Nano-formulations
Nano-formulations have emerged as an attractive strategy for incorporation in lipid molecules that have poor water solubility, such as mitotane. Mitotane nano-formulations are expected to improve the therapeutic effect, enhance bioavailability, and reduce the toxic effects of mitotane [80]. Three formulations are being developed:(i) self-microemulsifying drug delivery system (SMEDDS),(ii) lipid-based nanocarriers, and (iii) micelles.
(i) SMEDDS: SMEDDS is an approach to incorporating lipid molecules. Preconcentrated microemulsion is useful for enhancing the dissolution rate of poorly water-soluble drugs and increasing bioavailability [81]. The formulation mitotane-SMEDDS contains Capryol®, Tween®, and Cremophor® at the same concentrations. SMEDDS was found to cross the intestinal barrier much faster than a solution of mitotane, with a bioavailability of 3.4% [82]. However, no studies have been performed yet to evaluate if SMEDDS can also decrease gastrointestinal toxicity, which occurs due to the poor solubility of mitotane in the gastrointestinal system. Moreover, there is a lack of preclinical studies, including in vitro and in vivoobservations, to investigate whether SMEDDS could enhance the antisecretory and antitumor effects in ACC. Nevertheless, SMEDDS can be considered as a new tool for optimizing the administration of mitotane and additional studies should be performed in this regard.
(ii) Lipid-based nanocarriers: Solid lipid nanoparticles (SLNs) or nanostructured lipid carriers (NLCs) consist of either solid or lipid nanoparticles. NLCs are a novel type of lipid nanoparticles that use a solid matrix [80]. In fact, mitotane was efficiently loaded in SLNs and in NLCs, as potential delivery systems for enhancing the therapeutic effects of mitotane, improving bioavailability, and controlling drug release [83]. However, no additional studies have been carried out yet to evaluate the efficacy of nano-formulations in ACC.
(iii) Micelles: Micelles are promising nanocarrier systems for drug delivery, especially for antitumor agents [84]. Polymeric micelles are structures formed by an arrangement of amphiphilic copolymers in aqueous solutions [85]. The advantages of this nano-formulation are control of drug release, tissue-penetrating ability, and reduced toxicity [84]. As mitotane has poor solubility in water and consequently in plasma, Haider and colleagues [86] developed a micelle poly(2-methyl-2-oxazoline)-block-poly(2-butyl-2-oxazoline)-block-poly(2-methyl-2-oxazoline) (pMeOx-pBuOx-pMeOx) based mitotane nano-formulation with high drug loading. Micellar mitotane exhibits comparable efficacy with its ethanol equivalent, suggesting that this nano-formulation is suitable for intravenous administration and may improve mitotane plasma concentration and consequently the efficacy. Additional studies about the safety and tolerability of this injectable formulation are warranted [86].
Conclusion and future directions
Mitotane is the only drug approved for ACC treatment since there is a lack of new compounds with specific antisecretory and antitumor effects. However, its pharmacokinetic features do not make mitotane an ideal drug for ACC because of its very poor absorption. In addition, the polymorphism of CYPs may also be involved in the variability of the therapeutic effect of mitotane among patients. Consequently, high doses are employed, inducing several side effects. Although the mechanism of action is not well elucidated, there is evidence that mitotane might control steroid production and induce apoptosis through ER stress and inhibition of mitochondrial respiration. The formation of reactive species during β-hydroxylation, such as DDAC, should also be considered in the mechanism of mitotane action, as this can lead to the acylation of cellular molecules and induce cell death. Furthermore, the ability of mitotane to bind to adrenal mitochondria via steroidogenic enzymes (i.e. CYP11B1 and CYP11A1) suggest that mitotane is metabolized in the adrenals. However, the pharmacokinetics and exact mechanisms of action of mitotane still need to be thoroughly clarified to understand the variability of the pharmacokinetic and therapeutic effects among patients.
New formulations or compounds containing mitotane or its metabolites can be an attractive option to improve chemotherapy treatment and decrease mitotane toxicity. Nano-formulations are currently the most studied option, since they can apparently enhance bioavailability, adrenal drug delivery, and decrease side effects, mainly in the gastrointestinal system. There are only few studies evaluating new formulations of mitotane. Therefore, it is necessary to conduct new studies in this field to improve ACC treatment. Despite this, due to the antisecretory and antitumor effects of mitotane in adrenal tumor cells, it continues to be the drug of choice for improving the survival of patients with ACC.