FA receptor-targeted pH-sensitive polymeric micelles co-encapsulating quercetin and paclitaxel for synergistic reversal of drug resistance in non-small cell lung cancer

The FA-modified pH-sensitive micelles (FA-PM@QCT/PTX) can enhance tumor targeting and lysosome-triggered drug release. • The system reverses chemotherapy resistance via the synergistic action of co‑delivered quercetin and paclitaxel, significantly enhancing cytotoxicity and inducing apoptosis in drug‑resistant cancer cells. • The system demonstrates potent antitumor efficacy with excellent biocompatibility in vivo , markedly inhibiting tumor growth while showing minimal systemic toxicity. Background Chemotherapy remains a major challenge in the effective treatment of non-small cell lung cancer (NSCLC), particularly due to chemotherapy resistance. Natural products, including Chinese herbal extracts, have shown potential for improving chemotherapy sensitivity, but their clinical application is limited by poor tumor targeting and insufficient in vivo stability. Purpose This study aimed to improve PTX-based treatment against resistant NSCLC by developing a FA receptor-targeted pH-sensitive co-delivery system for QCT and PTX. Study design A novel FA receptor-targeted pH-responsive nano-delivery system, FA-PM@QCT/PTX, was constructed and evaluated using PTX-resistant A549/Taxol cells and A549/Taxol tumor-bearing mouse models. Methods FA-PM@QCT/PTX was prepared and characterized in terms of particle size, PDI, zeta potential, encapsulation efficiency, and drug-loading content. In vitro pH-responsive release, cellular uptake, QCT/PTX synergism, cytotoxicity, apoptosis, cell-cycle distribution, P-gp expression, PI3K/Akt signaling, apoptosis-related proteins, and intracellular PTX retention were evaluated in A549/Taxol cells. Pharmacokinetics, tissue distribution, antitumor efficacy, survival benefit, and preliminary systemic safety were further assessed in A549/Taxol tumor-bearing mice. Results FA-PM@QCT/PTX showed a particle size of 166.75 ± 4.10 nm, a PDI of 0.14 ± 0.03, and a zeta potential of -6.34 ± 0.52 mV. The encapsulation efficiencies were 82.48 ± 3.82% for QCT and 84.17 ± 1.21% for PTX, with drug-loading contents of 3.64 ± 0.17% and 3.59 ± 0.11%, respectively. The self-assembled micelles could be internalized by tumor cells via FA receptor-mediated uptake and promote drug release under acidic lysosomal conditions. Chou-Talalay analysis showed that QCT enhanced the inhibitory effect of PTX on A549/Taxol cells, and the actual PTX:QCT molar ratio in FA-PM@QCT/PTX was approximately 1:3, which remained synergistic with a combination index (CI) value of 0.927 ± 0.021. Mechanistically, FA-PM@QCT/PTX reduced P-gp expression, enhanced intracellular PTX retention, suppressed PI3K/Akt signaling, and promoted apoptosis-related pathway activation. In vivo , FA-PM@QCT/PTX improved tumor drug accumulation and prolonged the median survival of A549/Taxol tumor-bearing mice to 52 days without obvious systemic toxicity. Conclusions These results suggest that FA-PM@QCT/PTX may provide a promising co-delivery strategy for improving PTX-based treatment against resistant NSCLC. Download: Download high-res image (371KB) Download: Download full-size image