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Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer
Batakrishna Jana1, Seongeon Jin1, Eun Min Go2
1Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea.
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 cancer by bypassing the classical caspase-dependent apoptotic pathway. However, 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, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. 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 both in cancer and drug-resistant cancer xenograft models.
Insights
Researchers developed a peptide amphiphile that self-assembles inside cancer lysosomes, triggering cell death. This targeted approach offers a novel strategy for treating cancers, including drug-resistant types.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Lysosomes are crucial for cancer cell proliferation and are key targets for cancer therapy.
- Lysosomal membrane permeabilization induces cancer cell death, bypassing traditional apoptosis pathways.
- Existing lysosome-targeting anticancer drugs lack selectivity for cancer cells.
Purpose of the Study:
- To develop a peptide amphiphile for intra-lysosomal self-assembly to target cancer cells selectively.
- To investigate the potential of enzyme-instructed self-assembly for cancer therapy.
- To evaluate the efficacy of this approach against drug-resistant cancers.
Main Methods:
- Design of a peptide amphiphile that self-assembles within lysosomes.
- Utilizing cathepsin B enzyme for instructed supramolecular assembly.
- Assessment of lysosomal damage and cancer cell death induction.
- In vivo studies using tumor-targeting ligands in xenograft models.
Main Results:
- The peptide amphiphile self-assembles specifically within cancer lysosomes.
- Assembly induces lysosomal swelling, membrane permeabilization, and damage.
- This leads to caspase-independent cancer cell death.
- The approach shows efficacy against drug-resistant cancers and inhibits tumor growth in vivo.
Conclusions:
- Intra-lysosomal self-assembly of peptide amphiphiles is a viable strategy for cancer therapy.
- This method offers high selectivity and overcomes drug resistance.
- The targeted delivery and assembly mechanism show significant potential for cancer treatment.
