Abstract
The top-performing linear poly(β-amino ester) (LPAE), poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (C32), has demonstrated gene transfection efficiency comparable to viral-mediated gene delivery. Herein, we report the synthesis of a series of highly branched poly(5-amino-1-pentanol-co-1,4-butanediol diacrylate) (HC32) and explore how the branching structure influences the performance of C32 in gene transfection. HC32 were synthesized by an “A2 + B3 + C2” Michal addition strategy. Gaussia luciferase (Gluciferase) and green fluorescent protein (GFP) coding plasmid DNA were used as reporter genes and the gene transfection efficiency was evaluated in human cervical cancer cell line (HeLa) and human recessive dystrophic epidermolysis bullosa keratinocyte (RDEBK) cells. We found that the optimal branching structure led to a much higher gene transfection efficiency in comparison to its linear counterpart and commercial reagents, while preserving high cell viability in both cell types. The branching strategy affected DNA binding, proton buffering capacity and degradation of polymers as well as size, zeta potential, stability, and DNA release rate of polyplexes significantly. Polymer degradation and DNA release rate played pivotal parts in achieving the high gene transfection efficiency of HC32-103 polymers, providing new insights for the development of poly(β-amino ester)s-based gene delivery vectors.
Highlights
Gene therapy is broadly defined as the procedure used to genetically modify the target cells with the intention of altering gene expression to prevent, relieve, or reverse pathological genetic deficiency conditions including both inherited and acquired diseases
The efforts to develop enhanced polymeric vectors resulted in major advances such as larger gene delivery capacities, lower immunogenicity and easier manufacturing processes compared to the current viral vector technology [7,8]
Linear C32-103 were first synthesized by copolymerization of
Summary
Gene therapy is broadly defined as the procedure used to genetically modify the target cells with the intention of altering gene expression to prevent, relieve, or reverse pathological genetic deficiency conditions including both inherited and acquired diseases. Over the past two decades, the high efficacies of trans-gene expression by viral vectors has made them attractive and advanced their applications in numerous clinical trials. The technology of viral gene therapy is hampered by its limited nucleic acid packaging ability [4]. In the area of non-viral gene delivery systems, the utilization of cationic polymers in clinical applications has increased from 2004. Polymers 2017, 9, 161 to 2017 while viral products saw a dramatic decrease [6]. The efforts to develop enhanced polymeric vectors resulted in major advances such as larger gene delivery capacities, lower immunogenicity and easier manufacturing processes compared to the current viral vector technology [7,8]. Linear poly(β-amino ester)s (LPAEs), one type of the most versatile polymeric vectors first developed in
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