title: Development of Branched Poly(5-Amino-1-pentanol-co-1,4-butanediol Diacrylate) with High Gene Transfection Potency Across Diverse Cell Types.
abstract: One of the most significant challenges in the development of polymer materials for gene delivery is to understand how topological structure influences their transfection properties. Poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (C32) has proven to be the top-performing gene delivery vector developed to date. Here, we report the development of branched poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (HC32) as a novel gene vector and elucidate how the topological structure affects gene delivery properties. We found that the branched structure has a big impact on gene transfection efficiency resulting in a superior transfection efficiency of HC32 in comparison to C32 with a linear structure. Mechanistic investigations illustrated that the branched structure enhanced DNA binding, leading to the formation of toroidal polyplexes with smaller size and higher cationic charge. Importantly, the branched structure offers HC32 a larger chemical space for terminal functionalization (e.g., guanidinylation) to further enhance the transfection. Moreover, the optimized HC32 is capable of transfecting a diverse range of cell types including cells that are known to be difficult to transfect such as stem cells and astrocytes with high efficiency. Our study provides a new insight into the rational design of poly(β-amino ester) (PAE) based polymers for gene delivery.
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Dezhong
authors.initials: D
authors.lastname: Zhou
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Jonathan
authors.initials: J
authors.lastname: O'Keeffe Ahern
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Sigen
authors.initials: S
authors.lastname: A
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Qian
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.|College of Materials Science and Engineering, Sichuan University , Chengdu 610064, Sichuan, China.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Huang
authors.affiliation: Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Udo
authors.initials: U
authors.lastname: Greiser
authors.affiliation: School of Materials Science and Engineering, Tianjin University , Tianjin 300072, China.|Charles Institute of Dermatology, University College Dublin , Belfield, Dublin 4, Ireland.
authors.forename: Wenxin
authors.identifier: http://orcid.org/0000-0002-5053-0611
authors.initials: W
authors.lastname: Wang
mesh_terms: D016475:3T3 Cells; D000179:Acrylates / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018076:DNA, Complementary / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D014162:Transfection / Q000379:methods*
chemical_list: D000179:Acrylates; D018076:DNA, Complementary; D011108:Polymers
keywords: diverse cell types; gene transfection; high efficiency; highly branched; poly(β-amino ester); terminal functionalization