CAIX-Targeting Self-Assembly of Peptide Amphiphile in Low Therapeutic Range Inducing Cellular Apoptosis

Abstract

Organelle-localization induced supramolecular self-assembly (OLISA) system has been reported for inducing cellular death by destroying an organelle, in which self-assembly structure is formed under spatiotemporal control. It is a novel strategy that could circumvent drug resistance, but overcoming off-targeting effect still re-mains a challenge to solve. Here, we hypothesize that cancer overexpressed enzyme targeting system can be a novel approach to increase the selectivity toward cancer cells, detouring normal cells. We describe an am-phiphilic tetrapeptide, Pep-AT, which contains two different kinds of functional ligands. One is an acetazolamide moiety, which is known for its targeting ability toward carbonic anhydrase IX enzyme (CAIX), and the other is triphenylphosphine (TPP) moiety for increasing organelle membrane interaction. Due to its intrinsic amphiphilic nature, Pep-AT can assemble into nanofiber above critical aggregation concentration. After Pep-AT targets CAIX, a local concentration of Pep-AT around cancer cells increases due to a far-from equilibrium toward CAIX over time, which can endow Pep-AT with driving force to achieve high concentration forming nanofiber structure on a plasma membrane. The nanofiber can be internalized into a lysosome through CAIX-mediated endocytosis. Moreover, a cohesion of the TPP moiety due to self-assembly gives Pep-AT a force to disrupt the organelle membrane. Therefore, Pep-AT can induce the cellular death even in a low therapeutic dose (<100 µM concentration) with the selectivity toward cancer cells.