title: Poly (ethylene glycol) prodrug for anthracyclines via N-Mannich base linker: design, synthesis and biological evaluation.
abstract: Poly (ethylene glycol)s (PEGs) are potential drug carriers for improving the therapeutic index of anticancer agents. In this work, a novel methodology for constructing PEG prodrug of anthracycline anticancer drugs was developed based on N-Mannich base of salicylamide and its 2-acyloxymethylated derivative. The resultant conjugates first subjected to in vitro hydrolysis testing, which revealed the release behavior of newly synthesized PEG prodrugs could be adjusted by the status of 2-hydroxy group of salicylamide. These PEG prodrugs also demonstrated superior cytotoxicity in antiproliferative assay. O-blocked doxorubicin prodrug with PEG20k as carrier was selected for further in vivo assessments and presented longer circulating life in pharmacokinetic experiment. This high molecular prodrug was also found to be more efficacious against S-180 xenografted tumor than equivalent amount of doxorubicin.
authors.affiliation: National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, POBox353, Beijing 100190, China.
authors.forename: Yong-Jiang
authors.initials: YJ
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Zhi-Guo
authors.initials: ZG
authors.lastname: Su
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Ma
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D008297:Male; D008352:Mannich Bases; D051379:Mice; D008813:Mice, Inbred ICR; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs; D012457:Salicylamides / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008352:Mannich Bases; D011355:Prodrugs; D012457:Salicylamides; D011092:Polyethylene Glycols; D004317:Doxorubicin; C031060:salicylamide