Next-generation sabizabulin nanoformulation for cervical cancer treatment

Background: Cervical cancer (CC) remains a significant global health burden in women, with intrinsic and acquired chemotherapy resistance limiting therapeutic efficacy. Sabizabulin (VERU-111) is an orally bioavailable colchicine-binding site inhibitor that offers a new way to treat cancer by targeting microtubule dynamics and changing the HPV-driven CC phenotype. However, optimization of its pharmaceutical formulation is critical to maximize efficacy while minimizing systemic toxicity and improving tumor-specific drug accumulation. In this study, we engineered and evaluated a next-generation nanoparticle formulation of sabizabulin to enhance its bioavailability, improve tumor-targeted delivery, and overcome chemotherapy resistance in CC models. Methods: We engineered a multi-layered Pluronic F127 and polyvinyl alcohol stabilized and poly-L-lysine coated Sabizabulin-loaded poly(lactic-co-glycolic acid) nanoparticle formulation (PSab-NPs). PSab-NPs were characterized for physicochemical properties, stability, and drug loading efficiency by TEM, FT-IR, DSC, TGA, and HPLC. Cellular internalization was assessed after 6 hours of incubation with PSab-NPs in CC cells. To determine the therapeutic efficacy of PSab-NPs, we performed various in vitro (MTS, wound healing, Boyden chamber, real-time xCELLigence, and apoptosis assays) and in vivo xenograft mouse models using CC cells. We evaluated the effect of PSab-NPs on various key oncogenic signaling pathways using Western blot, immunohistochemistry (IHC), confocal microscopy, and qRT-PCR. Results: Our novel PSab-NPs formulation provided an average size of 120-150 nm in dynamic light scattering (DLS) and exhibited -10.46 to -12.73 mV zeta potential with an outstanding loading efficiency. Cellular uptake and internalization studies demonstrate that PSab-NPs efficiently evade lysosomal degradation, facilitating strong endosomal release into the cytosol. PSab-NPs showed remarkable anti-cancer potential in various CC cells (HeLa, SiHa, CaSki, and C33A). Mechanistically, PSab-NPs more effectively modulate the PI3K/AKT/MDM2 signaling pathway and suppress HPV E6 and E7 in vitro and CaSki cell-derived xenografts in athymic nude mice. Conclusions: Taken together, our findings suggest that PSab-NPs represent a novel, promising nanoparticle platform that has more anti-cancer potential than free sabizabulin. PSab-NPs may reduce the toxicity and improve the bioavailability of free sabizabulin and could be used for the effective management of CC.