title: Endosomal pH-activatable poly(ethylene oxide)-graft-doxorubicin prodrugs: synthesis, drug release, and biodistribution in tumor-bearing mice.
abstract: Novel poly(ethylene oxide)-graft-doxorubicin (PEO-g-DOX) prodrugs with DOX covalently conjugated to PEO via a pH-sensitive hydrazone bond were developed. PEO-g-DOX conjugates could be readily prepared in the following steps: (i) anionic ring-opening copolymerization of ethylene oxide (EO) and allyl glycidyl ether (AGE) afforded functional PEO with controlled molecular weights, low polydispersities, and multiple pendant double bonds (PEO-g-allyl); (ii) conjugation of PEO-g-allyl with methyl mercaptoacetate, followed by treating with hydrazine hydrate, quantitatively transformed allyl into hydrazide groups (PEO-g-hydrazide); and (iii) DOX was covalently immobilized to PEO-g-hydrazide via acid-labile hydrazone bonds (PEO-g-DOX). Here on the basis of PEO-g-allyl(4.4) (M(n GPC) = 22 400, PDI = 1.19) and PEO-g-allyl(7.1) (M(n GPC) = 15 300, PDI = 1.16, the subscription refers to number of allyl groups per chain) two freely water-soluble PEO-g-DOX prodrugs with 2.9 and 3.6 DOX per molecule (denoted as PEO-g-DOX(2.9) and PEO-g-DOX(3.6), corresponding to drug loading content of 5.6 and 9.0 wt %, respectively) were obtained. The in vitro release studies confirmed much faster release of DOX at pH 5.0 and 6.0 than at pH 7.4. For example, approximately 16, 52, and 61% of drug were released in 22 h, and 23, 83, and 92% of drug were released in 120 h from PEO-g-DOX(2.9) at pH 7.4, 6.0 and 5.0, respectively. Notably, confocal laser scanning microscope (CLSM) observations revealed that DOX was released and delivered into the nuclei of RAW 264.7 cells following 24 h of incubation. MTT assays demonstrated that PEO-g-DOX(2.9) had pronounced cytotoxic effects to RAW 264.7, HeLa, and 4T1 breast tumor cells with IC(50) values of about 26.5, 42.5, and 32.0 μg DOX equiv/mL, whereas the corresponding polymer carrier PEO-g-hydrazide(4.4) was nontoxic. The In Vivo pharmacokinetics and biodistribution studies in mice showed that PEO-g-DOX(2.9) prodrugs had significantly prolonged circulation time and enhanced drug accumulation in the tumor as compared with free DOX. We are convinced that endosomal pH-activatable PEO-g-DOX prodrugs have tremendous potential for targeted cancer therapy.
authors.affiliation: Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, P R China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.forename: Ru
authors.initials: R
authors.lastname: Cheng
authors.forename: Huiquan
authors.initials: H
authors.lastname: Tao
authors.forename: Shoubao
authors.initials: S
authors.lastname: Ma
authors.forename: Weiwei
authors.initials: W
authors.lastname: Guo
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.forename: Haiyan
authors.initials: H
authors.lastname: Liu
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Liu
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000818:Animals; D004317:Doxorubicin / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009374:Neoplasms, Experimental / Q000473:pathology*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D011355:Prodrugs; D011092:Polyethylene Glycols; D004317:Doxorubicin