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pH-Responsive, Lysine-Based, Hyperbranched Polymers Mimicking Endosomolytic Cell-Penetrating Peptides for Efficient Intracellular Delivery

Chem. Mater., DOI: 10.1021/acs.chemmater.7b00054 (2017).

Shiqi Wang and Rongjun Chen

The insufficient delivery of biomacromolecular therapeutic agents into the cytoplasm of mammalian cells remains a major barrier to their pharmaceutical applications. Cell-penetrating peptides (CPPs) are considered as potential carriers for cytoplasmic delivery of macromolecular drugs. However, due to the positive charge of most CPPs, strong non-specific cell membrane bindings may lead to relatively high toxicity. In this study, we report a series of anionic, CPP-mimicking, lysine-based hyperbranched polymers, which caused complete membrane disruption at late endosomal pH while remained non-lytic at physiological pH. The pH-responsive conformational alterations and the multivalency effect of the hyperbranched structures were demonstrated to effectively facilitate their interaction with cell membranes, thus leading to significantly enhanced membrane-lytic activity compared with their linear counterpart. The unique structures and pH-responsive cell-penetrating abilities make the novel hyperbranched polymers promising candidates for cytoplasmic delivery of biomacromolecular payloads.

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DOI: 10.1021/acs.chemmater.7b00054

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