Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Langer, Carolin, Köll-Weber, Monika, Holzer, Martin, Hantel, Constanze, Süss, Regine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501383/
https://www.ncbi.nlm.nih.gov/pubmed/36145639
http://dx.doi.org/10.3390/pharmaceutics14091891
_version_ 1784795461096308736
author Langer, Carolin
Köll-Weber, Monika
Holzer, Martin
Hantel, Constanze
Süss, Regine
author_facet Langer, Carolin
Köll-Weber, Monika
Holzer, Martin
Hantel, Constanze
Süss, Regine
author_sort Langer, Carolin
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9501383
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-95013832022-09-24 Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids Langer, Carolin Köll-Weber, Monika Holzer, Martin Hantel, Constanze Süss, Regine Pharmaceutics Article 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. MDPI 2022-09-07 /pmc/articles/PMC9501383/ /pubmed/36145639 http://dx.doi.org/10.3390/pharmaceutics14091891 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Langer, Carolin
Köll-Weber, Monika
Holzer, Martin
Hantel, Constanze
Süss, Regine
Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
title Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
title_full Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
title_fullStr Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
title_full_unstemmed Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
title_short Mitotane Nanocarriers for the Treatment of Adrenocortical Carcinoma: Evaluation of Albumin-Stabilized Nanoparticles and Liposomes in a Preclinical In Vitro Study with 3D Spheroids
title_sort mitotane nanocarriers for the treatment of adrenocortical carcinoma: evaluation of albumin-stabilized nanoparticles and liposomes in a preclinical in vitro study with 3d spheroids
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9501383/
https://www.ncbi.nlm.nih.gov/pubmed/36145639
http://dx.doi.org/10.3390/pharmaceutics14091891
work_keys_str_mv AT langercarolin mitotanenanocarriersforthetreatmentofadrenocorticalcarcinomaevaluationofalbuminstabilizednanoparticlesandliposomesinapreclinicalinvitrostudywith3dspheroids
AT kollwebermonika mitotanenanocarriersforthetreatmentofadrenocorticalcarcinomaevaluationofalbuminstabilizednanoparticlesandliposomesinapreclinicalinvitrostudywith3dspheroids
AT holzermartin mitotanenanocarriersforthetreatmentofadrenocorticalcarcinomaevaluationofalbuminstabilizednanoparticlesandliposomesinapreclinicalinvitrostudywith3dspheroids
AT hantelconstanze mitotanenanocarriersforthetreatmentofadrenocorticalcarcinomaevaluationofalbuminstabilizednanoparticlesandliposomesinapreclinicalinvitrostudywith3dspheroids
AT sussregine mitotanenanocarriersforthetreatmentofadrenocorticalcarcinomaevaluationofalbuminstabilizednanoparticlesandliposomesinapreclinicalinvitrostudywith3dspheroids