β-Glucan-Assisted Oral Delivery of Navitoclax for Reversing Chemoresistance in Triple-Negative Breast Cancer

Abstract

Chemoresistance driven by apoptotic evasion remains a critical barrier in treating aggressive triple-negative breast cancers (TNBC). In this study, we established a paclitaxel-resistant TNBC subline (PTXR MDA-MB231) through four months of chronic exposure and evaluated therapeutic reversal using navitoclax (NAVI), a Bcl-2 inhibitor. Confocal microscopy confirmed a 53.13% upregulation of antiapoptotic Bcl-2 protein in the PTXR MDA-MB231 line compared with nonresistant MDA-MB231 cells. To overcome NAVI’s poor water solubility and risk of systemic toxicity, we engineered self-assembled β-glucan/Navitoclax (BG/NAVI) nanoparticles with a hydrodynamic diameter of 318.1 ± 13.6 nm (PDI: 0.21 ± 0.04) and an encapsulation efficiency of 57.5 ± 3.2%. In vitro flow cytometry showed that although PTXR cells were highly cross-resistant to paclitaxel (19.37% apoptosis), treatment with NAVI successfully restored sensitivity, inducing 72.37% total apoptosis. Pharmacokinetic profiling in Sprague–Dawley rats demonstrated that oral administration of BG/NAVI (5 mg/kg) produced a sustained absorption profile (Tmax = 4 h) and a 1.3-fold enhancement in oral bioavailability compared with free NAVI. Importantly, in an in vivo PTXR xenograft model, oral delivery of BG/NAVI (150 mg/kg in every 5 days for 4 doses) yielded in a robust 60% tumor-volume reduction, compared with only a 35% response in nonresistant tumors, without causing weight loss or vital organ toxicity. Collectively, these findings demonstrate that BG-assisted oral carrier platforms can systemically deliver Bcl-2 inhibitors and bypass apoptosis-evading mechanisms associated with chemoresistance.