Surfactant‐Stripped Cabazitaxel Micelles Stabilized by Clotrimazole or Mifepristone

Abstract

Taxane 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.

Current development of cabazitaxel drug delivery systems

“…For example, co‐delivery of IKBKE siRNA, CTX, and siRNA with the acid‐sensitive linkage allowed proper size for EPR effect and superior drug accumulation in tumors (Zhao et al, 2020). In addition, the CTX polymeric micelles have made breakthroughs in terms of stability, with the help of co‐loading with the other drugs, the CTX micelles reached a year‐long aqueous stability (Sun, Chitgupi, et al, 2020). The recent progress of CTX‐conjugates mainly focuses on “smart” release such as acid‐sensitive release, sustainable release, and GSH‐triggered release.…”

“…By removing unimers (free surfactants) via ultrafiltration at low temperature, the solution can be concentrated, leading to very high drug loading capacity and drug‐to‐excipient molar ratio. Sun et al loaded CTX into the Pluronic micelles and it could be concentrated to a high drug‐to‐surfactant ratio (Figure 6; Sun, Chitgupi, et al, 2020). Coloading of the antifungal clotrimazole and the abortifacient mifepristone in micelles enabled the CTX micelles to be stable in aqueous solution for over a year, achieving a milestone for the hydrophobic drug stabilized in aqueous solution, while Tween‐80 based CTX only survive for less than 2 days upon preparation prior to injection.…”

“…Zhang et al, 2016). Additional advantages lie in its excellent self-assembly ability and temperature-sensitive critical micelle temperature (CMT), which has been reported for loading hydrophobic drugs, like cabazitaxel (Song et al, 2014;B. Sun, Chitgupi, et al, 2020;B.…”

Surfactant‐Stripped Micelles with Aggregation‐Induced Enhanced Emission for Bimodal Gut Imaging In Vivo and Microbiota Tagging Ex Vivo

“…(about 1.2 mg in 200 μL) TABID SSAMs in mice (Figure 4d). The co-loader enhancement has been observed to a range of surfactant-stripped micelles, [57,58] and is likely explained by additional molecular interaction between the co-loader and TABID within the micelles. The complete excretion of the contrast agent, with no dye was detectable in main organs including liver, spleen, kidney, heart and lungs, stomach, intestine (Figure 4e), which is consistent with our prior finding of orally-administered surfactant-stripped micelles [27] and gut confinement presents advantages for imaging intestinal processes and contrast agent safety.…”

Akt inhibition improves the efficacy of cabazitaxel nanomedicine in preclinical taxane-resistant cancer models

“…Its commercial formulation Jevtana® was approved by the US Food and Drug Administration (FDA) in 2010 for the treatment of patients with hormone-refractory metastatic prostate cancers [5]. However, the clinical e cacy of cabazitaxel is generally limited by poor water solubility and dose-limiting toxicities with low safety pro les [6,7].…”