title: Synthesis and evaluation of water-soluble poly(vinyl alcohol)-paclitaxel conjugate as a macromolecular prodrug.
abstract: Paclitaxel (PTX) is an antitumor agent for the treatment of various human cancers. Cremophor EL and ethanol are used to formulate PTX in commercial injection solutions, because of its poor solubility in water. However, these agents cause severe allergic reaction upon intravenous administration. The aim of this study is to synthesize water-soluble macromolecular prodrugs of PTX for enhancing the therapeutic efficacy. Poly(vinyl alcohol) (PVA, 80 kDa), water-soluble synthetic polymer, was used as a drug carrier which is safe and stable in the body. The 2'-hydroxyl group of PTX was reacted with succinic anhydride and then carboxylic group of the succinyl spacer was coupled to PVA via ethylene diamine spacer, resulting the water-soluble prodrug of poly(vinyl alcohol)-paclitaxel conjugate (PVA-SPTX). The solubility of PTX was greatly enhanced by the conjugation to PVA. The release of PTX from the conjugate was accelerated at the neutral to basic conditions in in vitro release experiment. [125 I]-labeled PVA-SPTX was retained in the blood circulation for several days and was gradually distributed into the tumorous tissue after intravenous injection to the tumor-bearing mice. PVA-SPTX inhibited the growth of sarcoma 180 cells subcutaneously inoculated in mice. It was suggested that the water-solubility of PTX was markedly enhanced by the conjugation to PVA, and PVA-SPTX effectively delivered PTX to the tumorous tissue due to the enhanced permeability and retention (EPR) effect.
authors.affiliation: Laboratory of Biopharmaceutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Atsufumi
authors.initials: A
authors.lastname: Kakinoki
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kaneo
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Yoshitsugu
authors.initials: Y
authors.lastname: Hosokawa
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000493:pharmacokinetics; D004337:Drug Carriers; D006863:Hydrogen-Ion Concentration; D007275:Injections, Intravenous; D007700:Kinetics; D007939:Leukemia L1210 / Q000188:drug therapy; D008297:Male; D051379:Mice; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D011142:Polyvinyl Alcohol; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D012510:Sarcoma 180 / Q000188:drug therapy; D012995:Solubility; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution; D014867:Water
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D011355:Prodrugs; D014867:Water; D004317:Doxorubicin; D011142:Polyvinyl Alcohol; D017239:Paclitaxel