Interfacial lipid digestion-responsive injectable nanoemulsions enhance lapatinib efficacy in triple-negative breast cancer.

Abstract

Lapatinib (LPT), a brick-dust kinase inhibitor, shows slow oral bioavailability and dose-limiting gastrointestinal side effects that frequently lead to therapeutic discontinuation. Increasing oral bioavailability does not mitigate these adverse effects, and developing complex LPT delivery systems is challenging due to its poor solubility in organic or lipid solvents. Here, we identified a synergistic lipid-surfactant nanoemulsion system comprising Miglyol 812-oleic acid (1:1) oil phase, Solutol HS-15-TPGS (1:2) surfactant, and PEG-400 cosurfactant as a solubilization space for LPT and formulated it into a nanoemulsion delivery system (MIOL-NE). Phase analyses and Box-Behnken (BBD) optimization yielded MIOL-NE size (117 nm) suitable for parenteral administration. Stable LPT-loaded MIOL-NE (10 mg/g) was subsequently prepared (LPT-MIOL-NE). In vitro release in the presence and absence of lipase indicated mixed diffusion- and digestion-governed kinetics for LPT from the NE. LPT-MIOL-NE showed a more selective cytotoxicity (MDAMB-231 to NKE and HEK-293 cells) than LPT suspension, while preserving downstream effects of tyrosine kinase inhibition and suppression of cell invasion. Pharmacokinetic evaluation in Wistar rats revealed 2.4-times higher Cmax and 5.3-times higher AUC0-24 for intraperitoneally administered LPT-MIOL-NE than for the LPT suspension. In 4T1-bearing orthotopic BALBc nude mice, LPT-MIOL-NE at a 6 mg/kg i.m. dose reduced tumor volumes to90 mm3 (82 mm3 with i.p.) compared to 120 mm3 in control animals during the 21-day intervention. The results establish that NE can enhance the efficacy of LPT following i.m./i.p administration and open the scope for future investigations to delineate the contribution of colloidal uptake to post-digestive molecular transport in determining drug absorption from i.m./i.p-administered nanoemulsion (NE).