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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume -, Issue -, Pages -Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.3c04467
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Lysosomes are important organelles and targets for cancer therapy. Recent studies have shown that lysosomal membrane permeabilization can induce cell death, providing an effective way to treat cancer. However, most lysosome-targeted anticancer drugs lack selectivity for cancer cells. This study demonstrates the use of intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. The peptide amphiphile localizes in the cancer lysosome and undergoes enzyme-instructed supramolecular assembly, leading to lysosomal damage and caspase-independent apoptotic death of cancer cells.
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.
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