Degradable gene delivery systems based on Pluronics-modified low-molecular-weight polyethylenimine: preparation, characterization, intracellular trafficking, and cellular distribution

Wei Fan^1,2,*, Xin Wu^1,*, Baoyue Ding^3,*, Jing Gao⁴, Zhen Cai¹, Wei Zhang¹, Dongfeng Yin¹, Xiang Wang¹, Quangang Zhu¹, Jiyong Liu¹, Xueying Ding⁴, Shen Gao<sup>1

1</sup>Department of Pharmaceutics, Changhai Hospital, Second Military Medical University, Shanghai, ²Department of Pharmaceutics, The 425th Hospital of PLA, Sanya, ³Department of Pharmaceutics, Medical College of Jiaxing University, Jiaxing, ⁴Department of Pharmaceutics, School of Pharmacy, Second Military Medical University, Shanghai, People's Republic of China

*These authors contributed equally to this work

Background: Cationic copolymers consisting of polycations linked to nonionic amphiphilic block polymers have been evaluated as nonviral gene delivery systems, and a large number of different polymers and copolymers of linear, branched, and dendrimeric architectures have been tested in terms of their suitability and efficacy for in vitro and in vivo transfection. However, the discovery of new potent materials still largely relies on empiric approaches rather than a rational design. The authors investigated the relationship between the polymers' structures and their biological performance, including DNA compaction, toxicity, transfection efficiency, and the effect of cellular uptake.
Methods: This article reports the synthesis and characterization of a series of cationic copolymers obtained by grafting polyethyleneimine with nonionic amphiphilic surfactant polyether-Pluronic^® consisting of hydrophilic ethylene oxide and hydrophobic propylene oxide blocks. Transgene expression, cytotoxicity, localization of plasmids, and cellular uptake of these copolymers were evaluated following in vitro transfection of HeLa cell lines with various individual components of the copolymers.
Results: Pluronics can exhibit biological activity including effects on enhancing DNA cellular uptake, nuclear translocation, and gene expression. The Pluronics with a higher hydrophilic-lipophilic balance value lead to homogeneous distribution in the cytoplasm; those with a lower hydrophilic-lipophilic balance value prefer to localize in the nucleus.
Conclusion: This Pluronic-polyethyleneimine system may be worth exploring as components in the cationic copolymers as the DNA or small interfering RNA/microRNA delivery system in the near future.

Keywords: Pluronics, gene transfer, nonviral vectors, transfection efficiency, cellular uptake

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