosphate buffered saline (pH 7.0) and the initial absorbance at 400nm noted to follow the release of 4-nitrophenol (UV- Visible Spectrophotometer Shimadzu UV-1601 ). The reaction mixture, initially pale yellow, decolourises after the first six aliquots of triethylamine then progressively deepens to yellow colour.
  • Table 2 Amount of total APE (determined by UV at 295nm), amounts of free APE and ellipticine (determined by HPLC after extraction) present in HPMA copolymer-GG-APE
  • HPMA copolymer- GFLG-ONp (1 equivalent, calculated as 4-nitrophenyl ester) and APE.2HCI (2 equivalents) were dissolved in minimal volumes of dry dimethyl sulphoxide. Triethylamine (2 equivalents) was added to the copolymer solution to neutralise the hydrochlo de protons of the APE.2HCI solution which was added dropwise to the reaction mixture. Aminolysis was allowed to proceed for 5 hours.
  • Table 3 Amount of total APE (determined by UV at 295nm), amounts of free APE and ellipticine (determined by HPLC after extraction) present in HPMA copolymer-GFLG-APE (10 mol%)
  • HCI 6N 1ml of HCI 6N was added to 900 ⁇ l of a solution of HPMA copolymer- APE. The mixture was then incubated at 100°C during 3 hours, the HCI was then neutralised by adding 1ml of NaOH solution (6N) and 1.5ml of ammonium formate buffer (1M), and 100 ⁇ l of doxorubicin solution (0.3g/l, internal standard ) were added to this mixture.
  • HPMA copolymers-APE conjugates and for comparison the HPMA- GFLG precursor after hydrolysis of the ONp ester linkage, were analysed by size exclusion chromatography (SEC) performed using a system composed of two TSK-gel column in series (G3000 PW followed by G2000 PW) with a guard column (ProgelTM PWXL). The detection was achieved using a Refractometer (153 Refractive index detector Gilson) and a UV-visible detector (UV Savern Analytical SA6504) in series. The mobile phase used was a Tris buffer (Tris 0.05M, NaCI 0.5M) delivered at 1 ml/min by a pump (Jasco PU-980).
  • Figure 2 shows size exclusion chromatograms for the conjugates and polymer comparison, showing refractive index (Rl) (y axis) against time (x axis).
  • Example 7 Comparative solubilities of APE.2HCI and HPMA-Glv-Phe- Leu-Glv-APE (5mol%) in phosphate buffered saline.
  • Example 8 Degradation of HPMA copolvmers-APE bv tritosomes (Rat liver lysosomes)
  • Rat lysosomal enzymes, tritosomes were prepared according to the method described by Trouet (1974 14 ) and the protein content was determined using bicinchonninic acid assay, which consists of comparing the UV absorbance at 550nm of solutions of tritosomes at different concentrations containing bicinchonninic acid and copper sulfate with the absorbance of solutions of bovine serum albumin at different concentrations containing also bicinchonninic acid and copper sulfate. The protein content of the tritosomes was found to be 1.697mg/ml.
  • proteolytic activity was determined as the release of p-nitroaniiine from N- benzoyl-Phe-Val-Arg-p-Nitroanilide by the tritosomes (Trouet, 1974 14 ). Activity of the proteases was found to be 25 nM/min/mg protein. This test is 0 carried out to validate that an individual preparation contains appropriate enzymatic activity against a standard substrate.
  • FIG 3 shows the total amount of APE released against time from the conjugates HPMA-GG-APE (product of example 2) and HPMA-GFLG- APE (Examples 1.1.1 , 1.2.1 and 3).
  • the product of Example 1.1.1 contains 2.3 weight% of APE, and 2.6% of the total APE is free.
  • the results for APE release are based on the total APE detected, ie., including the inherent free APE. All these conjugates were incubated at 37°C either in the presence of tritosomes (WT) or without tritosomes (WOT) at a concentration of 46 ⁇ g/ml in APE.
  • WT tritosomes
  • WOT tritosomes
  • Example 1 The two HPMA copolymer-GFLG-APE conjugates which have different amount of spacer arms batch, Example 1.2.1 (5mol%) and Example 3 (10mol%) but which have the same total amount of APE bound, released APE at the same rate.
  • the conjugates release drug in relation to the the peptide spacer used and the amount of APE bound and the content of peptidyl side chains.
  • Example 9 Evaluation of the hemolytic properties of HPMA copolymer- APE. ellipticine and free APE
  • HPMA-GFLG-APE Product of Examples 1.1.1 and 1.2.1
  • HPMA-GG- APE Example 2
  • APE and ellipticine were incubated at 37°C with rat erythrocytes (final drug concentration between 5mg/ml to 1 ⁇ g/ml) for 1 and 24 hours.
  • the cell debris was then removed by centrifugation and the hemoglobin released through the red blood cell (RBC) lysis assessed by use of a micro-titre plate reader at 550nm. The readings are calculated as RBC lysis percent compared with total hemolysis by Triton X-100.
  • the results for ellipticine and APE are shown in Figure 4, whilst the results for the conjugates (and APE for comparison) are shown in Figure 5.

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Abstract

Cette invention se rapporte à des conjugués polymères et copolymères d'un composé hétérocyclique bioactif, dont la structure générale est représentée par la formule (I). Dans un mode de réalisation préféré, la 6-(3-aminopropyl)-ellipticine (APE) est liée à un copolymère par l'intermédiaire de chaînes latérales de peptides pendantes et labiles d'un point de vue lysosomique. L'agent bioactif est lié au polymère par aminolyse de groupes ester représentés par la formule (II) de p-nitrophényle à terminaison carboxy.
PCT/US1999/027167 1999-11-17 1999-11-17 Conjugues de copolymere hpma et d'ellipticine WO2001036002A1 (fr)

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AU18204/00A AU1820400A (en) 1999-11-17 1999-11-17 Conjugates of hpma copolymer and ellipticin

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
JP2005529870A (ja) * 2002-04-11 2005-10-06 チルドレンズ メディカル センター コーポレーション Ｔｎｐ−４７０ポリマー複合体及びその使用
US7332523B2 (en) 2002-04-11 2008-02-19 Children's Medical Center Corporation TNP-470 polymer conjugates and use thereof

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