In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization

Angew Chem Int Ed Engl. 2021 Sep 22. doi: 10.1002/anie.202111839. Online ahead of print.ABSTRACTTherapeutic peptides have been widely concerned because of their good biocompatibility, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization and anticancer efficacy. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK] 2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP) on the cell membrane, KYp can be dephosphorylated and self-assembles in situ , which induces the aggregation of ALP and the protein-lipid phase separation on the cell membrane. ALP is involved in the assembly of peptides, forming the large aggregates and entering cells, which leads to the enhanced permeability of cell membrane. Consequently, the peptide drugs internalization is ~2-fold enhanced compared to non-responsive peptide nanoparticle, and IC 50 value of KYp is approximately ~5 times lower than that of free peptide. Finally, the tumor of mice treated with KYp is suppressed effectively, showing the negligible side effect in vivo . Therefore, the in vivo self-assembly induced phase separation on the cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.PMID:34549872 | DOI:10.1...
Source: Angewandte Chemie - Category: Chemistry Authors: Source Type: research