Work

Study on the inhibition of non-small cell lung cancer mediated by chitosan-based gene carrier delivering STAT3-shRNA

Year: 2024

Type: article

Abstract: Systemic chemotherapy and radiotherapy often yield poor effect in the postoperative treatment of non-small cell lung cancer (NSCLC) and induce drug resistance. Herein, we proposed a targeted therapeutic approach utilizing gene carrier-mediated specific shRNA method. Firstly, the targeted short hairpin shRNA sequence, designed based on the STAT3 gene sequence, was inserted into the eukaryotic expression vector pGPU6/GFP/Neo to form the recombinant plasmid STAT3-shRNA. Next, a novel gene carrier, Vitamin E Succinate-Chitosan-Histidine (VES-CTS-His, VCH), was synthesized through an acylation reaction. The VCH was combined with pGPU6/GFP/Neo STAT3-shRNA recombinant plasmid by electrostatic interactions to form stable particles. VCH/pDNA, with typical nanoscale dimensions, could accumulate in tumor tissues through the EPR effect and enter tumor cells via endocytosis. VCH exhibited good pH responsiveness and could dissociate in the acidic microenvironment of tumors, thereby releasing the plasmids. Subsequently, the plasmids could downregulate STAT3 expression through RNAi effect. Inhibiting or blocking the expression of the STAT3 gene could significantly enhance the apoptotic induction and growth inhibition effects on NSCLC cells through the PI3K and mTOR signaling pathways, thereby achieving the goal of tumor treatment. This study provides a novel method for the construction of novel non-viral gene carriers and clinical gene-targeted therapy for NSCLC. Scheme 1. (A) Construction of VCH/pDNA nanoparticles and the pathway of entering into cells. (B) Mechanism of VCH/pDNA nanoparticles specifically targeting STAT3. • A multifunctional drug delivery carrier (VCH) was fabricated by vitamin E succinate, chitosan and histidine. • The VCH showed good cytocompatibility, biosecurity and transfection efficiency. • The VCH showed pH sensitivity and mitochondrial targeting ability • The VCH/pDNA nanoparticles could specifically down-regulate the expression level of STAT3 protein. • The VCH/pDNA reduced the tumor growth efficiently obviously in vivo.

Source: International Journal of Biological Macromolecules

DOI: 10.1016/j.ijbiomac.2024.138211