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Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines

A design strategy for macromolecular prodrugs is described, that are expected to exhibit robust activity against most solid tumor types while resulting in minimal toxicities to normal tissues. This approach exploits the enhanced permeability, and retention (EPR) effect, and utilizes carefully engine...

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Detalles Bibliográficos
Autores principales: Penketh, Philip G., Williamson, Hugh S., Baumann, Raymond P., Shyam, Krishnamurthy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825511/
https://www.ncbi.nlm.nih.gov/pubmed/33419160
http://dx.doi.org/10.3390/molecules26020259
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author Penketh, Philip G.
Williamson, Hugh S.
Baumann, Raymond P.
Shyam, Krishnamurthy
author_facet Penketh, Philip G.
Williamson, Hugh S.
Baumann, Raymond P.
Shyam, Krishnamurthy
author_sort Penketh, Philip G.
collection PubMed
description A design strategy for macromolecular prodrugs is described, that are expected to exhibit robust activity against most solid tumor types while resulting in minimal toxicities to normal tissues. This approach exploits the enhanced permeability, and retention (EPR) effect, and utilizes carefully engineered rate constants to selectively target tumor tissue with short-lived cytotoxic moieties. EPR based tumor accumulation (half-life ~ 15 h) is dependent upon the ubiquitous abnormal solid tumor capillary morphology and is expected to be independent of individual tumor cell genetic variability that leads to resistance to molecularly targeted agents. The macromolecular sulfonylhydrazine-based prodrugs hydrolyze spontaneously with long half-life values (~10 h to >300 h dependent upon their structure) resulting in the majority of the 1,2-bis(sulfonyl)-1-alkylhydrazines (BSHs) cytotoxic warhead being released only after tumor sequestration. The very short half-life (seconds) of the finally liberated BSHs localizes the cytotoxic stress to the tumor target site by allowing insufficient time for escape. Thus, short lifespan anticancer species are liberated, and exhibit their activity largely within the tumor target. The abnormal tumor cell membrane pH gradients favor the uptake of BSHs compared to that of normal cells, further enhancing their selectivity. The reliance on physicochemical/chemical kinetic parameters and the EPR effect is expected to reduce response variability, and the acquisition of resistance.
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spelling pubmed-78255112021-01-24 Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines Penketh, Philip G. Williamson, Hugh S. Baumann, Raymond P. Shyam, Krishnamurthy Molecules Article A design strategy for macromolecular prodrugs is described, that are expected to exhibit robust activity against most solid tumor types while resulting in minimal toxicities to normal tissues. This approach exploits the enhanced permeability, and retention (EPR) effect, and utilizes carefully engineered rate constants to selectively target tumor tissue with short-lived cytotoxic moieties. EPR based tumor accumulation (half-life ~ 15 h) is dependent upon the ubiquitous abnormal solid tumor capillary morphology and is expected to be independent of individual tumor cell genetic variability that leads to resistance to molecularly targeted agents. The macromolecular sulfonylhydrazine-based prodrugs hydrolyze spontaneously with long half-life values (~10 h to >300 h dependent upon their structure) resulting in the majority of the 1,2-bis(sulfonyl)-1-alkylhydrazines (BSHs) cytotoxic warhead being released only after tumor sequestration. The very short half-life (seconds) of the finally liberated BSHs localizes the cytotoxic stress to the tumor target site by allowing insufficient time for escape. Thus, short lifespan anticancer species are liberated, and exhibit their activity largely within the tumor target. The abnormal tumor cell membrane pH gradients favor the uptake of BSHs compared to that of normal cells, further enhancing their selectivity. The reliance on physicochemical/chemical kinetic parameters and the EPR effect is expected to reduce response variability, and the acquisition of resistance. MDPI 2021-01-06 /pmc/articles/PMC7825511/ /pubmed/33419160 http://dx.doi.org/10.3390/molecules26020259 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Penketh, Philip G.
Williamson, Hugh S.
Baumann, Raymond P.
Shyam, Krishnamurthy
Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
title Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
title_full Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
title_fullStr Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
title_full_unstemmed Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
title_short Design Strategy for the EPR Tumor-Targeting of 1,2-Bis(sulfonyl)-1-alkylhydrazines
title_sort design strategy for the epr tumor-targeting of 1,2-bis(sulfonyl)-1-alkylhydrazines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825511/
https://www.ncbi.nlm.nih.gov/pubmed/33419160
http://dx.doi.org/10.3390/molecules26020259
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