title: A pH-responsive cyclodextrin-based hybrid nanosystem as a nonviral vector for gene delivery.
abstract: The absence of safe, efficient, cost-effective, and easily scalable delivery platforms is one of the most significant hurdles and critical issues that limit the bench to bedside translation of oligonucleotides-based therapeutics. Acid-labile materials are of special interest in developing nonviral vectors due to their capability of intracellularly delivering therapeutic payload. In this study, a nanovector was designed by integrating a pH-responsive cyclodextrin material and low molecular weight polyethylenimine (PEI). Antisense oligonucleotide (ASON) Bcl-xl could be encapsulated into this hybrid nanosystem with extremely high loading efficiency by a nanoemulsion technique. The developed pH-responsive ASON nanotherapeutics could be efficiently transfected into human lung adenocarcinoma cells in a time- and dose-dependent manner, resulting in effective cell growth inhibition, significant suppression on the expression of Bcl-xl mRNA/protein, and efficient cell apoptosis. Importantly, the new nanovector showed drastically higher efficacy and lower cytotoxicity when compared with PLGA-based counterpart and commonly used cationic vectors like branched PEI (25,000 Da) and Lipofectamine 2000. This pH-responsive hybrid nanosystem may serve as a safe and efficient nonviral vector that may find wide applications in gene therapy.
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Huaping
authors.initials: H
authors.lastname: Chen
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Dou
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Binfeng
authors.initials: B
authors.lastname: He
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Zhenghua
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China.
authors.forename: Changzheng
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Chengde
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, Chongqing 400038, China. Electronic address: jxzhang1980@gmail.com.
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Respiratory Diseases, Xinqiao Hospital of Third Military Medical University, Chongqing 400037, China. Electronic address: wanggs2003@163.com.
authors.forename: Guansong
authors.initials: G
authors.lastname: Wang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003505:Cyclodextrins / Q000737:chemistry*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D019344:Lactic Acid / Q000737:chemistry; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000737:chemistry* / Q000633:toxicity / Q000648:ultrastructure; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014780:Viruses / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D003505:Cyclodextrins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D051020:bcl-X Protein; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid