Surfactant‐Stripped Cabazitaxel Micelles Stabilized by Clotrimazole or Mifepristone

Abstract

AbstractTaxane chemotherapy formulations are used to treat advanced cancers, but limited solubility and propensity for aggregation in water complicates their development. Many involve drug dissolution in organic solvents and liquid surfactants, or use of lyophilization and reconstitution approaches. “Surfactant‐stripping,” has been previously reported, in which hydrophobic drugs were first dispersed in Pluronic (Poloxamer) surfactant, then subjected to membrane processing below the critical micelle temperature, to remove free and loose surfactant while retaining the active cargo. In the present work, stabilized, surfactant‐stripped (sss) cabazitaxel (CTX) micelles with potential for long‐term aqueous storage are developed. Some 50 hydrophobic co‐loaders cargos are screened for capacity to prevent aggregation of CTX, of which approximately 10 are effective. Further screening identifies the antifungal clotrimazole and the abortificant mifepristone as the most effective stabilizers for sss‐CTX micelles, via interference with the CTX aggregation process. Micelles remain stable for hundreds of days in aqueous storage and suppress the growth of orthotopic 4T1 murine mammary tumors. Pharmacokinetics, tubulin stabilization, and neutropenia induction of sss‐CTX are generally comparable to a TWEEN‐80 CTX formulation. These data reveal sss‐CTX as a taxane delivery vehicle with a high drug‐to‐surfactant ratio and capacity for extended aqueous storage.