Construction of a mitotane delivery system based on γ-cyclodextrin metal organic framework and its enhanced anti-tumor activity

Adrenocortical carcinoma (ACC) is an aggressive cancer with an urgent need for more effective and safer therapies. Mitotane (MT), has its clinical utility compromised by poor aqueous solubility and low oral bioavailability. In response, a novel nano-delivery platform was fabricated by encapsulating MT into γ-cyclodextrin metal-organic framework (γ-CD-MOF), denoted as MT@γ-CD-MOF. The composite was prepared via a solvothermal method. Comprehensive characterization combined with molecular simulation confirmed the successful loading of MT in a molecularly dispersed state within the γ-CD cavities, with a drug loading capacity of 20.04% and an approximately 3.8-fold increase in apparent solubility. In vitro studies demonstrated that MT@γ-CD-MOF suppressed the proliferation and migration of SW-13 ACC and enhanced pro-apoptotic effects by activating Caspase-3 and increasing intracellular reactive oxygen species levels. Importantly, in vivo pharmacokinetic studies in rats revealed a substantial improvement in oral bioavailability, with the area under the concentration-time curve from 0 to 24 h (AUC_{0-24 h}) increasing by 1.71-fold compared with raw MT. These results indicate that MT@γ-CD-MOF is an efficient and biocompatible oral delivery platform, offering a promising formulation strategy to enhance the therapeutic efficacy of MT against ACC.