title: PEG-polypeptide block copolymers as pH-responsive endosome-solubilizing drug nanocarriers.
abstract: Herein we report the potential of click chemistry-modified polypeptide-based block copolymers for the facile fabrication of pH-sensitive nanoscale drug delivery systems. PEG-polypeptide copolymers with pendant amine chains were synthesized by combining N-carboxyanhydride-based ring-opening polymerization with post-functionalization using azide-alkyne cycloaddition. The synthesized block copolymers contain a polypeptide block with amine-functional side groups and were found to self-assemble into stable polymersomes and disassemble in a pH-responsive manner under a range of biologically relevant conditions. The self-assembly of these block copolymers yields nanometer-scale vesicular structures that are able to encapsulate hydrophilic cytotoxic agents like doxorubicin at physiological pH but that fall apart spontaneously at endosomal pH levels after cellular uptake. When drug-encapsulated copolymer assemblies were delivered systemically, significant levels of tumor accumulation were achieved, with efficacy against the triple-negative breast cancer cell line, MDA-MB-468, and suppression of tumor growth in an in vivo mouse model.
authors.affiliation: Department of Chemical Engineering and Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
authors.forename: Mohiuddin A
authors.initials: MA
authors.lastname: Quadir
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Morton
authors.forename: Zhou J
authors.initials: ZJ
authors.lastname: Deng
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Shopsowitz
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Murphy
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Epps
authors.forename: Paula T
authors.initials: PT
authors.lastname: Hammond
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D011992:Endosomes / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D058105:Polymerization; D011108:Polymers / Q000737:chemistry*; D012995:Solubility
chemical_list: D004337:Drug Carriers; D010455:Peptides; D011108:Polymers; D011092:Polyethylene Glycols; D004317:Doxorubicin