Co-delivery of doxorubicin and silybin via taurine-conjugated chitosan-modified TAUT-targeted liposomes enhances oral bioavailability and alleviates doxorubicin-induced cardiomyocyte toxicity in vitro.

Abstract

Oral administration remains the most convenient and patient-preferred route for therapeutic drug delivery. However, the clinical translation of oral doxorubicin (DOX) is severely hampered by its low oral bioavailability, which remains a major challenge for oral chemotherapy. Herein, we report the development of taurine-conjugated chitosan (TAU-CS)-modified liposomes co-encapsulating silybin (SLB) and DOX (designated TAU-CS/LIP@DOX + SLB), a system engineered to enhance the oral bioavailability of DOX while reducing DOX-induced cardiomyocyte toxicity in vitro. The optimized liposomes displayed a homogeneous spherical morphology, with a mean particle size of 183.7 nm, a zeta potential of +9.89 mV, and encapsulation efficiencies over 90% for both active pharmaceutical ingredients. TAU-CS functionalization significantly augmented the mucoadhesion of the liposomes, resulting in 2.08-fold higher cellular uptake in Caco-2 cells relative to free DOX. In vitro cytotoxicity assessments demonstrated that TAU-CS/LIP@DOX + SLB reduced DOX-induced toxicity in H9C2 cardiomyocytes compared with free DOX and the other tested formulations. Remarkably, TAU-CS/LIP@DOX + SLB achieved an absolute oral bioavailability of 28.89% and a 73.38% inhibition rate against CYP3A4. Collectively, these findings establish taurine transporter (TAUT)-targeted DOX/SLB co-loaded liposomes as an oral delivery platform that enhances DOX systemic exposure through intestinal uptake and metabolic-barrier modulation while reducing DOX-induced cardiomyocyte toxicity in vitro.