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RGD-Functionalized ZIF-8 Nanocarriers Enable Highly Selective Delivery of Repurposed Gliclazide in Breast Cancer
Gaayatri Silvaraju1, Mostafa Yousefzadeh Borzehandani2, Nur Airin Syahira Johari1
1Department of Chemical Engineering Technology, Faculty of Chemical and Process Engineering Technology, University of Malaysia Pahang Al-Sultan Abdullah (UMPSA), 26300 Gambang, Pahang, Malaysia.
Abstract:
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.
Insights
This study repurposed the antidiabetic drug gliclazide (GLI) into RGD-functionalized nanoparticles for targeted breast cancer therapy. The novel nanocarrier system demonstrated enhanced cancer cell toxicity and improved selectivity.
Area of Science:
- Nanotechnology
- Materials Science
- Biomedical Engineering
Background:
- Conventional breast cancer chemotherapy faces challenges including systemic toxicity, poor selectivity, and drug resistance.
- Gliclazide (GLI), an antidiabetic drug, shows potential for anticancer applications.
- Developing targeted drug delivery systems is crucial for improving therapeutic efficacy and reducing side effects.
Purpose of the Study:
- To repurpose gliclazide (GLI) by encapsulating it within zeolitic imidazolate framework-8 (nZIF-8) nanoparticles.
- To functionalize the nanoparticles with an arginylglycylaspartic acid (RGD) peptide for tumor-homing capabilities, creating RGD@nZIF-8/GLI.
- To evaluate the physicochemical properties, drug release kinetics, and in vitro cytotoxicity of the RGD-functionalized nanoparticles for breast cancer treatment.
Main Methods:
- Synthesis of nanosized zeolitic imidazolate framework-8 (nZIF-8) via a one-pot solvothermal method.
- Encapsulation of gliclazide (GLI) into nZIF-8 and surface functionalization with RGD peptide.
- Characterization of nanocarrier structure, physicochemical properties, drug loading, in vitro release studies at different pH, and cytotoxicity assays against MCF-7 and MRC-5 cell lines.
Main Results:
- The RGD@nZIF-8/GLI nanoparticles maintained structural integrity with successful GLI encapsulation and RGD functionalization.
- High encapsulation efficiency (>99%) and stable drug loading were achieved.
- The nanoparticles exhibited pH-responsive drug release, with accelerated release at acidic pH (5.5).
- RGD@nZIF-8/GLI demonstrated enhanced cytotoxicity against MCF-7 breast cancer cells (44% at 1 μg mL⁻¹) and reduced toxicity toward normal MRC-5 fibroblasts, leading to a higher selectivity index.
Conclusions:
- RGD-functionalized nZIF-8 nanoparticles represent a promising platform for targeted breast cancer therapy.
- The nanocarrier system effectively delivers repurposed gliclazide with improved selectivity and pH-responsive release.
- This approach offers a potential strategy to overcome limitations of conventional chemotherapy in breast cancer treatment.
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