Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids

Adrenocortical carcinoma (ACC) is a heterogeneous malignancy related to poor prognosis and limited treatment options. The orphan drug mitotane (MT) is still a cornerstone in ACC therapy, however, its application is characterized by low aqueous solubility, poor bioavailability, and unfavorable pharma...

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Published in:Pharmaceutics 2022-09, Vol.14 (9), p.1891
Main Authors: Langer, Carolin, Köll-Weber, Monika, Holzer, Martin, Hantel, Constanze, Süss, Regine
Format: Article
Language:English
Subjects:
3D spheroids
adrenocortical carcinoma
Albumin
albumin nanoparticles
Analysis
Cancer therapies
cancer therapy
Cell culture
Cytotoxicity
Dosage and administration
Drug delivery systems
Drug dosages
Fibroblasts
Health aspects
Hydrochloric acid
Liposomes
Measurement
Medical prognosis
Mitotane
Nanoparticles
Pharmacokinetics
Physiology
Proteins
Sodium
Tumors
Zirconium oxides
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Summary:Adrenocortical carcinoma (ACC) is a heterogeneous malignancy related to poor prognosis and limited treatment options. The orphan drug mitotane (MT) is still a cornerstone in ACC therapy, however, its application is characterized by low aqueous solubility, poor bioavailability, and unfavorable pharmacokinetics, often resulting in below-target plasma concentrations or toxic side effects. Throughout the last decades, nanoparticulate formulations have become attractive carriers to improve anticancer therapy. In this study, injectable MT liposomes (DOPC-MT) and albumin-stabilized MT nanoparticles (BSA-MT) were investigated in depth with respect to their physicochemical properties, and their colloidal and therapeutical stability upon storage. Furthermore, in vitro cytotoxicity was evaluated using the ACC model cell line NCI-H295R for preparing multicellular tumor spheroids, and was compared to non-malignant human dermal fibroblasts. Our results clearly demonstrate that BSA-MT, unlike DOPC-MT, represents a stable and storable MT formulation with a high drug concentration in an aqueous medium. Dual centrifugation was established as a reproducible method for nanoparticle preparation. Although an efficient cytotoxic effect on ACC tumor spheroids was demonstrated, concomitant low toxicity to fibroblasts suggests that higher drug concentrations may be tolerated in vivo. Consequently, BSA-MT is a novel and promising therapeutical approach to address key challenges in MT treatment.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics14091891