title: Cell-Targeting Cationic Gene Delivery System Based on a Modular Design Rationale.
abstract: En route to target cells, a gene carrier faces multiple extra- and intracellular hurdles that would affect delivery efficacy. Although diverse strategies have been proposed to functionalize gene carriers for individually overcoming these barriers, it is challenging to generate a single multifunctional gene carrier capable of surmounting all these barriers. Aiming at this challenge, we have developed a supramolecular modular approach to fabricate a multifunctional cationic gene delivery system. It consists of two prefunctionalized modules: (1) a host module: a polymer (PCD-SS-PDMAEMA) composed of poly(β-cyclodextrin) backbone and disulfide-linked PDMAEMA arms, expectedly acting to compact DNA and release DNA upon cleavage of disulfide linkers in reductive microenvironment; and (2) a guest module: adamantyl and folate terminated PEG (Ad-PEG-FA), expectedly functioning to reduce nonspecific interactions, improve biocompatibility, and provide folate-mediated cellular targeting specificity. Through the host-guest interaction between β-cyclodextrin units of the "host" module and adamantyl groups of the "guest" module, the PCD-SS-PDMAEMA-1 (host) and Ad-PEG-FA (guest) self-assemble forming a supramolecular pseudocopolymer (PCD-SS-PDMAEMA-1/PEG-FA). Our comprehensive analyses demonstrate that the functions preassigned to the two building modules are well realized. The gene carrier effectively compacts DNA into stable nanosized polyplexes resistant to enzymatic digestion, triggers DNA release in reducing environment, possesses significantly improved hemocompatibility, and specifically targets folate-receptor positive cells. Most importantly, endowed with these predesigned functions, the PCD-SS-PDMAEMA-1/PEG-FA supramolecular gene carrier exhibits excellent transfection efficacy for both pDNA and siRNA. Thus, this work represents a proof-of-concept example showing the efficiency and convenience of an adaptable, modular approach for conferring multiple functions to a single supramolecular gene carrier toward effective in vivo delivery of therapeutic nucleic acids.
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors.forename: Luming
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Respiration, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei 430022, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qi
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Li
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University , Wuhan 430072, China.
authors.forename: Yunti
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Biomedical Polymers of Ministry of Education and Department of Chemistry, Wuhan University , Wuhan 430072, China.
authors.forename: Xulin
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei 430022, China.
authors.forename: Guobin
authors.initials: G
authors.lastname: Wang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.|Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei 430022, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan 430022, China.|Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei 430022, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
mesh_terms: D002412:Cations / Q000008:administration & dosage*; D004247:DNA / Q000737:chemistry; D018014:Gene Transfer Techniques; D006801:Humans; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D014162:Transfection / Q000592:standards
chemical_list: D002412:Cations; D011108:Polymers; D011092:Polyethylene Glycols; D004247:DNA
keywords: cyclodextrin; disulfide bond; folate; gene delivery; host−guest interaction; poly(ethylene glycol)