A carrier free delivery system of a MAGL inhibitor is effective on ovarian cancer.

Autor: Palazzolo S; Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy., Saorin G; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30172 Venice, Italy., Corona G; Immunopathology and Cancer Biomarkers Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy., Granchi C; Department of Pharmacy, University of Pisa Via Bonanno 6 56126 Pisa Italy., Tuccinardi T; Department of Pharmacy, University of Pisa Via Bonanno 6 56126 Pisa Italy., Kamensek U; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia., Brezar SK; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia., Cemazar M; Department of Experimental Oncology, Institute of Oncology Ljubljana, Zaloska cesta 2, SI-1000 Ljubljana, Slovenia., Canzonieri V; Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy., Rizzolio F; Pathology Unit, Centro di Riferimento Oncologico di Aviano (C.R.O.) IRCCS, 33081 Aviano, Italy; Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, 30172 Venice, Italy. Electronic address: flavio.rizzolio@unive.it.
Jazyk: angličtina
Zdroj: European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V [Eur J Pharm Biopharm] 2024 Oct; Vol. 203, pp. 114397. Date of Electronic Publication: 2024 Jul 06.
DOI: 10.1016/j.ejpb.2024.114397
Abstrakt: Monoacylglycerol lipase (MAGL) is a promising target for cancer therapy due to its involvement in lipid metabolism and its impact on cancer hallmarks like cell proliferation, migration, and tumor progression. A potent reversible MAGL inhibitor, MAGL23, has been recently developed by our group, demonstrating promising anticancer activities. To enhance its pharmacological properties, a nanoformulation using nanocrystals coated with albumin was prepared (MAGL23AF). In a previous work, the formulated inhibitor showed potency in ovarian and colon cancer cell lines in terms of IC 50 , and was tested on mice in order to assess its biocompatibility, organs biodistribution and toxicity. In the present work, we expanded the investigation to assess the potential in vivo application of MAGL23AF. Stability assays in serum and in human derived microsomes showed a good structural stability in physiological conditions of MAGL23AF. The antitumor efficacy tested on mice bearing ovarian cancer tumor xenografts demonstrated that MAGL23AF is more potent than the non-formulated drug, leading to necrosis-driven cancer cell death. In vivo studies revealed that albumin-complexed nanocrystals improved the therapeutic window of MAGL23, exhibiting a favorable biodistribution with slightly increased accumulation in the tumor. In conclusion, the MAGL23AF showed increased in vitro stability in conditions mirroring the bloodstream environment and hepatic metabolism coupled with an optimal antitumor efficacy in vivo. These results not only validates the efficacy of our formulation but also positions it as a promising strategy for addressing challenges related to the solubility of drugs in body fluids.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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