Spatiotemporal Self-assembly of Peptide Amphiphile by CAIX-Targeting Induces Cancer-Lysosomal Membrane Disruption

Abstract

The controllable peptide self-assembly has been emerged as novel strategy for modulating cellular behavior. Since cellular milieu is highly dynamic, cellular fate can be precisely controlled when proper spatiotemporal control is achieved. In order to achieve spatiotemporal control inside cells, enzyme instructed self-assembly system has been widely used. However, this strategy usually exhibits a minimal impact on the cellular fate. Recently, studies have been reported to directly modulate cellular fate by disrupting lipophilic membrane using self-assembly with high positively charged bioactive epitope. Herein, we designed Pep-AT, functionalized by acetazolamide and triphenylphosphonium (TPP), in which self-assembly behavior can be tuned depending on pH. At pH 7.4, a large aggregate with negative surface charge is formed due to deprotonation of acetazolamide. However, a highly ordered self-assembly structure with positive surface charge is formed at pH 4.5 with protonation of acetazolamide and TPP. At the cellular level, Pep-AT can target CAIX selectively overexpressed cancerous membrane, and trapped into lysosome via CAIX-mediated endocytosis in spatiotemporal manner. At only lysosome environment, Pep-AT can interact and disrupt the membrane due to presentation of high positive charge from TPP, and induce cellular apoptosis. This study demonstrates controllable self-assembly system at cellular level in combination with enhancement for the interaction with lipophilic membrane. Thus, this system presents the possibility of further application into cancer therapy by modulating cellular behavior directly.