Development of ursolic acid-loaded cubosomal nanocarriers: enhanced dissolution, pharmacokinetics, bioavailability,...

Ursolic acid (UA) is a promising anticancer agent whose therapeutic application is hindered by poor aqueous solubility, limited permeability, rapid elimination, and low oral bioavailability. In this study, UA-loaded cubosomal nanoparticles (UA-CN) were developed and optimized using a three-factor, three-level Box-Behnken design. The effects of glyceryl monooleate, Poloxamer 407, and microfluidization cycles on particle size, zeta potential, and entrapment efficiency were systematically evaluated. The optimized UA-CN exhibited a particle size of 131.9 ± 4.12 nm, zeta potential of - 44.2 ± 3.67 mV, and entrapment efficiency of 96.16 ± 1.89%. FTIR, XRD, and DSC analyses supported UA incorporation into the cubosomal matrix and a reduction in its crystalline character. In vitro dissolution studies demonstrated markedly enhanced drug release from UA-CN, with approximately 90% of UA released within 24 h compared with 38% from the pure drug. Pharmacokinetic evaluation in rabbits showed an approximately six-fold increase in oral bioavailability following UA-CN administration. The optimized cubosomal formulation also exhibited enhanced anticancer activity, supporting its potential to improve the biopharmaceutical performance of UA and its utility as a nanocarrier for breast cancer therapy.