title: Comb-like amphiphilic polypeptide-based copolymer nanomicelles for co-delivery of doxorubicin and P-gp siRNA into MCF-7 cells.
abstract: A comb-like amphiphilic copolymer methoxypolyethylene glycol-graft-poly(L-lysine)-block-poly(L-phenylalanine) (mPEG-g-PLL-b-Phe) was successfully synthesized. To synthesize mPEG-g-PLL-b-Phe, diblock copolymer PLL-b-Phe was first synthesized by successive ring-opening polymerization of α-amino acid N-carboxyanhydrides followed by the removal of benzyloxycarbonyl protecting groups, and then mPEG was grafted onto PLL-b-Phe by reductive amination via Schiff's base formation. The chemical structures of the copolymers were identified by (1)H NMR. mPEG-g-PLL-b-Phe copolymer had a critical micelle concentration of 6.0mg/L and could self-assemble in an aqueous solution into multicompartment nanomicelles with a mean diameter of approximately 78 nm. The nanomicelles could encapsulate doxorubicin (DOX) through hydrophobic and π-π stacking interactions between DOX molecules and Phe blocks and simultaneously complex P-gp siRNA with cationic PLL blocks via electrostatic interactions. The DOX/P-gp siRNA-loaded nanomicelles showed spherical morphology, possessed narrow particle size distribution and had a mean particle size of 120 nm. The DOX/P-gp siRNA-loaded nanomicelles exhibited pH-responsive release behaviors and displayed accelerated release under acidic conditions. The DOX/P-gp siRNA-loaded nanomicelles were efficiently internalized into MCF-7 cells, and DOX released could successfully reach nuclei. In vitro cytotoxicity assay demonstrated that the DOX/P-gp siRNA-loaded nanomicelles showed a much higher cytotoxicity in MCF-7 cells than DOX-loaded nanomicelles due to their synergistic killing effect and that the blank nanomicelles had good biocompatibility. Thus, the novel comb-like mPEG-g-PLL-b-Phe nanomicelles could be a promising vehicle for co-delivery of chemotherapeutic drug and genetic material.
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: ailisuo@mail.xjtu.edu.cn.
authors.forename: Aili
authors.initials: A
authors.lastname: Suo
authors.affiliation: State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China. Electronic address: jmqian@mail.xjtu.edu.cn.
authors.forename: Junmin
authors.initials: J
authors.lastname: Qian
authors.affiliation: State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Liu
authors.affiliation: State Key Laboratory for Mechanical Behavior of Materials, Xi'an Jiaotong University, Xi'an 710049, China.
authors.forename: Weijun
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
authors.forename: Hejing
authors.initials: H
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D008823:Micelles; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010455:Peptides / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D010455:Peptides; D011108:Polymers; D034741:RNA, Small Interfering; D004317:Doxorubicin
keywords: Co-delivery; Doxorubicin; MCF-7 cells; Multicompartment nanomicelles; P-gp siRNA; Polypeptide