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A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types
SIMPLE SUMMARY: Many cancer drugs are cytotoxic, which means that they kill cancer cells effectively but are also toxic to normal cells. To overcome this problem, we designed a novel compound, VIP236, which consists of three components. The first part enables the drug to target and bind to a protein...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773721/ https://www.ncbi.nlm.nih.gov/pubmed/35053556 http://dx.doi.org/10.3390/cancers14020391 |
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author | Lerchen, Hans-Georg Stelte-Ludwig, Beatrix Kopitz, Charlotte Heroult, Melanie Zubov, Dmitry Willuda, Joerg Schlange, Thomas Kahnert, Antje Wong, Harvey Izumi, Raquel Hamdy, Ahmed |
author_facet | Lerchen, Hans-Georg Stelte-Ludwig, Beatrix Kopitz, Charlotte Heroult, Melanie Zubov, Dmitry Willuda, Joerg Schlange, Thomas Kahnert, Antje Wong, Harvey Izumi, Raquel Hamdy, Ahmed |
author_sort | Lerchen, Hans-Georg |
collection | PubMed |
description | SIMPLE SUMMARY: Many cancer drugs are cytotoxic, which means that they kill cancer cells effectively but are also toxic to normal cells. To overcome this problem, we designed a novel compound, VIP236, which consists of three components. The first part enables the drug to target and bind to a protein called ‘α(V)β(3) integrin’ on the surface of cancer cells. The second part is a new cytotoxic drug, VIP126. The third component links the two parts together and can only be sliced by the enzyme neutrophil elastase. Neutrophil elastase is found in high quantities in tumors, ensuring that VIP126 is released near the cancer cells and less around normal cells. VIP126, when delivered as a component of VIP236, kills tumor cells in mouse cancer models without the toxicity seen with standard chemotherapy. VIP236 may be a new modality for targeting cancer cells directly, while reducing the harmful effects to normal tissue. ABSTRACT: To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an α(V)β(3) integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the α(V)β(3) binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing α(V)β(3) as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma. |
format | Online Article Text |
id | pubmed-8773721 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87737212022-01-21 A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types Lerchen, Hans-Georg Stelte-Ludwig, Beatrix Kopitz, Charlotte Heroult, Melanie Zubov, Dmitry Willuda, Joerg Schlange, Thomas Kahnert, Antje Wong, Harvey Izumi, Raquel Hamdy, Ahmed Cancers (Basel) Article SIMPLE SUMMARY: Many cancer drugs are cytotoxic, which means that they kill cancer cells effectively but are also toxic to normal cells. To overcome this problem, we designed a novel compound, VIP236, which consists of three components. The first part enables the drug to target and bind to a protein called ‘α(V)β(3) integrin’ on the surface of cancer cells. The second part is a new cytotoxic drug, VIP126. The third component links the two parts together and can only be sliced by the enzyme neutrophil elastase. Neutrophil elastase is found in high quantities in tumors, ensuring that VIP126 is released near the cancer cells and less around normal cells. VIP126, when delivered as a component of VIP236, kills tumor cells in mouse cancer models without the toxicity seen with standard chemotherapy. VIP236 may be a new modality for targeting cancer cells directly, while reducing the harmful effects to normal tissue. ABSTRACT: To improve tumor selectivity of cytotoxic agents, we designed VIP236, a small molecule–drug conjugate consisting of an α(V)β(3) integrin binder linked to a modified camptothecin payload (VIP126), which is released by the enzyme neutrophil elastase (NE) in the tumor microenvironment (TME). The tumor targeting and pharmacokinetics of VIP236 were studied in tumor-bearing mice by in vivo near-infrared imaging and by analyzing tumor and plasma samples. The efficacy of VIP236 was investigated in a panel of cancer cell lines in vitro, and in MX-1, NCI-H69, and SW480 murine xenograft models. Imaging studies with the α(V)β(3) binder demonstrated efficient tumor targeting. Administration of VIP126 via VIP236 resulted in a 10-fold improvement in the tumor/plasma ratio of VIP126 compared with VIP126 administered alone. Unlike SN38, VIP126 is not a substrate of P-gp and BCRP drug transporters. VIP236 presented strong cytotoxic activity in the presence of NE. VIP236 treatment resulted in tumor regressions and very good tolerability in all in vivo models tested. VIP236 represents a novel approach for delivering a potent cytotoxic agent by utilizing α(V)β(3) as a targeting moiety and NE in the TME to release the VIP126 payload—designed for high permeability and low efflux—directly into the tumor stroma. MDPI 2022-01-13 /pmc/articles/PMC8773721/ /pubmed/35053556 http://dx.doi.org/10.3390/cancers14020391 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 Lerchen, Hans-Georg Stelte-Ludwig, Beatrix Kopitz, Charlotte Heroult, Melanie Zubov, Dmitry Willuda, Joerg Schlange, Thomas Kahnert, Antje Wong, Harvey Izumi, Raquel Hamdy, Ahmed A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types |
title | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types |
title_full | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types |
title_fullStr | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types |
title_full_unstemmed | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types |
title_short | A Small Molecule–Drug Conjugate (SMDC) Consisting of a Modified Camptothecin Payload Linked to an α(V)ß(3) Binder for the Treatment of Multiple Cancer Types |
title_sort | small molecule–drug conjugate (smdc) consisting of a modified camptothecin payload linked to an α(v)ß(3) binder for the treatment of multiple cancer types |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773721/ https://www.ncbi.nlm.nih.gov/pubmed/35053556 http://dx.doi.org/10.3390/cancers14020391 |
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