Membrane-Anchoring, Comb-Like Pseudopeptides for Efficient, pH-Mediated Membrane Destabilization and Intracellular...

Area of Science:

• Polymer Chemistry
• Biomaterials Science
• Nanotechnology

Background:

• Endosomal escape is a major hurdle for effective intracellular drug delivery, particularly for large molecules like macromolecular drugs.
• Developing strategies to overcome endosomal barriers is crucial for advancing therapeutic applications.

Purpose of the Study:

• To synthesize and characterize novel pH-responsive, membrane-anchoring polymers for enhanced endosomal release.
• To investigate the structure-activity relationship of these polymers concerning their endosomolytic efficiency and cytotoxicity.

Main Methods:

• Synthesis of comb-like pseudopeptidic polymers by grafting decylamine (NDA) onto poly(l-lysine iso-phthalamide).
• Evaluation of polymer properties, including aqueous solution behavior, membrane destabilization activity at different pH values, and in-vitro cytotoxicity.
• Investigation of the mechanism of membrane destabilization, including polymer-mediated pore formation.

Main Results:

• The optimal polymer, with 18 mol % NDA, showed limited hemolysis at pH 7.4 but rapid and near-complete membrane destabilization at endosomal pH (within 20 min).
• The hydrophobic side chains were essential for membrane anchoring and destabilization.
• The polymer demonstrated significant endosomolytic activity, facilitating the release of endocytosed materials into the cytoplasm of various cell lines.

Conclusions:

• Synthetic pH-responsive, membrane-anchoring polymers can effectively promote endosomal escape.
• These polymers represent a promising strategy for improving intracellular delivery of therapeutic agents, especially macromolecular drugs.
• The findings highlight the potential of tailored polymer design for overcoming biological barriers in drug delivery.