Co-encapsulated resveratrol and paclitaxel in liposomes coating with RGDfC peptide for drug resistance reversal in renal cell carcinoma.

BACKGROUND: Drug resistance critically impedes renal cell carcinoma therapy. A dual-targeted liposomal system that codelivered resveratrol (RES) and paclitaxel (PTX) with αvβ3 integrin-targeting was developed to overcome multidrug resistance (MDR).

METHODS: RGDfC peptide-functionalized liposomes (PTX/RES-RGDfC-Lip) were synthesized via film hydration-ultrasound methods. The particle size, zeta potential, drug encapsulation efficiency, and release kinetics were evaluated. P-glycoprotein (P-gp) modulation, cellular uptake, and chemosensitization in PTX-resistant A498 cells (PTX-res-A498) and in vivo antitumor efficacy were studied in xenograft models.

RESULTS: The RGDfC ligand enables selective tumor delivery by binding to αvβ3 integrins that are overexpressed in the renal carcinoma vasculature, whereas RES enhances PTX efficacy by modulating P-gp-mediated drug efflux. Liposomes were synthesized via film hydration-ultrasound methods and systematically characterized for size (109.8 ± 4.2 nm), zeta potential (-8.91 ± 0.75 mV), dual-drug encapsulation efficiency (RES: 90.56 ± 4.30%; PTX: 90.23 ± 4.66%), and sustained release kinetics. In vitro studies demonstrated 3.19-fold greater cellular uptake in resistant renal carcinoma cells (PTX-res-A498 cells) than in nontargeted formulations. In vivo, PTX/RES-RGDfC-Lip resulted in 70.2% tumor reduction in xenograft models. Mechanistic studies confirmed the RES-mediated downregulation of P-gp expression and the restoration of chemosensitivity.

CONCLUSION: This dual-targeted codelivery system represents a promising strategy for overcoming MDR in advanced renal carcinoma.