Intra-Lysosomal Assembly of Peptides for Highly Selective Cancer Cell Death and Overcoming of Drug Resistance

Abstract

Lysosomes remain powerful organelles and important targets for cancer therapy, because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancers by bypassing the classical caspase-dependent apoptotic pathway. However, very few therapeutic strategies target the lysosomes of cancer cells. Most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, and eventually causes caspase-independent apoptotic death of cancer cells. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth.