WO1997036616A2 - Agent anti-tumoral - Google Patents

Agent anti-tumoral Download PDF

Info

Publication number
WO1997036616A2
WO1997036616A2 PCT/GB1997/000917 GB9700917W WO9736616A2 WO 1997036616 A2 WO1997036616 A2 WO 1997036616A2 GB 9700917 W GB9700917 W GB 9700917W WO 9736616 A2 WO9736616 A2 WO 9736616A2
Authority
WO
WIPO (PCT)
Prior art keywords
pdm
moiety
leu
gly
agent
Prior art date
Application number
PCT/GB1997/000917
Other languages
English (en)
Other versions
WO1997036616A3 (fr
Inventor
Leonard William Seymour
Etienne Honore Schacht
Heidi Soyez
Original Assignee
The University Of Birmingham
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 The University Of Birmingham filed Critical The University Of Birmingham
Priority to EP97915567A priority Critical patent/EP0891191A1/fr
Publication of WO1997036616A2 publication Critical patent/WO1997036616A2/fr
Publication of WO1997036616A3 publication Critical patent/WO1997036616A3/fr

Links

Classifications

    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers

Definitions

  • This invention relates to an anti-tumor agent and is more particularly concerned with an anti-tumor agent utilising an active alkylating moiety selected from the class of compounds referred to as "nitrogen mustards", for example N,N-di(2-chloroethyl)-4-phenylenediamine (hereinafter sometimes referred to as "PDM”) and active analogues thereof.
  • Nitrogen mustards are so called because of their ability to form cyclic onium salts in an analogous manner to the ability of mustard gas to form cyclic sulphonium salts. Nitrogen mustards have not previously found acceptability for use as anti-tumor agents because of their high systemic toxicity and short half-life.
  • an anti-tumor agent comprising a macromolecular carrier moiety; an active alkylating moiety which is a nitrogen mustard; and a stabilising moiety linking the active alkylating moiety with the carrier moiety, said stabilising moiety being an oligopeptide which is capable of being cleaved by a tumour-associated protease and which stabilises the active alkylating moiety by electron withdrawal and/or by inducing formation of aggregates.
  • the active alkylating moiety is stabilised so that, instead of having a free-form half- life of typically about 1 1 minutes, when linked to the stabilising and carrier moieties as in the present invention, it has a typical half-life of about 1 1 hours.
  • the stabilising moiety has been cleaved in use by the tumour-associated protease, the released alkylating moiety is very effective in killing the targeted tumor cells whilst degrading rapidly to reduce systemic toxicity.
  • the oligopeptide is preferably one which can be cleaved by a
  • the oligopeptide is preferably a tetra-, penta- or hexa-peptide, more preferably a tetra- or penta-peptide, and most preferably a tetra-peptide.
  • the peptides in the oligopeptide will be identified by reference to their positions relative to the active alkylating moiety, with the peptide nearest the active alkylating moiety being designated as peptide 1 , the adjacent peptide being designated as peptide 2, and so on.
  • Peptide 1 is preferably Leu, although Gly may be possible.
  • Peptide 2 is preferably Ala, particularly when peptide 1 is Leu, although Leu may be possible if peptide 1 is Gly.
  • Peptide 3 is preferably Phe or Leu, particularly when peptide 1 is Leu and peptide 2 is Ala; and most preferably petide 3 is Phe, particularly when peptide 1 is Leu and peptide 2 is Ala.
  • Peptide 4 is preferably Gly or Ala and most preferably is Gly.
  • oligopeptide terminates with, or consists of, the tetra-peptide, Gly-Phe-Ala-Leu, although it is considered that oligopeptides terminating with, or consisting of, the tetra-peptide Gly- Phe-Leu-Gly or Ala-Leu-Ala-Leu may be used.
  • the macromolecular carrier moiety is preferably hydrophilic and is most preferably a polymeric moiety such as poly-[N 5 -(2-hydroxyethyl)-L- glutamine] (PHEG) or any other per se known macromolecular moiety, for example as described in EP-A-0187547.
  • PHEG poly-[N 5 -(2-hydroxyethyl)-L- glutamine]
  • the active alkylating moiety is a nitrogen mustard, for example N,N-di(2- chloroethyl)-4-phenylenediamine (PDM) which may be produced using the following reaction scheme:-
  • the PDM may be replaced by any active analogous mustard, for example:-
  • R 1 and R 2 are independently selected from
  • the anti-tumor agent of the present invention can be produced by first coupling the nitrogen mustard with an oligopeptide in accordance with the reaction scheme below (given, by way of example, for PDM):-
  • R is an oligopeptide moiety as described above.
  • the resultant low molecular weight peptidyl-PDM derivative may then be coupled to a 4-n ⁇ trophenyl chloroformate activated poly-[N 5 -(2- hydroxyethyl)-L-glutam ⁇ ne] (PHEG) which can be produced in
  • poly-L-glutamic acid derivatives can be produced in a similar way using other aminoalkanols, eg aminopropanol, in place of the
  • the anti-tumor agent may be administered intravenously, intraperitoneally or intra-arterially.
  • Poly-[N 5 -(2-hydroxyethyl)-L-glutamine] (PHEG) was used in this Example as the macromolecular carrier because it is non toxic, non immunogenic and possesses primary hydroxyl side groups which can be easily converted into reactive carbonate esters by reaction with a
  • chloroformate-type compound eg 4-nitrophenyl chloroformate
  • this synthetic polyaminoacid is a good substrate for lysosomal enzymes, preventing unwanted accumulation of the polymer in the body.
  • glycine was used because this yields a water-soluble, low molecular weight Gly-PDM derivative.
  • Gly-Leu-Phe-PDM and Gly-Phe-Ala-leu PDM were also prepared.
  • amine-containing peptide-PDM moieties were coupled to the chloroformate activated carrier.
  • the hydrolytic stability of PDM, water-soluble Gly-PDM and the oligopeptide-PDM derivatives was investigated in buffers of lysosomal and physiological pH. Dynamic laser light scattering provided insight in the obtained results. Furthermore, the degradation in presence of tritosomes, cathepsin A and collagenase type IV was studied.
  • aminoacids and peptides were obtained from Bachem Chem Co. (Bubendorf Switzerland), 4-nitrophenyl chloroformate was obtained from Merck (Darmstadt, Germany).
  • Collagenase type IV was obtained from Sigma Chem. Co. (St. Louis, Missouri, U.S.A). All other chemicals were purchased from Acros (Beerse, Belgium).
  • N-carboxyan hydride was prepared by reaction of ⁇ -benzyl-L- glutamine with diphosgene in ethylacetate.
  • the NCA was crystallised twice from ethyl acetate/hexane.
  • Poly-( ⁇ -benzyl-L-glutamine) (PBLG) was prepared by polymerisation of the respective NCA in
  • PBLG was precipitated in excess methanol/ether (2/1 v/v), filtered and dried.
  • Aminolysis with 2-aminomethanol in presence of 2-hydroxypyridine as a catalyst was carried out in DMF.
  • PHEG was precipitated in excess ether/ethanol (4/1 v/v), filtered and dialyzed against water for 2 days. After freeze-drying, pure PHEG was obtained as a white powder.
  • 3 mg of PDM or Gly-PDM were dissolved in 40 ml of buffer and at regular times samples were withdrawn and analyzed using RP-HPLC (column: Zorbax ODS C18 4.6mm x 150 mm flow : 1 ml/min injection volume : 20 ⁇ l).
  • 0.51 mg Na 2 S 2 O 4 were simultaneously added to the incubation mixture to prevent oxidation of the mustard.
  • the percentage of hydrolysis of the mustard was calculated by comparing the area under the curve (AUC) at a certain time to the AUC at the start oi the reaction.
  • the retention times of PDM and Gly-PDM are 7.2 min, respectively 4.5 min.
  • Collagenase IV from Clostridium histolytcum was dissolved in phosphate buffered saline (PBS) to poduce concentrations of 4.5 mg/ml, 1 mg/ml and 0.1 mg/ml.
  • 1 mg PHEG-peptidylPDM conjugate was dissolved in 0.6 ml PBS, 0.4 ml of enzyme solution were added and the mixture was incubated at 37 °C.
  • MCF7 wt cells were suspended in a solution of RPMI-medium (5% Fetal Calf Serum and 1 % L-glutamine) after removal rom their flasks with trypsin.
  • the solution contained 10 4 cell/ml.
  • the cells were added to flat-bottomed 96-welled plates and incubated for 24 hours.
  • P-O-PDM PHEG-Gly-Phe-Ala-Leu-PDM
  • Test example 1 was repeated with the exception that C26 cells were used instead of MCF7 wt cells. The results obtained are shown in Fig. 6 and in Table 4 below.
  • Conditioned cell medium was prepared by collecting medium containing tumour-secreted proteases from A-375M cells ( containing approximately 750 x 10 4 cells in 10ml of DME-medium) after incubation of these cells in their flasks for 72 hours. This medium was used as such, without further dilution or purification.
  • PDM 4mg PDM were dissolved in 2 ml of distilled water and the solution was filtered. A 100 ⁇ M stock solution of PDM in DME-medium was made up and further diluted to 50, 10, 1 and 0.1 ⁇ M. After removal of the medium, 100 ⁇ l of each solution together with 100 ⁇ l of FCM or CCM were added to the wells, and the plates were incubated for 72 hours.
  • mice Female BALB/c mice (5-6 weeks old) were subcutaneously inoculated with 10 5 C26 murine colorectal carcinoma cells. When the tumours were palpable, groups of 5 animlas were treated in vivo on each of three consecutive days with either free PDM (2 or 5 mg/kg), P-O-PDM (2, 5 or 8 mg/kg related to the PDM component) or saline (as a control). The animals were weighed daily and tumour growth measured. Animals receiving free PDM (5 mg/kg) showed rapid weight loss and were put down after 4-6 days following treatment due to treatment-related toxicity. Animals treated with PDM (2 mg/kg) showed tumour growth identical with saline-treated control animals and they were put down after 10-12 days due to tumour burden.
  • P-O-PDM 8mg/kg (17 17, 18, 18, 18.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Agent anti-tumoral composé d'une partie porteuse macromoléculaire, d'une partie alkylante active, en l'occurence de la moutarde azotée, et d'une partie de stabilisation qui lie la partie alkylante à la partie porteuse. La partie de stabilisation est un oligopeptide pouvant être clivé par une protéase associée à la tumeur et qui stabilise la partie alkylante par retrait d'électrons et/ou en provoquant la formation d'agrégats.
PCT/GB1997/000917 1996-04-02 1997-04-01 Agent anti-tumoral WO1997036616A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP97915567A EP0891191A1 (fr) 1996-04-02 1997-04-01 Agent anti-tumoral

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9606975.2A GB9606975D0 (en) 1996-04-02 1996-04-02 Anti-tumor agent
GB9606975.2 1996-04-02

Publications (2)

Publication Number Publication Date
WO1997036616A2 true WO1997036616A2 (fr) 1997-10-09
WO1997036616A3 WO1997036616A3 (fr) 1997-11-06

Family

ID=10791505

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1997/000917 WO1997036616A2 (fr) 1996-04-02 1997-04-01 Agent anti-tumoral

Country Status (3)

Country Link
EP (1) EP0891191A1 (fr)
GB (1) GB9606975D0 (fr)
WO (1) WO1997036616A2 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078791A2 (fr) * 1999-06-17 2000-12-28 Universiteit Gent DERIVES FONCTIONNELS POLY-α-AMINO ACIDE UTILES POUR LA MODIFICATION DE MATIERES A ACTIVITE BIOLOGIQUE ET APPLICATION DE CES DERIVES
WO2001018548A2 (fr) * 1999-09-09 2001-03-15 Dade Behring Marburg Gmbh Groupes protecteurs pour marquage biologique
WO2002034237A1 (fr) * 2000-08-22 2002-05-02 New River Pharmaceuticals, Inc. Systemes de liberations d'agents actifs et procedes de protection et d'administration d'agents actifs
EP1490090A2 (fr) * 2002-02-22 2004-12-29 New River Pharmaceuticals Inc. Systemes de distribution d'agents actifs et methodes de protection et d'administration d'agents actifs
US7018654B2 (en) 1999-03-05 2006-03-28 New River Pharmaceuticals Inc. Pharmaceutical composition containing an active agent in an amino acid copolymer structure
US7060708B2 (en) 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US7338939B2 (en) 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
US7375082B2 (en) 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
US7375083B2 (en) 2003-09-30 2008-05-20 Shire Llc Pharmaceutical compositions for prevention of overdose or abuse
US7622441B2 (en) 2002-02-22 2009-11-24 Shire Llc Sustained release pharmaceutical compounds to prevent abuse of controlled substances

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106397102A (zh) * 2016-08-29 2017-02-15 山东同成医药股份有限公司 卤代烃产品及其密封保温增压式生产方法
CN106905191B (zh) * 2017-03-05 2019-03-29 北京化工大学 一种含有羟肟酸基团的氮芥类化合物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017471A (en) * 1975-09-15 1977-04-12 G. D. Searle & Co. Immunological compounds
EP0040506A2 (fr) * 1980-05-21 1981-11-25 Teijin Limited Polymère réactif et procédé pour sa préparation
EP0187547A2 (fr) * 1985-01-04 1986-07-16 Ceskoslovenska akademie ved Médicaments synthétiques polymères

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4017471A (en) * 1975-09-15 1977-04-12 G. D. Searle & Co. Immunological compounds
EP0040506A2 (fr) * 1980-05-21 1981-11-25 Teijin Limited Polymère réactif et procédé pour sa préparation
EP0187547A2 (fr) * 1985-01-04 1986-07-16 Ceskoslovenska akademie ved Médicaments synthétiques polymères

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 118, no. 24, 14 June 1993 Columbus, Ohio, US; abstract no. 240632, BRUNEEL, D. ET AL: "Polymeric prodrugs of melphalan with increased hydrolytic stability" XP002040095 & PROC. PROGRAM INT. SYMP. CONTROLLED RELEASE BIOACT. MATER., 18TH (1991), 333-4. EDITOR(S): KELLAWAY, IAN W. PUBLISHER: CONTROLLED RELEASE SOC., DEERFIELD, ILL. CODEN: 58GMAH, 1991, *
J. CONTROLLED RELEASE (1989), 10(1), 17-25 CODEN: JCREEC;ISSN: 0168-3659, 1989, XP002040093 PYTELA, J. ET AL: "Poly(N5-hydroxyalkylglutamines). IV. Enzymic degradation of N5-(2-hydroxyethyl)-L-glutamine homopolymers and copolymers" *
J. CONTROLLED RELEASE (1994), 31(1), 89-97 CODEN: JCREEC;ISSN: 0168-3659, 1994, XP000456583 MARRE, ANNE DE ET AL: "Evaluation of the hydrolytic and enzymic stability of macromolecular Mitomycin C derivatives" *
J. CONTROLLED RELEASE (1996), 39(1), 79-92 CODEN: JCREEC;ISSN: 0168-3659, 1996, XP002040091 NICHIFOR, MARIETA ET AL: "Macromolecular prodrugs of 5-fluorouracil. 2: Enzymic degradation" *
MAKROMOL. CHEM. (1992), 193(12), 3023-30 CODEN: MACEAK;ISSN: 0025-116X, 1992, XP000324000 DE MARRE, ANNE ET AL: "Preparation of 4-nitrophenyl carbonate esters of poly[5N-(2-hydroxyethyl)-L-glutamine] and coupling with bioactive agents" *

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7018654B2 (en) 1999-03-05 2006-03-28 New River Pharmaceuticals Inc. Pharmaceutical composition containing an active agent in an amino acid copolymer structure
US7060708B2 (en) 1999-03-10 2006-06-13 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
US7005123B1 (en) 1999-06-17 2006-02-28 Universiteit Gent Functional poly-α-amino-acid derivatives useful for the modification of biologically active materials and their application
WO2000078791A3 (fr) * 1999-06-17 2001-12-13 Univ Gent DERIVES FONCTIONNELS POLY-α-AMINO ACIDE UTILES POUR LA MODIFICATION DE MATIERES A ACTIVITE BIOLOGIQUE ET APPLICATION DE CES DERIVES
WO2000078791A2 (fr) * 1999-06-17 2000-12-28 Universiteit Gent DERIVES FONCTIONNELS POLY-α-AMINO ACIDE UTILES POUR LA MODIFICATION DE MATIERES A ACTIVITE BIOLOGIQUE ET APPLICATION DE CES DERIVES
WO2001018548A2 (fr) * 1999-09-09 2001-03-15 Dade Behring Marburg Gmbh Groupes protecteurs pour marquage biologique
WO2001018548A3 (fr) * 1999-09-09 2001-11-22 Dade Behring Inc Groupes protecteurs pour marquage biologique
US6783947B1 (en) 1999-09-09 2004-08-31 Dade Behring Marburg Gmbh Protecting groups for biological labeling
US6716452B1 (en) 2000-08-22 2004-04-06 New River Pharmaceuticals Inc. Active agent delivery systems and methods for protecting and administering active agents
WO2002034237A1 (fr) * 2000-08-22 2002-05-02 New River Pharmaceuticals, Inc. Systemes de liberations d'agents actifs et procedes de protection et d'administration d'agents actifs
US7427600B2 (en) 2000-08-22 2008-09-23 Shire Llc Active agent delivery systems and methods for protecting and administering active agents
EP2266590A2 (fr) 2002-02-22 2010-12-29 Shire LLC Système d'administration de substances actives et méthodes de protection et d'administration de substances actives
EP1490090A4 (fr) * 2002-02-22 2006-09-20 New River Pharmaceuticals Inc Systemes de distribution d'agents actifs et methodes de protection et d'administration d'agents actifs
US7375082B2 (en) 2002-02-22 2008-05-20 Shire Llc Abuse-resistant hydrocodone compounds
EP1490090A2 (fr) * 2002-02-22 2004-12-29 New River Pharmaceuticals Inc. Systemes de distribution d'agents actifs et methodes de protection et d'administration d'agents actifs
US7622441B2 (en) 2002-02-22 2009-11-24 Shire Llc Sustained release pharmaceutical compounds to prevent abuse of controlled substances
JP2005524677A (ja) * 2002-02-22 2005-08-18 ニュー リバー ファーマシューティカルズ インコーポレイテッド 活性物質送達系及び活性物質を保護し投与する方法
EP2266590A3 (fr) * 2002-02-22 2011-04-20 Shire LLC Système d'administration de substances actives et méthodes de protection et d'administration de substances actives
EP2316468A1 (fr) 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine
EP2316469A1 (fr) 2002-02-22 2011-05-04 Shire LLC Système de distribution et méthodes de protection et d'administration de dextroamphetamine
US7338939B2 (en) 2003-09-30 2008-03-04 New River Pharmaceuticals Inc. Abuse-resistant hydrocodone compounds
US7375083B2 (en) 2003-09-30 2008-05-20 Shire Llc Pharmaceutical compositions for prevention of overdose or abuse

Also Published As

Publication number Publication date
WO1997036616A3 (fr) 1997-11-06
EP0891191A1 (fr) 1999-01-20
GB9606975D0 (en) 1996-06-05

Similar Documents

Publication Publication Date Title
US5853713A (en) Biologically compatible linear block copolymers of polyalkylene oxide and peptide units
EP0187547B1 (fr) Médicaments synthétiques polymères
EP2052011B1 (fr) Agent ciblé thérapeutique dendrimère de polylysine
US7893023B2 (en) Prodrugs activated by plasmin and their use in cancer chemotherapy
RU2149646C1 (ru) Полимерный конъюгат, фармацевтическая композиция
Subr et al. Polymers containing enzymatically degradable bonds, XII. Effect of spacer structure on the rate of release of daunomycin and adriamycin from poly [N-(2-hydroxypropyl)-methacrylamide] copolymer drag carriers in vitro and antitumour activity measured in vivo
US9289510B2 (en) Polymeric drug delivery conjugates and methods of making and using thereof
Przybylski et al. Pharmacologically active polymers, 17. Syntheses and characterization of polymeric derivatives of the antitumor agent methotrexate
WO2000069472A2 (fr) Composes de promedicaments anti-tumoraux actives par des enzymes
EP0961619A1 (fr) Promedicaments hydrolysables pour la liberation de medicaments anticancereux dans des cellules metastatiques
WO1997036616A2 (fr) Agent anti-tumoral
US20110160147A1 (en) Novel dual targeting antitumoral conjugates
CA2333321A1 (fr) Complexe medicamenteux
Li et al. A stimuli-responsive Janus peptide dendron–drug conjugate as a safe and nanoscale drug delivery vehicle for breast cancer therapy
EP1753776B1 (fr) Camptothecines conjuguees en position 7 avec des peptides cycliques utilisees comme agents cytostatiques
JPH09501674A (ja) ミトマイシンを組み込む薬配達薬剤
US6376617B1 (en) Bioactive derivatives of camptothecin
JP2004504358A (ja) 抗腫瘍薬のポリマー複合体
US11319341B2 (en) Immune-stimulating soluble doxorubicin-conjugated complex
De Marre et al. Synthesis of macromolecular Mitomycin C derivatives
Nichifor et al. Macromolecular prodrugs of 5-fluorouracil. 1: Synthesis and hydrolytic stability
Ohya et al. Synthesis of 6‐O‐carboxymethylchitin immobilizing doxorubicins through tetrapeptide spacer groups and its enzymatic release behavior of doxorubicin in vitro
Soyez et al. Macromolecular derivatives of N, N-di-(2-chloroethyl)-4-phenylenediamine mustard. 1. Synthesis and in vitro hydrolytic stability
Pató et al. Synthesis of New Poly (N-Vinyl Pyrrolidone-Co-Maleic Acid) Peptide Hormone Conjugates with Anticancer Activity
Song et al. Synthesis and antitumor activity of poly (organophosphazene)/doxorubicin conjugates

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

AK Designated states

Kind code of ref document: A3

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

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
WWE Wipo information: entry into national phase

Ref document number: 1997915567

Country of ref document: EP

NENP Non-entry into the national phase in:

Ref country code: CA

NENP Non-entry into the national phase in:

Ref country code: JP

Ref document number: 97535049

Format of ref document f/p: F

WWP Wipo information: published in national office

Ref document number: 1997915567

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1997915567

Country of ref document: EP