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

preprint
submitted on 29.04.2019 and posted on 01.05.2019 by Malik Salman Haider, Jochen Schreiner, Sabine Kendl, Matthias Kroiß, Robert Luxenhofer
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) even after many months of treatment which is caused by low water solubility and unfavorable pharmacokinetic properties such as poor bioavailability and high volume of distribution of MT. The clinical need and previously reported extraordinary high drug loading of poly(2-methyl-2-oxazoline)-block-poly(2-butyl-2-oxazoline)-block-poly(2-methyl-2-oxazoline) (A-pBuOx-A) based micelles for paclitaxel (PTX), led us to develop MT loaded micelles which may enable an injectable formulation. We successfully solubilized up to 6 g/L of MT in an aqueous formulation. The MT loaded nanoformulations were characterized by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and powder X-ray

diffraction (XRD), confirmed the amorphous nature of drug in the formulations. The polymer itself did not show cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, we demonstrated micellar MT to exhibit comparable efficacy to its ethanol solution. We postulate that this formulation would be suitable for i.v. application and more rapid attainment of therapeutic plasma concentrations. In conclusion, we consider our micellar formulation a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity towards ACC in vitro.

Funding

Deutsche Forschungsgemeinschaft

Higher Education Commission

Deutscher Akademischer Austauschdienst

History

Email Address of Submitting Author

robert.luxenhofer@uni-wuerzburg.de

Institution

University of Würzburg

Country

Germany

ORCID For Submitting Author

0000-0001-5567-7404

Declaration of Conflict of Interest

RL is listed as co-inventor of several patents pertinent to the present contribution and is cofounder of Delaqua Pharmaceutical Inc. intending commercial development of poly(2-oxazoline) based drug delivery systems.

Version Notes

first submitted manuscript

Exports