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Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels
[Image: see text] The reactivation of the innate immune system by toll-like receptor (TLR) agonists holds promise for anticancer immunotherapy. Severe side effects caused by unspecific and systemic activation of the immune system upon intravenous injection prevent the use of small-molecule TLR agoni...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American
Chemical Society
2020
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304817/ https://www.ncbi.nlm.nih.gov/pubmed/32255626 http://dx.doi.org/10.1021/acs.biomac.0c00205 |
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author | Kockelmann, Johannes Stickdorn, Judith Kasmi, Sabah De Vrieze, Jana Pieszka, Michaela Ng, David Yuen W. David, Sunil A. De Geest, Bruno G. Nuhn, Lutz |
author_facet | Kockelmann, Johannes Stickdorn, Judith Kasmi, Sabah De Vrieze, Jana Pieszka, Michaela Ng, David Yuen W. David, Sunil A. De Geest, Bruno G. Nuhn, Lutz |
author_sort | Kockelmann, Johannes |
collection | PubMed |
description | [Image: see text] The reactivation of the innate immune system by toll-like receptor (TLR) agonists holds promise for anticancer immunotherapy. Severe side effects caused by unspecific and systemic activation of the immune system upon intravenous injection prevent the use of small-molecule TLR agonists for such purposes. However, a covalent attachment of small-molecule imidazoquinoline (IMDQ) TLR7/8 agonists to pH-degradable polymeric nanogels could be shown to drastically reduce the systemic inflammation but retain the activity to tumoral tissues and their draining lymph nodes. Here, we introduce the synthesis of poly(norbornene)-based, acid-degradable nanogels for the covalent ligation of IMDQs. While the intact nanogels trigger sufficient TLR7/8 receptor stimulation, their degraded version of soluble, IMDQ-conjugated poly(norbornene) chains hardly activates TLR7/8. This renders their clinical safety profile, as degradation products are obtained, which would not only circumvent nanoparticle accumulation in the body but also provide nonactive, polymer-bound IMDQ species. Their immunologically silent behavior guarantees both spatial and temporal control over immune activity and, thus, holds promise for improved clinical applications. |
format | Online Article Text |
id | pubmed-7304817 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | American
Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-73048172020-06-22 Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels Kockelmann, Johannes Stickdorn, Judith Kasmi, Sabah De Vrieze, Jana Pieszka, Michaela Ng, David Yuen W. David, Sunil A. De Geest, Bruno G. Nuhn, Lutz Biomacromolecules [Image: see text] The reactivation of the innate immune system by toll-like receptor (TLR) agonists holds promise for anticancer immunotherapy. Severe side effects caused by unspecific and systemic activation of the immune system upon intravenous injection prevent the use of small-molecule TLR agonists for such purposes. However, a covalent attachment of small-molecule imidazoquinoline (IMDQ) TLR7/8 agonists to pH-degradable polymeric nanogels could be shown to drastically reduce the systemic inflammation but retain the activity to tumoral tissues and their draining lymph nodes. Here, we introduce the synthesis of poly(norbornene)-based, acid-degradable nanogels for the covalent ligation of IMDQs. While the intact nanogels trigger sufficient TLR7/8 receptor stimulation, their degraded version of soluble, IMDQ-conjugated poly(norbornene) chains hardly activates TLR7/8. This renders their clinical safety profile, as degradation products are obtained, which would not only circumvent nanoparticle accumulation in the body but also provide nonactive, polymer-bound IMDQ species. Their immunologically silent behavior guarantees both spatial and temporal control over immune activity and, thus, holds promise for improved clinical applications. American Chemical Society 2020-04-07 2020-06-08 /pmc/articles/PMC7304817/ /pubmed/32255626 http://dx.doi.org/10.1021/acs.biomac.0c00205 Text en Copyright © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. |
spellingShingle | Kockelmann, Johannes Stickdorn, Judith Kasmi, Sabah De Vrieze, Jana Pieszka, Michaela Ng, David Yuen W. David, Sunil A. De Geest, Bruno G. Nuhn, Lutz Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels |
title | Control over Imidazoquinoline Immune Stimulation by
pH-Degradable Poly(norbornene) Nanogels |
title_full | Control over Imidazoquinoline Immune Stimulation by
pH-Degradable Poly(norbornene) Nanogels |
title_fullStr | Control over Imidazoquinoline Immune Stimulation by
pH-Degradable Poly(norbornene) Nanogels |
title_full_unstemmed | Control over Imidazoquinoline Immune Stimulation by
pH-Degradable Poly(norbornene) Nanogels |
title_short | Control over Imidazoquinoline Immune Stimulation by
pH-Degradable Poly(norbornene) Nanogels |
title_sort | control over imidazoquinoline immune stimulation by
ph-degradable poly(norbornene) nanogels |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304817/ https://www.ncbi.nlm.nih.gov/pubmed/32255626 http://dx.doi.org/10.1021/acs.biomac.0c00205 |
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