Demystifying targeting potential of surface-functionalized liposome for BTK inhibitor delivery in breast cancer therapy: Multiphase validation from in-silico to in-vivo.

Surface-functionalized nanocarriers have transformed cancer therapy by enabling targeted delivery of anti-cancer agents. In the present work, Tocophersolan (TPGS), a water-soluble form of natural Vitamin E, was evaluated as a targeting ligand for delivering the Bruton's Tyrosine Kinase (BTK) inhibitor, Ibrutinib (IBT), for breast cancer (BC) treatment. Computational studies revealed strong TPGS binding to ERα (-7.45 kcal/mol) and EGFR (-6.39 kcal/mol), receptors commonly overexpressed in BC. A TPGS-coated liposomal IBT formulation (IBT-T-Lipo) was developed via Microfluidizer® LM20, producing uniform liposomes (191.5 ± 4.42 nm, PDI 0.223, zeta potential -21.89 mV) with enhanced encapsulation (1.56-fold) and sustained release over 72 h. FT-IR, DSC, and PXRD confirmed surface modification. IBT-T-Lipo demonstrated potent anticancer efficacy, reducing IC values by 4.24- and 8.06-fold in MCF-7 and MDA-MB-231 cells, respectively, while enhancing apoptosis, elevating the Bax/Bcl-2 ratio, and suppressing migration. Anti-angiogenic activity was confirmed via chick embryo assay, and in-vivo studies showed prolonged circulation and marked tumor inhibition. Results of in-silico study further supported the experimental findings, showing strong correlation with the observed in-vitro and in-vivo effects. Collectively, these results establish TPGS-liposomes as an efficient delivery platform that augments IBT's therapeutic potential in BC through both active and passive targeting.