Highly branched poly(β-amino ester)s for skin gene therapy.
Poly(β-amino ester)s (PAEs) have emerged as a promising class of gene delivery vectors with performances that can even be compared to viruses. However, all of the transfection studies (over 2350 PAEs) have been limited to linear poly(β-amino ester)s (LPAEs) despite increasing evidence that polymer structure significantly affects performance. Herein, we describe the development of highly branched poly(β-amino ester)s (HPAEs) via a new "A2+B3+C2" Michael addition approach demonstrating 2 to 126-fold higher in vitro transfection efficiencies of different cell types in comparison to their linear LPAE counterparts as well as greatly out-performing the leading transfection reagents SuperFect and the "gold-standard" polyethyleneimine (PEI) - especially on skin epidermal cells. More importantly, the ability to correct a skin genetic defect is demonstrated in vivo utilizing a recessive dystrophic epidermolysis bullosa (RDEB) knockout mouse model. Our results provide evidence that the "A2+B3+C2" approach can be controlled and offers sufficient flexibility for the synthesis of HPAEs. The branched structures can significantly improve the transfection efficiency and safety of PAEs highlighting the great promise for the successful application of non-viral gene therapy in skin disease.
School of Materials Science and Engineering, Tianjin University, Tianjin, China; Charles Institute of Dermatology, School of Medicine and Biomedical Science, University College Dublin, Dublin 4, Ireland.
Dezhong
D
Zhou
Charles Institute of Dermatology, School of Medicine and Biomedical Science, University College Dublin, Dublin 4, Ireland.
Yongsheng
Y
Gao
Charles Institute of Dermatology, School of Medicine and Biomedical Science, University College Dublin, Dublin 4, Ireland.
Ahmed
A
Aied
Charles Institute of Dermatology, School of Medicine and Biomedical Science, University College Dublin, Dublin 4, Ireland.
Lara
L
Cutlar
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Olga
O
Igoucheva
The Leibniz Institute of Polymer Research Dresden (IPF), Dresden 01069, Germany.
Ben
B
Newland
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Vitali
V
Alexeeve
Charles Institute of Dermatology, School of Medicine and Biomedical Science, University College Dublin, Dublin 4, Ireland.
Udo
U
Greiser
Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Jouni
J
Uitto
School of Materials Science and Engineering, Tianjin University, Tianjin, China; Charles Institute of Dermatology, School of Medicine and Biomedical Science, University College Dublin, Dublin 4, Ireland. Electronic address: wenxin.wang@ucd.ie.
Wenxin
W
Wang
D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D024143:Collagen Type VII / Q000235:genetics; D004247:DNA / Q000008:administration & dosage*; D016108:Epidermolysis Bullosa Dystrophica / Q000628:therapy*; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D049452:Green Fluorescent Proteins / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics; D059630:Mesenchymal Stem Cells; D018345:Mice, Knockout; D011108:Polymers / Q000008:administration & dosage*; D012867:Skin
C583886:Col7a1 protein, mouse; D024143:Collagen Type VII; D011108:Polymers; C507253:poly(beta-amino ester); D049452:Green Fluorescent Proteins; D004247:DNA; D008156:Luciferases
Gene transfection; Highly branched polymers; Poly(β-amino ester); RDEB