Dataset Information

AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC.

ABSTRACT: 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.

SUBMITTER: Gu Y

PROVIDER: S-EPMC7816715 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC.

Gu Yu Y Lai Songtao S Dong Yang Y Fu Hao H Song Liwei L Chen Tianxiang T Duan Yourong Y Zhang Zhen Z

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20201204 2

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 ...[more]

PMID: 33511016

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Project description:BackgroundBased on the concept of "multimodal analgesia", a novel dual drug delivery system was designed to achieve synergistic analgesia between najanajaatra venom protein (αCT) and resveratrol (Res). In order to meet the joint loading of two drugs with different physicochemical properties without affecting each other, an oral Janus nanoparticle (JNP) with a unique cavity structure and synergistic drug delivery was constructed using an improved double emulsion solvent evaporation method, and combined with low-molecular-weight chitosan/sodium alginate and PLGA to achieve its pH-responsive.ResultsThe synthesized αCT/Res-JNPs are homogeneous in shape, with a two-compartment structure, approximately 230 nm in size, and zeta potential of 23.6 mV. Drug release assayed in vitro show that JNP was stable in simulated gastric juice (pH = 1.2) but was released in phosphate buffer saline (pH = 7.4). After intragastric administration in rats, PK evaluation showed that αCT/Res-JNPs could significantly improve the oral bioavailability, and the simultaneous encapsulation of the two drugs had no significant interaction on PK parameters. An obvious synergistic analgesic effects of αCT/Res-JNPs was confirmed in a spinal cord injury and acute pain model. Confocal laser scanning microscopy and single-pass intestinal perfusion model provided strong evidence that αCT/Res-JNPs could pass through intestinal epithelial cells, and the endocytosis pathway was mainly involved in the mediation and pinocytosis of reticulin. The concentrations of αCT and Res from αCT/Res-JNP in lymphatic transport were only about 8.72% and 6.08% of their blood concentrations at 1 h, respectively, which indicated that lymphatic transport in the form of JNP has limited advantages in improving the oral bioavailability of Res and αCT. Cellular uptake efficiency at 4 h was about 10-15% in Caco-2 cell lines for αCT/Res-JNP, but was reduced to 7% in Caco-2/HT29-MTX co-culture models due to the hindrance by the mucus layers. Approximately 12-17% of αCT/Res-JNP were transported across Caco-2/HT29-MTX/Raji monolayers. The cumulative absorption of JNP in three cell models was higher than that of free drug.ConclusionsThis study investigated the contribution of Janus nanoparticles in oral absorption, and provide a new perspective for oral administration and analgesic treatment of dual drug delivery system containing peptide drugs.

Dataset Information

AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC.

Publications

AZD9291 Resistance Reversal Activity of a pH-Sensitive Nanocarrier Dual-Loaded with Chloroquine and FGFR1 Inhibitor in NSCLC.

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