Self‐assembled Lipid Nanoparticles for Ratiometric Codelivery of Cisplatin and siRNA Targeting XPF to Combat Drug Resistance in Lung Cancer. Issue 9 (4th April 2019)

• Record Type: Journal Article
• Authors: Li, Cai; Li, Tianzhong; Huang, Linfeng; Yang, Mengsu; Zhu, Guangyu
• Is Part Of: Chemistry, an Asian journal. Volume 14:Issue 9(2019)
• Page Start: 1570
• Page End: 1576
• Publication Date: 2019-04-04
• Subjects: cisplatin -- drug delivery -- gene silencing -- nucleotide excision repair -- resistance; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/asia.201900005
• Languages: English
• ISSNs: 1861-4728

Abstract

Abstract: DNA damage repair through the nucleotide excision repair (NER) pathway is one of the major reasons for the decreased antitumor efficacy of platinum‐based anticancer drugs that have been widely applied in the clinic. Inhibiting the intrinsic NER function may enhance the antitumor activity of cisplatin and conquer cisplatin resistance. Herein, we report the design, optimization, and application of a self‐assembled lipid nanoparticle (LNP) system to simultaneously deliver a cisplatin prodrug together with siRNA targeting endonuclease xeroderma pigmentosum group F (XPF), a crucial component in the NER pathway. The LNP is able to efficiently encapsulate both the platinum prodrug and siRNA molecules with a tuned ratio. Both platinum prodrug and XPF‐targeted siRNA are efficiently carried into cells and released; the former damages DNA and the latter specifically downregulates both mRNA and protein levels of XPF to potentiate the platinum drug, leading to enhanced expression levels of apoptosis markers and improved cytotoxicity in both cisplatin‐sensitive and ‐resistant human lung cancer cells. Our results demonstrate an effective approach to utilize a multi‐targeted nanoparticle system that can specifically silence an NER‐related gene to promote apoptosis induced by cisplatin, especially in cisplatin‐refractory tumors. Abstract : Resistance is futile : A siRNA targeting endonuclease xeroderma pigmentosum group F (XPF) and a cisplatin prodrug were assembled into stable lipid nanoparticles. The multifunctional nanoplatform with an optimized ratio of siRNA and Pt efficiently induces DNA damage and inhibits nucleotide excision repair (NER) activity simultaneously to overcome cisplatin resistance.