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  3. Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer

Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer

  • Nat Commun. 2024 Mar 29;15(1):2759. doi: 10.1038/s41467-024-47080-3.
Yu-Yang Bi 1,  Qiu Chen 1,  Ming-Yuan Yang 1,  Lei Xing 1 2,  Hu-Lin Jiang 3 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China.
  • 3 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China. jianghulin3@gmail.com.
  • 4 Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, China Pharmaceutical University, Nanjing, 210009, China. jianghulin3@gmail.com.
  • 5 College of Pharmacy, Yanbian University, No.977, Gongyan Road, Yanji, 133000, China. jianghulin3@gmail.com.
PMID: 38553451 DOI: 10.1038/s41467-024-47080-3
Abstract

Non-small cell lung Cancer (NSCLC) shows high drug resistance and leads to low survival due to the high level of mutated Tumor Protein p53 (TP53). Cisplatin is a first-line treatment option for NSCLC, and the p53 mutation is a major factor in chemoresistance. We demonstrate that cisplatin chemotherapy increases the risk of TP53 mutations, further contributing to cisplatin resistance. Encouragingly, we find that the combination of cisplatin and fluvastatin can alleviate this problem. Therefore, we synthesize Fluplatin, a prodrug consisting of cisplatin and fluvastatin. Then, Fluplatin self-assembles and is further encapsulated with poly-(ethylene glycol)-phosphoethanolamine (PEG-PE), we obtain Fluplatin@PEG-PE nanoparticles (FP NPs). FP NPs can degrade mutant p53 (mutp53) and efficiently trigger endoplasmic reticulum stress (ERS). In this study, we show that FP NPs relieve the inhibition of cisplatin chemotherapy caused by mutp53, exhibiting highly effective tumor suppression and improving the poor NSCLC prognosis.

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