title: Development of zwitterionic polymer-based doxorubicin conjugates: tuning the surface charge to prolong the circulation and reduce toxicity.
abstract: Polymer-drug conjugates are commonly used as nano drug vehicles (NDVs) to delivery anticancer drugs. Zwitterionic polymers are ideal candidates to conjugate drugs because they show higher resistance to nonspecific protein adsorption in complex media than that of nonionic water-soluble polymers, such as poly(ethylene glycol). However, the charge balance characteristics of zwitterionic polymers used as NDVs will be broken from the inclusion of additional charged groups brought by conjugated drugs or functional groups, leading to the loss of resistance to protein adsorption. Consequently, the nonspecific protein adsorption on drug carriers will cause fast clearance from the blood system, an immune response, or even severe systemic toxicity. To overcome this drawback, a model zwitterionic polymer, poly(carboxybetaine methacrylate) (pCBMA), was modified by the introduction of a negatively charged component, to neutralize the positive charge provided by the model drug, doxorubicin (DOX). A DOX-conjugated NDV which possesses excellent resistance to nonspecific protein adsorption was achieved by the formation of a strongly hydrated pCBMA shell with a slightly negative surface charge. This kind of DOX-conjugated NDV exhibited reduced cytotoxicity and prolonged circulation time, and it accelerated DOX release under mild acid conditions. In tumor-bearing mouse studies a 55% tumor-inhibition rate was achieved without causing any body weight loss. These results indicate the importance of charge tuning in zwitterionic polymer-based NDVs.
authors.affiliation: State Key Laboratory of Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University , Hangzhou, Zhejiang 310027, P. R. China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Guanglong
authors.initials: G
authors.lastname: Ma
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Weifeng
authors.initials: W
authors.lastname: Lin
authors.forename: Fangqin
authors.initials: F
authors.lastname: Ji
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Bernards
authors.forename: Shengfu
authors.initials: S
authors.lastname: Chen
mesh_terms: D000327:Adsorption; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D001622:Betaine / Q000737:chemistry*; D019556:COS Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004317:Doxorubicin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000737:chemistry*; D011109:Polymethacrylic Acids / Q000737:chemistry*; D055672:Static Electricity; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D011109:Polymethacrylic Acids; C517178:polycarboxybetaine methacrylate; D001622:Betaine; D011092:Polyethylene Glycols; D004317:Doxorubicin