title: Charge-conversional PEG-polypeptide polyionic complex nanoparticles from simple blending of a pair of oppositely charged block copolymers as an intelligent vehicle for efficient antitumor drug delivery.
abstract: A tumor-acidity-activated charge-conversional polyionic complex nanoparticle system was developed by simply mixing a pair of oppositely charged block copolymers: anionic methoxy poly(ethylene glycol)-b-poly(l-glutamic acid-co-l-phenylalanine) (mPEG-b-P(Glu-co-Phe)) and cationic methoxy poly(ethy1ene glycol)-b-poly(l-lysine-co-l-phenylalanine) (mPEG-b-P(Lys-co-Phe)). The nanoparticles could stay negatively charged under normal physiological pH value and reverse the surface charge to positive at the tumor extracellular environment. Doxorubicin (DOX) was encapsulated into the nanoparticles fabricated by a self-assembly process, and the DOX-loaded polyionic complex nanoparticles (DOX-NPs) retained the charge-conversional property. In vitro DOX release study demonstrated that DOX release was promoted by the significantly increased acidity in endosomes and lysosomes (pH ≈ 5-6). Cellular uptake studies confirmed that the DOX-NPs could be more effectively internalized by cells at the tumor extracellular pH value. In vitro cytotoxicity assays demonstrated that the polyionic complex nanoparticles had good biocompatibility, and DOX-NPs showed efficient cell proliferation inhibition to HeLa and A549 tumor cells. Maximum tolerated dose (MTD) studies revealed that DOX-NPs had a significantly higher MTD (more than 25 mg of DOX/kg) in mice compared to that for free DOX (5 mg of DOX/kg). Furthermore, DOX-NPs showed superior antitumor activity and reduced side toxicity compared to free DOX in A549 tumor bearing nude mice.
authors.affiliation: Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, P. R. China.
authors.forename: Shixian
authors.initials: S
authors.lastname: Lv
authors.forename: Wantong
authors.initials: W
authors.lastname: Song
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Tang
authors.forename: Mingqiang
authors.initials: M
authors.lastname: Li
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.forename: Hua
authors.initials: H
authors.lastname: Hong
authors.forename: Xuesi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010455:Peptides; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin