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Old Drug, New Delivery Strategy: MMAE Repackaged

Targeting therapy is a concept that has gained significant importance in recent years, especially in oncology. The severe dose-limiting side effects of chemotherapy necessitate the development of novel, efficient and tolerable therapy approaches. In this regard, the prostate specific membrane antige...

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Autores principales: Lahnif, Hanane, Grus, Tilmann, Salvanou, Evangelia-Alexandra, Deligianni, Elisavet, Stellas, Dimitris, Bouziotis, Penelope, Rösch, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10218109/
https://www.ncbi.nlm.nih.gov/pubmed/37239890
http://dx.doi.org/10.3390/ijms24108543
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author Lahnif, Hanane
Grus, Tilmann
Salvanou, Evangelia-Alexandra
Deligianni, Elisavet
Stellas, Dimitris
Bouziotis, Penelope
Rösch, Frank
author_facet Lahnif, Hanane
Grus, Tilmann
Salvanou, Evangelia-Alexandra
Deligianni, Elisavet
Stellas, Dimitris
Bouziotis, Penelope
Rösch, Frank
author_sort Lahnif, Hanane
collection PubMed
description Targeting therapy is a concept that has gained significant importance in recent years, especially in oncology. The severe dose-limiting side effects of chemotherapy necessitate the development of novel, efficient and tolerable therapy approaches. In this regard, the prostate specific membrane antigene (PSMA) has been well established as a molecular target for diagnosis of, as well as therapy for, prostate cancer. Although most PSMA-targeting ligands are radiopharmaceuticals used in imaging or radioligand therapy, this article evaluates a PSMA-targeting small molecule–drug conjugate, and, thus, addresses a hitherto little-explored field. PSMA binding affinity and cytotoxicity were determined in vitro using cell-based assays. Enzyme-specific cleavage of the active drug was quantified via an enzyme-based assay. Efficacy and tolerability in vivo were assessed using an LNCaP xenograft model. Histopathological characterization of the tumor in terms of apoptotic status and proliferation rate was carried out using caspase-3 and Ki67 staining. The binding affinity of the Monomethyl auristatin E (MMAE) conjugate was moderate, compared to the drug-free PSMA ligand. Cytotoxicity in vitro was in the nanomolar range. Both binding and cytotoxicity were found to be PSMA-specific. Additionally, complete MMAE release could be reached after incubation with cathepsin B. In vivo, the MMAE conjugate displayed good tolerability and dose-dependent inhibition of tumor growth. Immunohistochemical and histological studies revealed the antitumor effect of MMAE.VC.SA.617, resulting in the inhibition of proliferation and the enhancement of apoptosis. The developed MMAE conjugate showed good properties in vitro, as well as in vivo, and should, therefore, be considered a promising candidate for a translational approach.
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spelling pubmed-102181092023-05-27 Old Drug, New Delivery Strategy: MMAE Repackaged Lahnif, Hanane Grus, Tilmann Salvanou, Evangelia-Alexandra Deligianni, Elisavet Stellas, Dimitris Bouziotis, Penelope Rösch, Frank Int J Mol Sci Article Targeting therapy is a concept that has gained significant importance in recent years, especially in oncology. The severe dose-limiting side effects of chemotherapy necessitate the development of novel, efficient and tolerable therapy approaches. In this regard, the prostate specific membrane antigene (PSMA) has been well established as a molecular target for diagnosis of, as well as therapy for, prostate cancer. Although most PSMA-targeting ligands are radiopharmaceuticals used in imaging or radioligand therapy, this article evaluates a PSMA-targeting small molecule–drug conjugate, and, thus, addresses a hitherto little-explored field. PSMA binding affinity and cytotoxicity were determined in vitro using cell-based assays. Enzyme-specific cleavage of the active drug was quantified via an enzyme-based assay. Efficacy and tolerability in vivo were assessed using an LNCaP xenograft model. Histopathological characterization of the tumor in terms of apoptotic status and proliferation rate was carried out using caspase-3 and Ki67 staining. The binding affinity of the Monomethyl auristatin E (MMAE) conjugate was moderate, compared to the drug-free PSMA ligand. Cytotoxicity in vitro was in the nanomolar range. Both binding and cytotoxicity were found to be PSMA-specific. Additionally, complete MMAE release could be reached after incubation with cathepsin B. In vivo, the MMAE conjugate displayed good tolerability and dose-dependent inhibition of tumor growth. Immunohistochemical and histological studies revealed the antitumor effect of MMAE.VC.SA.617, resulting in the inhibition of proliferation and the enhancement of apoptosis. The developed MMAE conjugate showed good properties in vitro, as well as in vivo, and should, therefore, be considered a promising candidate for a translational approach. MDPI 2023-05-10 /pmc/articles/PMC10218109/ /pubmed/37239890 http://dx.doi.org/10.3390/ijms24108543 Text en © 2023 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
Lahnif, Hanane
Grus, Tilmann
Salvanou, Evangelia-Alexandra
Deligianni, Elisavet
Stellas, Dimitris
Bouziotis, Penelope
Rösch, Frank
Old Drug, New Delivery Strategy: MMAE Repackaged
title Old Drug, New Delivery Strategy: MMAE Repackaged
title_full Old Drug, New Delivery Strategy: MMAE Repackaged
title_fullStr Old Drug, New Delivery Strategy: MMAE Repackaged
title_full_unstemmed Old Drug, New Delivery Strategy: MMAE Repackaged
title_short Old Drug, New Delivery Strategy: MMAE Repackaged
title_sort old drug, new delivery strategy: mmae repackaged
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10218109/
https://www.ncbi.nlm.nih.gov/pubmed/37239890
http://dx.doi.org/10.3390/ijms24108543
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