Folic Acid-Decorated Lipidic Nanocapsules Co-Loaded with Atorvastatin and Curcumin to Enhance Glioma Targeting in Mice

<b>Background</b>: Glioma remains an intractable and highly aggressive brain tumor, mainly due to the daunting obstacle presented by the blood-brain barrier (BBB). To overcome this challenge and enhance therapeutic efficacy, a dual-drug delivery system was engineered. This system co-encapsulated curcumin, a nutraceutical with multitargeted anticancer potential, with atorvastatin calcium, a repurposed anticancer agent, within lipidic nanocapsules (LNCs). <b>Methods</b>: LNCs were prepared via the phase inversion temperature method and optimized using a Box-Behnken design. The optimized LNCs were subsequently functionalized with folic acid (FA) to enable active targeting. FA-LNCs were characterized using XPS, TEM, in vitro release, and MTT cytotoxicity assays. Atorvastatin and curcumin were radiolabeled separately with iodine-131 to evaluate the in vivo pharmacokinetics in a glioma-bearing mouse model. <b>Results</b>: The optimized LNCs and FA-LNCs displayed a mean particle size of 97.98 ± 2.27 nm and 181.60 ± 2.83 nm, a polydispersity index of 0.32 ± 0.07 and 0.40 ± 0.02, and a zeta potential of -15.85 ± 1.35 mV and -11.90 ± 2.80, respectively. XPS and FTIR analyses verified FA conjugation. Both LNCs and FA-LNCs enhanced the in vitro cytotoxicity compared to free drugs; however, the most pronounced effect of FA functionalization was observed in vivo. Most significantly, FA-LNCs achieved markedly greater glioma accumulation than non-functionalized LNCs, with AUC values 2.0-fold higher for atorvastatin and 2.6-fold higher for curcumin. When compared to the free drug solutions, this efficiency was even more pronounced, with atorvastatin and curcumin showing enhancements of 8.2 and 12.4 times, respectively. <b>Conclusions</b>: FA-LNCs markedly improved glioma targeting efficiency and reduced systemic clearance, which underscores the therapeutic potential of integrating nutraceuticals with repurposed agents to achieve effective glioma therapy.