title: Prodrugs forming high drug loading multifunctional nanocapsules for intracellular cancer drug delivery.
abstract: Anticancer drugs embedded in or conjugated with inert nanocarriers, referred to as nanomedicines, show many therapeutic advantages over free drugs, but the inert carrier materials are the major component (generally more than 90%) in nanomedicines, causing low drug loading contents and thus excessive uses of parenteral excipients. Herein, we demonstrate a new concept directly using drug molecules to fabricate nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release. Taking advantage of the strong hydrophobicity of the anticancer drug camptothecin (CPT), one or two CPT molecule(s) were conjugated to a very short oligomer chain of ethylene glycol (OEG), forming amphiphilic phospholipid-mimicking prodrugs, OEG-CPT or OEG-DiCPT. The prodrugs formed stable liposome-like nanocapsules with a CPT loading content as high as 40 or 58 wt % with no burst release in aqueous solution. OEG-DiCPT released CPT once inside cells, which showed high in vitro and in vivo antitumor activity. Meanwhile, the resulting nanocapsules can be loaded with a water-soluble drug-doxorubicin salt (DOX.HCl)-with a high loading efficiency. The DOX.HCl-loaded nanocapsules simultaneously delivered two anticancer drugs, leading to a synergetic cytotoxicity to cancer cells. The concept directly using drugs as part of a carrier is applicable to fabricating other highly efficient nanocarriers with a substantially reduced use of inert carrier materials and increased drug loading content without premature burst release.
authors.affiliation: Center for Bionanoengineering and the State Key Laboratory for Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China 310027. shenyq@zju.edu.cn
authors.forename: Youqing
authors.initials: Y
authors.lastname: Shen
authors.forename: Erlei
authors.initials: E
authors.lastname: Jin
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.forename: Caitlin J
authors.initials: CJ
authors.lastname: Murphy
authors.forename: Meihua
authors.initials: M
authors.lastname: Sui
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Jinqiang
authors.initials: J
authors.lastname: Wang
authors.forename: Jianbin
authors.initials: J
authors.lastname: Tang
authors.forename: Maohong
authors.initials: M
authors.lastname: Fan
authors.forename: Edward
authors.initials: E
authors.lastname: Van Kirk
authors.forename: William J
authors.initials: WJ
authors.lastname: Murdoch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission; D008954:Models, Biological; D015394:Molecular Structure; D053769:Nanocapsules / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D053769:Nanocapsules; D011355:Prodrugs