Tocopherol-human serum albumin nanoparticles enhance lapatinib delivery and overcome doxorubicin resistance in breast cancer

<b>Introduction:</b> HER2, a tyrosine kinase receptor, is amplified in HER2-positive breast cancer, driving cell signaling and growth. <b>Aim:</b> This study aimed to combat multidrug resistance in Dox-insensitive breast adenocarcinoma by creating a nanoformulation therapy with a tyrosine kinase inhibitor. <b>Methodology:</b> Human serum albumin (HSA) was conjugated with α-D-tocopherol succinate to form nanoaggregates loaded with lapatinib (Lapa). <b>Results:</b> The resulting Lapa@HSA(VE) NPs were 117.2 nm in size and demonstrated IC50 values of 10.25 μg/ml on MCF7 (S) and 8.02 μg/ml on MCF7 (R) cell lines. <b>Conclusion:</b> Lapa@HSA(VE) NPs showed no hepatotoxicity, unlike free Lapa, as seen in acute toxicity studies in rats. α-D-tocopherol succinate (vitamin E) was conjugated to human serum albumin (HSA). The HSA-VE conjugate formed nanoparticles (NPs) by self-assembly without any external cross-linker and loaded Lapatinib (Lapa). The NPs were characterized thoroughly. Time-dependent uptake of NPs was observed in tested sensitive and resistant human breast cancer cell lines (MCF-7). The nanomedicine displayed enhanced cytotoxicity in breast cancer cell lines compared with free drugs at higher concentrations. Lapa@HSA(VE) NPs caused significantly higher reactive oxygen species (ROS) generation and mitochondrial depolarization in tested breast cancer cell lines compared with free Lapa. <i>In vivo</i> pharmacokinetic data showed sustained drug release from nanoformulation with decreased systemic clearance, and <i>in vivo</i>, toxicity study revealed that the nanoformulation considerably reduced hepatotoxicity compared with free Lapa.