A Micellar Mitotane Formulation with High Drug Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D in Vitro Tumor Models.

Abstract

Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L−1) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.

The Challenging Pharmacokinetics of Mitotane: An Old Drug in Need of New Packaging

“…For such administration, a suitable formulation is needed. Recently, we have reported a poly(2-oxazoline)s (POx)-based [ 110 ] mitotane-loaded micellar formulation developed by thin-film hydration method with very high LC of 36 wt% (mitotane solubility ≈ 6 g/l), which could potentially be explored as an injectable formulation [ 111 ] (Fig. 9 a–d).…”

“…e Cell viability and corresponding IC 50 values of mitotane dissolved in ethanol (red) and as micelle formulation (blue) in NCI-H295R monolayer after incubation for 24 and 48 h (left vertical panel) and 3D tumor spheroids at 24 h and 48 (right vertical panel) ( n = 3 ± SD). Modified with permission from [ 111 ] …”

“…Concerning in vivo administration, the safety of the polymer excipient is of utmost importance. The cytocompatibility of POx-based amphiphiles has been repetitively established [ 111 , 118 , 122 , 123 ], and the polymers are generally well tolerated at relevant doses after repeated injections.…”

Pharmacological profile and effects of mitotane in adrenocortical carcinoma

“…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(2methyl-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.…”

Tuning the Thermogelation and Rheology of Poly(2-Oxazoline)/poly(2-Oxazine)s Based Thermosensitive Hydrogels for 3D Bioprinting.

“…Polymers of cyclic imino ethers, particularly poly(2-oxazoline)s (POx) and poly(2-oxazine)s (POzi) [19] with a thermoresponsive profile [20,21] have attained significant attention in the past decade [21,22]. POx has shown huge potential in tissue engineering [23][24][25][26], drug delivery [27][28][29][30][31][32][33] and 3D (bio) printing [22,34]. They are structural isomers of polypeptides, are synthetically relatively easily accessed and are highly tunable in their physico-chemical characteristics [35].…”