title: Reversibly cross-linked polyplexes enable cancer-targeted gene delivery via self-promoted DNA release and self-diminished toxicity.
abstract: Polycations often suffer from the irreconcilable inconsistency between transfection efficiency and toxicity. Polymers with high molecular weight (MW) and cationic charge feature potent gene delivery capabilities, while in the meantime suffer from strong chemotoxicity, restricted intracellular DNA release, and low stability in vivo. To address these critical challenges, we herein developed pH-responsive, reversibly cross-linked, polyetheleneimine (PEI)-based polyplexes coated with hyaluronic acid (HA) for the effective and targeted gene delivery to cancer cells. Low-MW PEI was cross-linked with the ketal-containing linker, and the obtained high-MW analogue afforded potent gene delivery capabilities during transfection, while rapidly degraded into low-MW segments upon acid treatment in the endosomes, which promoted intracellular DNA release and reduced material toxicity. HA coating of the polyplexes shielded the surface positive charges to enhance their stability under physiological condition and simultaneously reduced the toxicity. Additionally, HA coating allowed active targeting to cancer cells to potentiate the transfection efficiencies in cancer cells in vitro and in vivo. This study therefore provides an effective approach to overcome the efficiency-toxicity inconsistence of nonviral vectors, which contributes insights into the design strategy of effective and safe vectors for cancer gene therapy.
authors.forename: Hua
authors.initials: H
authors.lastname: He
authors.affiliation: ‡Department of Chemistry, University of Illinois at Urbana-Champaign (UIUC), 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Bai
authors.forename: Jinhui
authors.initials: J
authors.lastname: Wang
authors.forename: Qiurong
authors.initials: Q
authors.lastname: Deng
authors.forename: Lipeng
authors.initials: L
authors.lastname: Zhu
authors.forename: Fenghua
authors.initials: F
authors.lastname: Meng
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Zhong
authors.forename: Lichen
authors.initials: L
authors.lastname: Yin
mesh_terms: D000818:Animals; D003432:Cross-Linking Reagents / Q000737:chemistry; D004247:DNA / Q000008:administration & dosage* / Q000235:genetics / Q000633:toxicity; D011992:Endosomes / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000628:therapy*; D011094:Polyethyleneimine / Q000737:chemistry
chemical_list: D003432:Cross-Linking Reagents; D011094:Polyethyleneimine; D006820:Hyaluronic Acid; D004247:DNA