title: Programmed Hydrolysis in Designing Paclitaxel Prodrug for Nanocarrier Assembly.
abstract: Nanocarriers delivering prodrugs are a way of improving in vivo effectiveness and efficiency. For therapeutic efficacy, the prodrug must hydrolyze to its parent drug after administration. Based on the fact that the hydrolysis is impeded by steric hindrance and improved by sufficient polarity, in this study, we proposed the PTX-S-S-VE, the conjugation of paclitaxel (PTX) to vitamin E (VE) through a disulfide bridge. This conjugate possessed the following advantages: first, it can be encapsulated in the VE/VE2-PEG2000/water nanoemulsions because of favorable hydrophobic interactions; second, the nanoemulsions had a long blood circulation time; finally, the concentrated glutathione in the tumor microenvironment could cleave the disulfide bond to weaken the steric hindrance and increase the polarity, promoting the hydrolysis to PTX and increasing the anticancer activity. It was demonstrated in vitro that the hydrolysis of PTX-S-S-VE was enhanced and the cytotoxicity was increased. In addition, PTX-S-S-VE had greater anticancer activity against the KB-3-1 cell line tumor xenograft and the tumor size was smaller after the 4(th) injection. The present result suggests a new way, use of reduction, to improve the in vivo anticancer activity of a prodrug for nanocarrier delivery by unshielding the ester bond and taking off the steric block.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Fu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou 510006, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Fallon
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: D
authors.initials: D
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
authors.forename: Z
authors.initials: Z
authors.lastname: He
authors.affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: F
authors.initials: F
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004220:Disulfides / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D049329:Nanostructures / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D014018:Tissue Distribution; D014810:Vitamin E / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004220:Disulfides; D004337:Drug Carriers; D011355:Prodrugs; D014810:Vitamin E; D011092:Polyethylene Glycols; D017239:Paclitaxel