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.