Development and Optimisation Using D-Optimal Design of Dual-Functionalized Hyaluronic Acid-Chitosan-Coated Mesoporous Silica Nanoparticles for Repurposed Propranolol Delivery in Breast Cancer: A Proof-of-Concept Study.

Drug repurposing combined with nanocarrier systems can accelerate cancer therapy development while reducing the time and cost of conventional drug discovery. We developed and optimised hyaluronic acid (HA)-chitosan (CH)-coated mesoporous silica nanoparticles (HA-CH-Prop-MSNPs) for delivery of the repurposed β-blocker propranolol. A two-stage D-optimal design optimised propranolol loading, then CH and HA coating, using particle size, polydispersity index (PDI), zeta potential, and entrapment efficiency (EE). The formulation (0.2% low-molecular-weight CH, 0.07% HA, 2 mg/mL propranolol, 10 mg/mL mesoporous silica nanoparticles) exhibited a particle size of 200.5 nm, PDI of 0.495, zeta potential of -25.7 mV, and EE of 91.2%. HA-CH coating provided controlled release and shifted the mechanism from near-Fickian diffusion toward an increasing contribution from polymer relaxation-controlled transport. Propranolol release was significantly higher at tumour-mimicking pH 5.5 than at physiological pH 7.4 across all formulations. Compared with free propranolol, HA-CH-Prop-MSNPs reduced the IC50 against MCF-7 breast cancer cells 2.8-fold while maintaining negligible carrier cytotoxicity. Under accelerated storage conditions (40 °C/75% RH), the formulation remained stable for six months, with less than a 2% reduction in EE. These findings provide proof of concept that HA-CH-coated mesoporous silica nanoparticles enhance the in vitro anticancer activity of repurposed propranolol through encapsulation and controlled release, laying the foundation for future investigation of HA-mediated cellular targeting.