Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy originating in the adrenal cortex, associated with a poor prognosis and a mean survival of approximately 15 months. Surgical resection remains the primary curative approach; however, the majority of patients present with advanced or metastatic disease, where therapeutic options are limited. Mitotane, a steroidogenesis inhibitor, is the only licensed systemic therapy for ACC. Despite its utility, mitotane is poorly tolerated due to its narrow therapeutic window and frequent adverse effects, limiting its use at therapeutic doses. Resistance to mitotane, particularly in metastatic ACC, is a significant clinical challenge, contributing to poor outcomes.
Our laboratory has demonstrated that metastatic ACC cell lines resistant to mitotane at usual pharmacological doses exhibit sensitivity to mitotane at supra-pharmacological concentrations, highlighting the potential for higher dosing strategies if targeted delivery can be achieved. To address this, we have developed a novel nanosponge delivery system with a cholesterol-based backbone designed for selective targeting of adrenocortical cancer cells. These nanosponges encapsulate mitotane and preferentially localize to the mitochondria of ACC cells, inducing autophagy and enhancing cytotoxic effects.
We now propose a therapeutic approach utilizing these mitotane-loaded nanosponges to deliver high concentrations of the drug directly to ACC cells while sparing healthy tissues. This strategy aims to overcome resistance mechanisms and improve therapeutic outcomes by exploiting the selective mitochondrial targeting of our nanosponge system. This innovation holds promise for advancing the treatment of ACC by enhancing mitotane efficacy while minimizing systemic toxicity, offering a new avenue for improving survival in this challenging malignancy.