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Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal

[Image: see text] Ensuring effective drug concentration specifically at sites of need, while limiting systemic side effects, remains a challenge in the discovery and use of new drug molecules. Carriers targeted through biological affinity (e.g., antibodies) afford a common means of drug localization...

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Autores principales: Zou, Lei, Braegelman, Adam S., Webber, Matthew J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598162/
https://www.ncbi.nlm.nih.gov/pubmed/31263763
http://dx.doi.org/10.1021/acscentsci.9b00195
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author Zou, Lei
Braegelman, Adam S.
Webber, Matthew J.
author_facet Zou, Lei
Braegelman, Adam S.
Webber, Matthew J.
author_sort Zou, Lei
collection PubMed
description [Image: see text] Ensuring effective drug concentration specifically at sites of need, while limiting systemic side effects, remains a challenge in the discovery and use of new drug molecules. Carriers targeted through biological affinity (e.g., antibodies) afford a common means of drug localization, yet often deliver considerably less than 1% of an administered drug to a desired site in the body. We report on an alternative targeting paradigm using pendant guest motifs to direct molecules to sites distinguished by a hydrogel bearing a high density of a complementary cucurbituril supramolecular host. Host–guest affinity (K(eq)) of 10(12) M(–1) serves to spatially localize ∼4% of a model small molecule within hours of its administration in mice. These high-affinity interactions furthermore ensure long-lasting retention of the model compound at the site of interest, and the site can be serially targeted upon repeated dosing. This supramolecular homing axis extends the localization of small molecule payloads beyond injectable hydrogels, enabling targeting of modified biomaterials. This approach also has promising therapeutic utility, improving efficacy of a guest-modified chemotherapeutic agent in a tumor model.
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spelling pubmed-65981622019-07-01 Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal Zou, Lei Braegelman, Adam S. Webber, Matthew J. ACS Cent Sci [Image: see text] Ensuring effective drug concentration specifically at sites of need, while limiting systemic side effects, remains a challenge in the discovery and use of new drug molecules. Carriers targeted through biological affinity (e.g., antibodies) afford a common means of drug localization, yet often deliver considerably less than 1% of an administered drug to a desired site in the body. We report on an alternative targeting paradigm using pendant guest motifs to direct molecules to sites distinguished by a hydrogel bearing a high density of a complementary cucurbituril supramolecular host. Host–guest affinity (K(eq)) of 10(12) M(–1) serves to spatially localize ∼4% of a model small molecule within hours of its administration in mice. These high-affinity interactions furthermore ensure long-lasting retention of the model compound at the site of interest, and the site can be serially targeted upon repeated dosing. This supramolecular homing axis extends the localization of small molecule payloads beyond injectable hydrogels, enabling targeting of modified biomaterials. This approach also has promising therapeutic utility, improving efficacy of a guest-modified chemotherapeutic agent in a tumor model. American Chemical Society 2019-06-12 2019-06-26 /pmc/articles/PMC6598162/ /pubmed/31263763 http://dx.doi.org/10.1021/acscentsci.9b00195 Text en Copyright © 2019 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
spellingShingle Zou, Lei
Braegelman, Adam S.
Webber, Matthew J.
Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal
title Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal
title_full Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal
title_fullStr Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal
title_full_unstemmed Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal
title_short Spatially Defined Drug Targeting by in Situ Host–Guest Chemistry in a Living Animal
title_sort spatially defined drug targeting by in situ host–guest chemistry in a living animal
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598162/
https://www.ncbi.nlm.nih.gov/pubmed/31263763
http://dx.doi.org/10.1021/acscentsci.9b00195
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