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Anticancer Efficacy of Photodynamic Therapy with Lung Cancer-Targeted Nanoparticles
Published on: December 1, 2016
Targeted Drug/Gene/Photodynamic Therapy via a Stimuli-Responsive Dendritic-Polymer-Based Nanococktail for Treatment
Jinxing Huang1, Cheng Zhuang1, Jie Chen1
1Precision Medicine Research Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
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.
Insights
A novel nanococktail therapy effectively targets drug-resistant non-small-cell lung cancer (NSCLC). This approach combines gefitinib and YAP-siRNA to overcome epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance, showing potent antitumor effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance is a major challenge in non-small-cell lung cancer (NSCLC) treatment.
- Yes-associated protein (YAP) is identified as a key driver of this EGFR-TKI resistance.
- Targeting YAP offers a potential therapeutic strategy for overcoming resistance in NSCLC.
Purpose of the Study:
- To develop a nanococktail therapeutic strategy for overcoming EGFR-TKI resistance in NSCLC.
- To achieve targeted co-delivery of gefitinib (EGFR-TKI) and YAP-siRNA using dendritic-polymer-based nanoparticles (NPs).
- To evaluate the efficacy and mechanisms of this combination therapy in preclinical models of resistant NSCLC.
Main Methods:
- Amphiphilic and block-dendritic-polymer-based nanoparticles (NPs) were synthesized for co-delivery.
- The NPs were designed for targeted cellular uptake, endosomal escape, and stimuli-responsive release of gefitinib and YAP-siRNA.
- In vivo efficacy was assessed in cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of gefitinib-resistant NSCLC.
Main Results:
- The NPs were effectively internalized into resistant NSCLC cells and released their payload intracellularly.
- The nanococktail preferentially accumulated at tumor sites, demonstrating potent antitumor efficacy with minimal toxicity after laser irradiation.
- Mechanism studies confirmed blockade of EGFR signaling, inhibition of YAP-mediated bypass pathways, and induction of apoptosis via photodynamic therapy (PDT).
Conclusions:
- Stimuli-responsive dendritic-polymer-based nanococktail therapy shows promise for treating EGFR-TKI resistant NSCLC.
- This combination approach sensitizes PDT and impairs glycolysis by downregulating HIF-1α.
- The developed nanomedicine offers a potential new strategy to overcome drug resistance in NSCLC.
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