RGD-Functionalized ZIF-8 Nanocarriers Enable Highly Selective Delivery of Repurposed Gliclazide in Breast Cancer

The development of targeted and efficient therapeutic platforms remains a critical challenge in breast cancer treatment due to the systemic toxicity, poor selectivity, and drug resistance associated with conventional chemotherapy. In this study, gliclazide (GLI), a clinically approved antidiabetic drug with emerging anticancer potential, was repurposed through encapsulation within nanosized zeolitic imidazolate framework-8 (nZIF-8), followed by surface functionalization with a tumor-homing arginylglycylaspartic acid (RGD) peptide to construct RGD@nZIF-8/GLI nanoparticles. The nanocarriers were synthesized via a one-pot solvothermal method and systematically characterized. The overall structural integrity of the nZIF-8 framework was preserved after drug encapsulation and peptide conjugation. At the same time, clear evidence of GLI incorporation and RGD functionalization was observed without disrupting Zn-N coordination. Physicochemical changes, including reduced porosity, increased particle size, and altered surface charge, collectively indicated effective pore filling and surface modification. The exceptionally high encapsulation efficiency (>99%) and stable drug loading further demonstrate GLI's strong affinity for the ZIF-8 framework and the robustness of the full nanocarrier system. In vitro release studies demonstrated pronounced pH-responsive behavior, with accelerated drug release at acidic pH 5.5. Cytotoxicity evaluation at 48 h revealed that RGD@nZIF-8/GLI enhanced toxicity against MCF-7 breast cancer cells (44% at 1 μg mL^-1) while maintaining reduced toxicity toward MRC-5 normal fibroblasts, resulting in a markedly improved selectivity index. Overall, this work demonstrates that RGD-functionalized nZIF-8 is a promising pH-responsive and selective nanoplatform for the targeted delivery of repurposed therapeutics in breast cancer treatment.