Targeting Cancer Chemotherapy Resistance by Precision Medicine-Driven Nanoparticle-Formulated Cisplatin
Svenja Siemer1, Tobias A Bauer2,3, Paul Scholz4
1Nanobiomedicine/ENT Department, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
ACS Nano
|November 5, 2021
Summary
Researchers identified the ion channel LRRC8A as key to cisplatin resistance in cancer. They developed nanoparticle cisplatin (NPCis) that bypasses LRRC8A, effectively killing resistant cancer cells and improving patient survival.
Area of Science:
- Oncology
- Nanotechnology
- Molecular Biology
Background:
- Therapy resistance is a major cause of cancer mortality.
- Precision medicine necessitates understanding and targeting cancer resistance mechanisms.
- Nanoparticles (NPs) offer potential for targeted cancer therapy.
Purpose of the Study:
- To identify key molecular players in cisplatin resistance.
- To develop nanoparticle-based therapeutics to overcome cisplatin resistance.
- To evaluate the clinical relevance of identified resistance mechanisms.
Main Methods:
- Generated cisplatin-resistant cancer cells.
- Utilized next-generation sequencing and CRISPR/Cas9 technology to identify resistance genes.
- Verified LRRC8A's role in cisplatin resistance.
- Developed and characterized cisplatin-loaded nanoparticles (NPCis).
- Assessed NPCis efficacy in 2D/3D spheroid models.
Main Results:
- Identified the ion channel LRRC8A as critical for cisplatin resistance.
- Demonstrated LRRC8A's differential expression in head and neck cancer patients, correlating with survival.
- Developed biocompatible, stable NPCis with favorable pharmacokinetic properties.
- NPCis eradicated cisplatin-resistant cells by bypassing LRRC8A via endocytic delivery, outperforming standard cisplatin.
Conclusions:
- LRRC8A is a critical determinant of cisplatin resistance.
- Nanoparticle cisplatin (NPCis) effectively overcomes LRRC8A-mediated resistance.
- LRRC8A can guide patient stratification for nanomedicine clinical trials targeting platinum-based therapy resistance.
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