Design, Formulation and Evaluation of Enzalutamide Nano Sponge Using BOX-Behnken Design for Management of Prostate Cancer

Enzalutamide (EZL) is a potent androgen receptor inhibitor widely used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, its poor aqueous solubility and limited oral bioavailability pose significant challenges in achieving optimal therapeutic outcomes. This study aimed to design and evaluate a sustained-release nano sponge (NS) delivery system for EZL using β-cyclodextrin (β-CD) as the polymer matrix. Nano sponges were prepared by the solvent evaporation method using dimethyl carbonate as a cross-linker and optimized through a Box-Behnken Design (BBD) under a Quality by Design (QbD) framework. The effects of polymer concentration, cross-linker amount, and reaction time were assessed on critical quality attributes such as particle size, entrapment efficiency, polydispersity index (PDI), and zeta potential. The optimized formulation exhibited a particle size of 168.9 nm, entrapment efficiency of 85.47%, and zeta potential of −26.75 mV, indicating good colloidal stability. Characterization through FTIR, DSC, and XRD confirmed successful drug encapsulation and reduced crystallinity. In vitro drug release studies demonstrated a biphasic release profile with sustained drug release up to 88.5% over 12 hours. Furthermore, pharmacokinetic evaluation in rats revealed a 2.5-fold increase in bioavailability, extended half-life, and improved mean residence time compared to free EZL. The findings suggest that β-CD-based nano sponges are a promising nanocarrier system for enhancing the solubility, stability, and therapeutic performance of EZL. This approach may improve patient compliance and treatment efficacy in prostate cancer therapy. Keywords Enzalutamide; Box-Behnken Design; prostate cancer; β-cyclodextrin; Pharmacokinetic; Nano sponges.