Journal
ADVANCED SCIENCE
Volume 8, Issue 2, Pages -Publisher
WILEY
DOI: 10.1002/advs.202002922
Keywords
autophagy; AZD9291; chloroquine; fibroblast growth factor receptor 1; nanoparticles
Categories
Funding
- National Natural Science Foundation of China [81601995, 81301996]
- Shanghai Science and Technology Committee [18411966100]
- Development Fund for Shanghai Talents [2019093]
- Nurture projects for basic research of Shanghai Chest Hospital [2018YNJCM04]
- Open Fund of Zhejiang Provincial Top Key Discipline of Pharmacology [YKFJ2-001]
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The study reveals activation of autophagy and FGFR1 signaling pathways in AZD9291 resistant NSCLC, and demonstrates that the pH-sensitive shell-core nanoparticles CP@NP-cRGD can effectively reverse resistance by inducing apoptosis, G0/G1 phase arrest, and downregulation of p-ERK1/2. The coloaded CQ and PD173074 nanoparticle has shown tumor targeting abilities, low toxicity and promising antitumor effects in mouse models, providing a potential novel approach for overcoming AZD9291 resistance in clinical settings.
AZD9291 can effectively prolong survival of non-small cell lung cancer (NSCLC) patients. Unfortunately, the mechanism of its acquired drug resistance is largely unknown. This study shows that autophagy and fibroblast growth factor receptor 1 signaling pathways are both activated in AZD9291 resistant NSCLC, and inhibition of them, respectively, by chloroquine (CQ) and PD173074 can synergistically reverse AZD9291 resistance. Herein, a coloaded CQ and PD173074 pH-sensitive shell-core nanoparticles CP@NP-cRGD is developed to reverse AZD9291 resistance in NSCLC. CP@NP-cRGD has a high encapsulation rate and stability, and can effectively prevent the degradation of drugs in circulation process. CP@NP-cRGD can target tumor cells by enhanced permeability and retention effect and the cRGD peptide. The pH-sensitive CaP shell can realize lysosome escape and then release drugs successively. The combination of CP@NP-cRGD and AZD9291 significantly induces a higher rate of apoptosis, more G0/G1 phase arrest, and reduces proliferation of resistant cell lines by downregulation of p-ERK1/2 in vitro. CQ in CP@NP-cRGD can block protective autophagy induced by both AZD9291 and PD173074. CP@NP-cRGD combined with AZD9291 shows adequate tumor enrichment, low toxicity, and excellent antitumor effect in nude mice. It provides a novel multifunctional nanoparticle to overcome AZD9291 resistance for potential clinical applications.
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