Solvent-Directed Self-Assembly of Sorafenib into Spherical Particles for Enhanced Anticancer Efficacy

Sorafenib, a clinically approved multityrosine kinase inhibitor, exhibits poor aqueous solubility, which limits its bioavailability and therapeutic efficacy. In this study, we introduce a solvent-directed self-assembly strategy to modulate the nanostructure of sorafenib without the use of external carriers or complex formulation techniques. In pure water, sorafenib forms large lamellar aggregates, whereas in 30% methanol–water mixtures, it self-assembles into uniform spherical particles approximately 450 nm in diameter. These spherical particles exhibit markedly enhanced cellular uptake (∼80%) and cytotoxicity (up to 60% at 40 μM) in HepG2 liver cancer cells compared to the poorly active lamellar form. In vivo pharmacokinetic analysis further reveals faster absorption, biphasic plasma distribution, and prolonged circulation of the spherical particle forms. These findings demonstrate that solvent-driven nanostructure modulation can serve as a simple yet effective strategy to improve the solubility-limited pharmacological performance of small-molecule drugs like sorafenib.