Targeted Drug/Gene/Photodynamic Therapy via a Stimuli-Responsive Dendritic-Polymer-Based Nanococktail for Treatment of EGFR-TKI-Resistant Non-Small-Cell Lung Cancer.

Abstract

Yes-associated protein (YAP) has been identified as a key driver for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance. Inhibition of YAP expression could be a potential therapeutic option for treating non-small-cell lung cancer (NSCLC). Herein, a nanococktail therapeutic strategy is proposed by employing amphiphilic and block-dendritic-polymer-based nanoparticles (NPs) for targeted co-delivery of EGFR-TKI gefitinib (Gef) and YAP-siRNA to achieve a targeted drug/gene/photodynamic therapy. The resulting NPs are effectively internalized into Gef-resistant NSCLC cells, successfully escape from late endosomes/lysosomes, and responsively release Gef and YAP-siRNA in an intracellular reductive environment. They preferentially accumulate at the tumor site after intravenous injection in both cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of Gef-resistant NSCLC, resulting in potent antitumor efficacy without distinct toxicity after laser irradiation. Mechanism studies reveal that the cocktail therapy could block the EGFR signaling pathway with Gef, inhibit activation of the EGFR bypass signaling pathway via YAP-siRNA, and induce tumor cell apoptosis through photodynamic therapy (PDT). Furthermore, this combination nanomedicine can sensitize PDT and impair glycolysis by downregulating HIF-1α. These results suggest that this stimuli-responsive dendritic-polymer-based nanococktail therapy may provide a promising approach for the treatment of EGFR-TKI resistant NSCLC.

• Authors: Jinxing Huang, Cheng Zhuang, Jie Chen, Xuanming Chen, Xiaojie Li, Ting Zhang, Bing Wang, Qiyi Feng, Xiuli Zheng, Meng Gong, Qiyong Gong, Kai Xiao, Kui Luo, Weimin Li
• Journal: Advanced materials (Deerfield Beach, Fla.) (Adv Mater) Vol. 34 Issue 27 Pg. e2201516 (Jul 2022) ISSN: 1521-4095 [Electronic] Germany
• PMID: 35481881 (Publication Type: Journal Article)
• Copyright: © 2022 Wiley-VCH GmbH.

Chemical References

• Pharmaceutical Preparations
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Stimuli Responsive Polymers
• EGFR protein, human
• ErbB Receptors

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
• Cell Line, Tumor
• Cell Proliferation
• Drug Resistance, Neoplasm
• ErbB Receptors (metabolism)
• Humans
• Lung Neoplasms (drug therapy, pathology)
• Pharmaceutical Preparations
• Photochemotherapy
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• RNA, Small Interfering (genetics)
• Stimuli Responsive Polymers
• Xenograft Model Antitumor Assays