title: Cisplatin-Induced Formation of Biocompatible and Biodegradable Polypeptide-Based Vesicles for Targeted Anticancer Drug Delivery.
abstract: Novel cisplatin (CDDP)-loaded, polypeptide-based vesicles for the targeted delivery of cisplatin to cancer cells have been prepared. These vesicles were formed from biocompatible and biodegradable maleimide-poly(ethylene oxide)114-b-poly(L-glutamic acid)12 (Mal-PEG114-b-PLG12) block copolymers upon conjugation with the drug itself. CDDP conjugation forms a short, rigid, cross-linked, drug-loaded, hydrophobic block in the copolymer, and subsequently induces self-assembly into hollow vesicle structures with average hydrodynamic diameters (Dh) of ∼ 270 nm. CDDP conjugation is critical to the formation of the vesicles. The reactive maleimide-PEG moieties that form the corona and inner layer of the vesicles were protected via formation of a reversible Diels-Alder (DA) adduct throughout the block copolymer synthesis so as to maintain their integrity. Drug release studies demonstrated a low and sustained drug release profile in systemic conditions (pH = 7.4, [Cl(-)] = 140 mM) with a higher "burst-like" release rate being observed under late endosomal/lysosomal conditions (pH = 5.2, [Cl(-)] = 35 mM). Further, the peripheral maleimide functionalities on the vesicle corona were conjugated to thiol-functionalized folic acid (FA) (via in situ reduction of a novel bis-FA disulfide, FA-SS-FA) to form an active targeting drug delivery system. These targeting vesicles exhibited significantly higher cellular binding/uptake into and dose-dependent cytotoxicity toward cancer cells (HeLa) compared to noncancerous cells (NIH-3T3), which show high and low folic acid receptor (FR) expression, respectively. This work thus demonstrates a novel approach to polypeptide-based vesicle assembly and a promising strategy for targeted, effective CDDP anticancer drug delivery.
authors.affiliation: †Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Shirbin
authors.affiliation: †Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Katharina
authors.initials: K
authors.lastname: Ladewig
authors.affiliation: †Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Fu
authors.affiliation: †Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Molly
authors.initials: M
authors.lastname: Klimak
authors.affiliation: ‡CSIRO Manufacturing Flagship, Clayton South, Victoria 3169, Australia.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: §School of Medicine, Deakin University, Geelong, Victoria 3216, Australia.
authors.forename: Wei
authors.initials: W
authors.lastname: Duan
authors.affiliation: †Polymer Science Group, Department of Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Melbourne, Victoria 3010, Australia.
authors.forename: Greg G
authors.initials: GG
authors.lastname: Qiao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D065546:Drug Liberation; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin