Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer

Abstract

Lysosomes remain powerful organellesand important targetsforcancer therapy because cancer cell proliferation is greatly dependenton effective lysosomal function. Recent studies have shown that lysosomalmembrane permeabilization induces cell death and is an effective wayto treat cancer by bypassing the classical caspase-dependent apoptoticpathway. However, most lysosome-targeted anticancer drugs have verylow selectivity for cancer cells. Here, we show intra-lysosomal self-assemblyof a peptide amphiphile as a powerful technique to overcome this problem.We designed a peptide amphiphile that localizes in the cancer lysosomeand undergoes cathepsin B enzyme-instructed supramolecular assembly.This localized assembly induces lysosomal swelling, membrane permeabilization,and damage to the lysosome, which eventually causes caspase-independentapoptotic death of cancer cells without conventional chemotherapeuticdrugs. It has specific anticancer effects and is effective againstdrug-resistant cancers. Moreover, this peptide amphiphile exhibitshigh tumor targeting when attached to a tumor-targeting ligand andcauses significant inhibition of tumor growth both in cancer and drug-resistantcancer xenograft models.