title: Enhanced shRNA delivery and ABCG2 silencing by charge-reversible layered nanocarriers.
abstract: Polycationic vectors have been used to deliver short hairpin RNAs (shRNAs) to knock-down genes for cancer therapies, but their inefficiency in lysosomal escape and shRNA release causes their low gene transcription efficiency. Herein, a three-layered polyethyleneimine (PEI)-coated gold nanocomplex interlaid with a pH-responsive charge-reversible chitosan-aconitic anhydride (CS-Aco) is constructed: a Au-PEI/CS-Aco/PEI/shRNA nanoparticle. The negatively charged CS-Aco hydrolyzes into positively charged CS in lysosomes, causing the nanocomposite to disassemble. The released Au-PEI nanoparticles efficiently rupture the lysosomes and thus release the PEI/shRNA polyplexes into cytoplasm, where they quickly disassociate because the PEI chains are short (1.2 kDa). As a consequence, the nanocomplexes display higher shRNA delivery efficiency than the 25 kDa PEI, and efficiently deliver shABCG2 to tumors and markedly silence ABCG2 expression, which sensitizes HepG2 cells to the drugs with minimal toxicity.
authors.affiliation: State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metals Chemistry and Resources Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, 730000, P. R. China.
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Chen
authors.forename: Lifen
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuling
authors.initials: Y
authors.lastname: He
authors.forename: Youqing
authors.initials: Y
authors.lastname: Shen
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Li
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D002469:Cell Separation; D048271:Chitosan / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004705:Endocytosis; D005434:Flow Cytometry; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008247:Lysosomes / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053761:Nanocomposites / Q000737:chemistry; D050997:Nanomedicine / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D004337:Drug Carriers; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D048271:Chitosan
keywords: ABCG2 silencing; RNA delivery; gold nanoparticles; layer-by-layer assembly; shRNA