Fraisinib in a Shell: Liposomal Encapsulation of a GARS1 Inhibitor for Controlled Anticancer Delivery

Fraisinib, a meso-(4-acetamidophenyl)-meso-hepta(methyl)calix[4]pyrrole derivative, has shown promising anticancer activity by targeting glycyl-tRNA synthetase, an emerging molecular target in oncology. However, its hydrophobic nature limits solubility in aqueous media and systemic administration, posing challenges for its clinical translation. To improve its solubility and anticancer efficacy, Fraisinib was encapsulated into biodegradable and biocompatible liposomes. In this study, different phospholipids were tested to find the optimal formulation to prepare Fraisinib-loaded liposomes that were fully characterized in terms of physicochemical properties, encapsulation efficiency, stability, and release profile. Liposomes, mainly composed of 1,2-distearoyl-sn-glycero-3-phosphocoline (DSPC), a lipid with high transition temperature, provided enhanced stability under physiological conditions, improving drug retention and controlled release. DSPC-based liposomes enabled the efficient encapsulation of Fraisinib at a 6% molar ratio, with high entrapment efficiency (~ 90%), mean particle size of 142 nm, and a stable zeta potential of -32 mV. The liposomal formulation exhibited a sustained and time-dependent release profile, with around 50% of the drug released over 72 h in buffer, and an accelerated release in serum (55% of the drug released in 48 h). In A549 cancer cells, Fraisinib-loaded liposomes induced a delayed cytotoxic effect consistent with controlled release, highlighting their potential to optimize pharmacokinetics and therapeutic outcomes. Altogether, these findings suggest that liposomal Fraisinib holds promise as a nanomedicine candidate for future clinical application in cancer therapy.