Bioreducible Zinc(II)-Coordinative Polyethylenimine with Low Molecular Weight for Robust Gene Delivery of Primary and Stem Cells

• Published in: Journal of the American Chemical Society Vol. 139; no. 14; pp. 5102 - 5109
• Main Authors: Liu, Shuai, Zhou, Dezhong, Yang, Jixiang, Zhou, Hao, Chen, Jiatong, Guo, Tianying
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 12.04.2017; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; PLATFORM; IN-VITRO; EFFICACY; TRANSFECTION; DNA; BRANCHED POLY(BETA-AMINO ESTERS); TOXICITY; SIRNA; ASTROCYTES; NUCLEIC-ACIDS
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.6b13337

To transform common low-molecular-weight (LMW) cationic polymers, such as poly­ethylen­imine (PEI), to highly efficient gene vectors would be of great significance but remains challenging. Because LMW cationic polymers perform far less efficiently than their high-molecular-weight counterparts, mainly due to weaker nucleic acid encapsulation, herein we report the design and synthesis of a dipicolyl­amine-based disulfide-containing zinc­(II) coordinative module (Zn-DDAC), which is used to functionalize LMW PEI (M w ≈ 1800 Da) to give a non-viral vector (Zn-PD) with high efficiency and safety in primary and stem cells. Given its high phosphate binding affinity, Zn-DDAC can significantly promote the DNA packaging functionality of PEI1.8k and improve the cellular uptake of formulated polyplexes, which is particularly critical for hard-to-transfect cell types. Furthermore, Zn-PD polymer can be cleaved by glutathione in cytoplasm to facilitate DNA release post internalization and diminish the cytotoxicity. Consequently, the optimal Zn-PD mediates 1–2 orders of magnitude higher gluciferase activity than commercial transfection reagents, Xfect and PEI25k, across diverse cell types, including primary and stem cells. Our findings provide a valuable insight into the exploitation of LMW cationic polymers for gene delivery and demonstrate great promise for the development of next-generation non-viral vectors for clinically viable gene therapy.