QbD-optimized HA–Pluronic nanomicelles for the targeted repurposing of tofacitinib in breast cancer

Abstract

Tofacitinib, a Janus kinase (JAK) inhibitor clinically approved for rheumatoid arthritis, holds significant potential for repurposing in breast cancer therapy due to its ability to suppress the oncogenic STAT3 signaling pathway; however, its therapeutic application is hindered by poor aqueous solubility, rapid systemic clearance, and non-specific distribution. To address these limitations, this study aimed to develop hyaluronic acid (HA)-decorated Pluronic F127 (PF127) micelles to enhance the solubility, bioavailability, and targeted delivery of Tofacitinib to CD44-overexpressing breast cancer cells. A Quality by Design (QbD) approach utilizing a Box–Behnken design (BBD) was employed to systematically optimize critical process parameters—drug-to-polymer ratio, polymer concentration, and stirring temperature—to minimize particle size and polydispersity index (PDI) while maximizing entrapment efficiency. The optimized micelles exhibited a uniform particle size of 159.2 ± 3.8 nm, a narrow PDI of 0.221, a high entrapment efficiency of 91.14%, and a negative zeta potential of −24.6 mV, ensuring colloidal stability. In vitro evaluation demonstrated a sustained, diffusion-controlled drug release profile and significantly enhanced cytotoxicity against MCF-7 breast cancer cells (IC₅₀ 14.2 µg mL⁻¹) compared to the free drug (IC₅₀ 46.8 µg mL⁻¹), attributed to CD44-mediated cellular uptake. Furthermore, in vivo pharmacokinetic analysis in Wistar rats revealed a 4.3-fold increase in oral bioavailability and a prolonged elimination half-life compared to free Tofacitinib, while histopathological studies confirmed the formulation's biocompatibility and safety in major organs. These findings collectively support the viability of the QbD-optimized HA–PF127 micellar system as a promising nanocarrier platform for the effective oral repurposing of Tofacitinib in breast cancer treatment.