Quality By Design Guided Hyaluronic Acid–Conjugated Chitosan Nanoparticles for CD44-Targeted and PH-Responsive Delivery of Exemestane in Breast Cancer

Breast cancer is the most common malignancy among women worldwide, with over 2.3 million new cases and approximately 685,000 deaths annually. Despite advances in therapy, limited tumor-specific targeting and systemic toxicity reduce treatment efficacy. This study aimed to develop hyaluronic acid–conjugated, Exemestane-loaded chitosan nanoparticles (HA-EXT-CS-NPs) for CD44-mediated targeting and pH-responsive drug delivery in breast cancer.

Nanoparticles were prepared using inverse ionic gelation with sodium tripolyphosphate as a crosslinker. A Box–Behnken Design optimized chitosan, TPP, and hyaluronic acid concentrations, evaluating particle size, polydispersity index (PDI), and entrapment efficiency. Morphology was assessed by SEM, and in vitro drug release was studied under different pH conditions.

The optimized HA-EXT-CS-NPs showed 69.86 ± 0.69% entrapment efficiency, a mean size of 253.56 nm, and a PDI of 0.243, indicating uniform distribution. SEM confirmed smooth, spherical particles. Drug release was pH-dependent, with 91.12% cumulative release at pH 5.5 compared to 77.18% from non-HA nanoparticles. The formulation remained stable under short-term storage.

HA-EXT-CS-NPs offer a stable, scalable nanocarrier enabling CD44-targeted and pH-sensitive Exemestane delivery, potentially enhancing intratumoral accumulation, reducing systemic toxicity, and improving therapeutic outcomes in breast cancer management.