Journal article
Nanoparticle Co-delivery of Microtubule Inhibitors and Cisplatin Overcomes DNA Repair-Mediated Resistance in Head and Neck Cancer
Molecular cancer therapeutics
09/23/2026
DOI: 10.1158/1535-7163.MCT-25-1239
PMID: 42777141
Abstract
Cisplatin remains a crucial chemotherapeutic for head and neck squamous cell carcinoma (HNSCC), but its effectiveness is limited by intrinsic or acquired resistance driven largely by enhanced DNA crosslink repair. Through a combined screen of DNA crosslink repair and cisplatin sensitivity modulators, our current study identifies a strong synergy between cisplatin and microtubule-targeting agents (MTAs), including taxanes and colchicine. MTAs suppress DNA crosslink repair and overcome cisplatin resistance in HNSCC cells. Mechanistically, MTAs impair the resolution of cisplatin-induced lesions, consistent with reduced recruitment of the XPF-ERCC1 endonuclease required for DNA crosslink unhooking. MTAs also diminish homologous recombination, accompanied by reduced recruitment of RPA32 and RAD51 to DNA damage sites. Moreover, MTAs disrupt DNA damage checkpoint activation in response to cisplatin, permitting cell cycle transit through S-phase despite persistent DNA damage. Together, these effects drive enhanced DNA damage accumulation and apoptosis in HNSCC cells treated with the cisplatin-MTA combination. To further harness this synergy for therapeutic benefit, we employ poly(2-oxazoline)-based (POx) micelles to co-encapsulate paclitaxel and a hydrophobic cisplatin prodrug with two aliphatic hexane chains (C6CP). This nanoformulation was developed to improve drug solubility and release profiles, resulting in optimized pharmacokinetics and enhanced tumor delivery and retention. Indeed, in syngeneic HNSCC models, nanoparticle co-delivery of paclitaxel and cisplatin prodrug produced markedly superior antitumor efficacy compared to the free drug combination. Collectively, our findings define a mechanism-guided, nanoparticle-enabled therapeutic approach for sensitizing HNSCC to platinum-based chemotherapy through selective disruption of DNA damage responses.
Details
- Title: Subtitle
- Nanoparticle Co-delivery of Microtubule Inhibitors and Cisplatin Overcomes DNA Repair-Mediated Resistance in Head and Neck Cancer
- Creators
- Xin Li - University of North Carolina at Chapel HillLiubov Palchak - University of North Carolina at Chapel HillLing Wang - University of North Carolina at Chapel HillDivya S Bhat - University of Iowa Holden Comprehensive Cancer CenterAliasger K Salem - University of IowaMarina Sokolsk - University of North Carolina at Chapel HillAlexander V Kabanov - University of North Carolina at Chapel HillAimin Peng - University of North Carolina at Chapel Hill
- Resource Type
- Journal article
- Publication Details
- Molecular cancer therapeutics
- DOI
- 10.1158/1535-7163.MCT-25-1239
- PMID
- 42777141
- NLM abbreviation
- Mol Cancer Ther
- ISSN
- 1538-8514
- eISSN
- 1538-8514
- Publisher
- American Association for Cancer Research
- Language
- English
- Electronic publication date
- 09/23/2026
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Research Administration; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
- Record Identifier
- 9985236322202771
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