title: Novel star HPMA-based polymer conjugates for passive targeting to solid tumors.
abstract: Novel star polymer-doxorubicin conjugates designed for passive tumor targeting have been developed and their potential for treatment of cancer has been investigated. In the present study the synthesis, physico-chemical characterization, drug release, bio-distribution and preliminary data of in vivo efficacy of the conjugates are described. In the water-soluble conjugates the core of a molecule formed by poly(amido amine) (PAMAM) dendrimers was grafted with semitelechelic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers bearing doxorubicin (Dox) attached by hydrazone bonds enabling intracellular pH-controlled hydrolytic drug release, or by GFLG sequence susceptible to enzymatic degradation. The controlled synthesis utilizing semitelechelic copolymer precursors facilitated preparation of polymer conjugates in a broad range of molecular weights (1.1-3.0·10(5) g/mol). In contrast to free drug or linear conjugates the star polymer-Dox conjugates exhibited prolonged blood circulation and enhanced tumor accumulation in tumor-bearing mice indicating important role of the EPR effect. The star polymer-Dox conjugates showed significantly higher anti-tumor activity in vivo than Dox?HCl or its linear or graft polymer conjugates, if treated with a single dose 15 or 5 mg Dox eq./kg. Method of tumor initialization (acute or chronic experimental tumor models) significantly influenced effectiveness of the treatment with much lower success in treatment of mice bearing chronic tumors.
authors: Institute of Macromolecular Chemistry, Prague, Czech Republic. etrych@imc.cas.cz
authors: T
authors: T
authors: Etrych
authors: J
authors: J
authors: Strohalm
authors: P
authors: P
authors: Chytil
authors: B
authors: B
authors: Říhová
authors: K
authors: K
authors: Ulbrich
mesh_terms: D000178:Acrylamides / Q000737:chemistry; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations; D050091:Dendrimers / Q000737:chemistry*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D006863:Hydrogen-Ion Concentration; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012995:Solubility; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D050091:Dendrimers; D004337:Drug Carriers; C104700:PAMAM Starburst; D014867:Water; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide