Complexation of the Antineoplastic Docetaxel with γ‑Cyclodextrin Significantly Improves Its Solubility and In Vitro Safety.

Docetaxel (DTX) is a frontline taxane for breast cancer, but its poor aqueous solubility, limited intestinal permeability, and rapid clearance compromise therapeutic efficacy. Moreover, the commercial formulation Taxotere induces severe side effects, including hypersensitivity reactions, neutropenia, neuropathy, musculoskeletal toxicity, and nasolacrimal duct stenosis. Here, we investigated γ-cyclodextrin (γ-CD) complexation as a strategy to enhance DTX performance. A DTX:γ-CD inclusion complex was obtained by cosolubilization and lyophilization, reaching equilibrium within 5 h at 25 °C, with an optimal 1:2 stoichiometry, but such determinations were hindered by variability in the measurements, indicating that the supramolecular association of DTX and γ-CD was not straightforward. Complex formation was supported by thermal, spectroscopic, and microscopic analyses, and it provided a 20-fold increase in docetaxel solubility. Molecular dynamics simulations confirmed the 1:2 DTX:γ-CD stoichiometry, revealing sequential binding of two γ-CD to the DTX carbamate group along with additional noninclusion interactions. Cytotoxicity assays in human umbilical vein endothelial cells (HUVEC) and HS578T breast cancer cells showed that the DTX:γ-CD complex preserved the antitumor activity of docetaxel across all tested concentrations while reducing toxicity in endothelial cells. At the highest concentration (0.1 mM), HUVEC viability remained close to 50% with the DTX:γ-CD complex, compared with only ∼20% for the commercial formulation, indicating a substantial protective effect without compromising cytotoxic efficacy against HS578T tumor cells. Overall, γ-CD complexation substantially improves DTX solubility and safety, supporting its potential as a promising alternative delivery system to enhance docetaxel's therapeutic index.