Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Lerchen, Hans-Georg, Stelte-Ludwig, Beatrix, Kopitz, Charlotte, Heroult, Melanie, Zubov, Dmitry, Willuda, Joerg, Schlange, Thomas, Kahnert, Antje, Wong, Harvey, Izumi, Raquel, Hamdy, Ahmed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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
_version_ 1784636164401004544
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
work_keys_str_mv AT lerchenhansgeorg asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT stelteludwigbeatrix asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT kopitzcharlotte asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT heroultmelanie asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT zubovdmitry asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT willudajoerg asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT schlangethomas asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT kahnertantje asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT wongharvey asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT izumiraquel asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT hamdyahmed asmallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT lerchenhansgeorg smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT stelteludwigbeatrix smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT kopitzcharlotte smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT heroultmelanie smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT zubovdmitry smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT willudajoerg smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT schlangethomas smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT kahnertantje smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT wongharvey smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT izumiraquel smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes
AT hamdyahmed smallmoleculedrugconjugatesmdcconsistingofamodifiedcamptothecinpayloadlinkedtoanavß3binderforthetreatmentofmultiplecancertypes