Fabrication of vesicle-incorporated etoposide-loaded nanocochleates for improved anticancer efficacy

Cancer is a major global health concern, characterized by uncontrolled cell proliferation and high mortality rates. Conventional chemotherapeutic agents often suffer from poor selectivity and systemic toxicity, limiting their clinical utility. Etoposide, a potent topoisomerase II inhibitor, is widely used to treat various types of cancers such as lung, testicular, and lymphomas. However, its clinical application is hampered due to low bioavailability and rapid clearance. To address, these limitations, nanocarrier-based systems such as liposomes and nanocochleates have been fabricated and explored. In the present study, etoposide was encapsulated within liposomes using the ethanol injection method. The optimized liposomal batch (ETNL5) exhibited favorable physicochemical properties such as entrapment efficiency (75.80 ± 1.26%), particle size (210.7 ± 0.15 nm), zeta potential (- 27.6 mV), and in vitro drug release of 92.34%. This formulation was further converted into nanocochleates (ETNC) using calcium-induced fusion with DMPG-Na and cholesterol. Pharmacokinetic evaluation demonstrated that ETNC significantly improved systemic exposure in regulated release format. ETNC showed the highest C_max (0.50 ± 1.52 µg/mL) and AUC_₀-∞ (116.74 ± 9.16 µg·min/mL), along with extended half-life (150.88 ± 13.25 min) and MRT (240.14 ± 36.98 min), indicating prolonged circulation and reduced clearance (0.08 mg/(µg/mL)/min), while the tissue distribution studies revealed enhanced lung accumulation (28.99 ± 0.02 µg/g) with minimal off-target exposure, suggesting potential for site-specific delivery. Overall, ETNC provide a stable, efficient, and targeted drug delivery platform with promising potential for improving cancer therapy. Their ability to enhance bioavailability, reduce toxicity, and selectively target organs makes them a superior alternative to conventional formulations.