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Transformable amyloid-beta mimetic peptide amphiphiles for lysosomal disruption in non-small cell lung cancer
Christopher M Baehr1, Lu Zhang1, Yi Wu2
1Department of Biochemistry & Molecular Medicine, University of California Davis, School of Medicine, 2700 Stockton Blvd, Sacramento, CA, 95817, USA.
Abstract:
Non-small cell lung cancer (NSCLC) is the largest contributor to cancer mortality in the United States. Traditional chemotherapies are toxic and prone to the development of drug-resistance. Recently, several drug candidates were shown to induce lysosomal membrane permeabilization (LMP) in aggressive cancers. This has led to increased interest in lysosome dysregulation as a therapeutic target. However, approaches are needed to overcome two limitations of current lysosomal inhibitors: low specificity and potency. Here, we report the development of a transformable nanomaterial which is triggered to induce LMP of lysosomes in NSCLC. The nanomaterial consists of peptide amphiphiles, which self-assemble into nanoparticles, colocalize with the lysosome, and change conformation to nanofibrils due to lysosomal pH shift, which leads to the disruption of the lysosome, cell death, and cisplatin sensitization. We have found that this cell-penetrating transformable peptide nanoparticle (CPTNP) was cytotoxic to NSCLC cells in the low-micromolar range and it synergized cisplatin cytotoxicity four-fold. Moreover, we demonstrate CPTNP's promising antitumor effect in mouse xenograft models with limited toxicity when given in combination with low dose cisplatin chemotherapy. This is the first example of enhanced LMP via transformable peptide nanomaterial and offers a promising new strategy for cancer therapy.
Insights
A novel transformable peptide nanoparticle effectively targets and disrupts cancer lysosomes, offering a new strategy for non-small cell lung cancer (NSCLC) therapy and enhancing chemotherapy effectiveness.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Non-small cell lung cancer (NSCLC) presents a significant mortality burden, with traditional chemotherapies limited by toxicity and drug resistance.
- Lysosomal membrane permeabilization (LMP) is an emerging therapeutic target for aggressive cancers, but current inhibitors lack specificity and potency.
- Developing targeted approaches to induce LMP is crucial for advancing cancer treatment.
Purpose of the Study:
- To engineer a novel transformable nanomaterial capable of inducing lysosomal membrane permeabilization (LMP) specifically in NSCLC cells.
- To evaluate the efficacy and synergistic potential of this nanomaterial in combination with existing chemotherapies.
- To investigate the therapeutic potential of this approach in preclinical cancer models.
Main Methods:
- Design and synthesis of peptide amphiphiles self-assembling into cell-penetrating transformable peptide nanoparticles (CPTNPs).
- Assessment of CPTNP-induced LMP, cytotoxicity, and synergy with cisplatin in NSCLC cell lines.
- Evaluation of CPTNP and cisplatin combination therapy in mouse xenograft models of NSCLC.
Main Results:
- CPTNPs were found to colocalize with lysosomes and transform into nanofibrils in response to the acidic lysosomal pH, leading to LMP and cancer cell death.
- CPTNPs demonstrated low-micromolar cytotoxicity against NSCLC cells and synergized cisplatin cytotoxicity four-fold.
- Combination therapy with CPTNP and low-dose cisplatin showed promising antitumor effects in vivo with limited toxicity.
Conclusions:
- The developed CPTNP represents a novel strategy for targeted LMP induction in NSCLC.
- This transformable nanomaterial offers enhanced potency and specificity, overcoming limitations of current lysosomal inhibitors.
- CPTNPs hold significant promise as a therapeutic agent for NSCLC, particularly in combination with chemotherapy.
