title: Properties of HPMA copolymer-doxorubicin conjugates with pH-controlled activation: effect of polymer chain modification.
abstract: Various conjugates of anticancer drug doxorubicin (DOX) covalently attached via hydrolytically degradable hydrazone bond to water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer drug carriers were synthesized. Three types of precursors containing either positively or negatively charged groups or a hydrophobic substituent were employed. In vitro incubation of the conjugates in buffers showed relative stability at pH 7.4 (modelling blood) and a fast DOX release at pH 5 (modelling intracellular environment). The presence of carboxylic groups in the copolymer structure resulted in an increase in the DOX release rate of 15-20% while no effect of the introduction of positively charged groups was observed if compared with the unmodified conjugate. Self-assembling of the oleoyl groups-containing conjugate led into formation of polymeric micelles with high apparent molecular weight (M(w)=170,000) in aqueous solution and resulted in a decrease in the DOX release rate of approximately 20%. The cytostatic activity of the conjugates tested on several cancer cell lines was comparable with that of free DOX.HCl, depending on the sensitivity of a particular cell line to DOX. All the conjugates showed a much higher antitumour activity in vivo than the free drug tested in mice bearing EL4 T-cell lymphoma and treated using the therapeutic regime of drug administration. The highest activity (100% long-term survivors) exhibited polymer-DOX conjugate containing negatively charged GFLG sequences.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Chytil
authors.forename: Tomás
authors.initials: T
authors.lastname: Etrych
authors.forename: Cestmír
authors.initials: C
authors.lastname: Konák
authors.forename: Milada
authors.initials: M
authors.lastname: Sírová
authors.forename: Tomás
authors.initials: T
authors.lastname: Mrkvan
authors.forename: Blanka
authors.initials: B
authors.lastname: Ríhová
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007700:Kinetics; D008297:Male; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D010316:Particle Size; D011108:Polymers / Q000737:chemistry; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D016019:Survival Analysis
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D007202:Indicators and Reagents; D008689:Methacrylates; D011108:Polymers; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate