title: The comparison of in vivo properties of water-soluble HPMA-based polymer conjugates with doxorubicin prepared by controlled RAFT or free radical polymerization.
abstract: Two conjugates of anticancer drug doxorubicin (Dox) covalently bound by the hydrolytically degradable hydrazone bond to the polymer carrier based on water-soluble N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers were synthesized and their properties were compared, namely their behavior in vivo. The polymer carriers differed in dispersity due to different methods of synthesis; the carrier with relatively high dispersity (HD) was prepared by free radical polymerization (Mw=29,900 g/mol, D=1.75) and the carrier with low dispersity (LD) by controlled radical polymerization (Mw=30,000 g/mol, D=1.13). Both polymer-Dox conjugates showed prolonged blood circulation and tumor accumulation of the drug in comparison with the free drug; e.g. the tumor-to-blood ratio for the polymer-bound Dox was 3-5 times higher. The LD polymer-Dox conjugate exhibited moderately higher tumor accumulation than the HD one at a dose of 1x15 mg Dox (eq.)/kg. Also, their anti-tumor activity did not differ when injected at this dose. However, the increase of the dose to 1x25 mg Dox (eq.)/kg resulted in the enhanced therapeutic activity of the conjugates, especially of the LD one with 100% of long-term survivals. The dispersity of polymer drug carriers influenced the tumor accumulation rate, which affected the overall anti-cancer activity of polymer-drug conjugates.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic. chytil@imc.cas.cz.
authors.forename: P
authors.initials: P
authors.lastname: Chytil
authors.forename: M
authors.initials: M
authors.lastname: Šírová
authors.forename: E
authors.initials: E
authors.lastname: Koziolová
authors.forename: K
authors.initials: K
authors.lastname: Ulbrich
authors.forename: B
authors.initials: B
authors.lastname: Říhová
authors.forename: T
authors.initials: T
authors.lastname: Etrych
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004337:Drug Carriers; D005260:Female; D005609:Free Radicals / Q000737:chemistry; D008297:Male; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011108:Polymers / Q000138:chemical synthesis*; D016019:Survival Analysis; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D005609:Free Radicals; D008689:Methacrylates; D011108:Polymers; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate