Assessment of pH-Responsive Ionisable Lipid Nanoparticles as Cisplatin Delivery Vehicles for Treating...

Background: Platinum-based chemotherapy, including cisplatin and carboplatin, is widely used to treat various cancers, including ovarian cancer. However, its clinical application is limited by dose-limiting toxicities and resistance, with a poor 5-year overall survival rate for ovarian cancer (35-40%). In this study, we used ionisable lipids and developed pH-responsive lipid nanoparticles (LNPs) to address platinum-resistance in ovarian carcinoma. Methods: Cisplatin was loaded into three LNP systems containing monoolein (MO) and synthetic cationic ionisable lipids (OE-Mo, OA-Py, and OA-Pi) dispersed in Pluronic F-127 with 0.9% NaCl. Cisplatin-loaded LNPs (Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP) were characterised for size, zeta potential, and internal mesophase structure. Encapsulation efficiencies were determined via HPLC after removing free drug by ultrafiltration. In vivo efficacy was tested using cisplatin-resistant human patient-derived xenograft (PDX) models. Results: The LNPs were well dispersed with particle size of 219-250 nm and a drug loading of ~1.2 mg/mL. Encapsulation efficiencies were 62%, 59%, and 64%, for Cis-OE-Mo-NP, Cis-OA-Py-NP, and Cis-OA-Pi-NP, respectively. Small angle X-ray scattering (SAXS) results showed that the LNPs are pH responsive with structural transitions from a cubic to a hexagonal phase at an acidic pH. Among the tested formulations, Cis-OA-Py-NP resulted in the most significant reduction in tumour volume by ~60% compared to treatment with cisplatin alone. However, they also showed significant toxicity, including >10% weight loss and gross lung and kidney damage, as confirmed by histology. Conclusions: These findings highlight the potential of Cis-OA-Py-NP in reducing tumour volume but underscore the need for further optimisation to improve safety and therapeutic applicability.