Dataset Information

Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels.

ABSTRACT: 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.

SUBMITTER: Kockelmann J

PROVIDER: S-EPMC7304817 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels.

Kockelmann Johannes J Stickdorn Judith J Kasmi Sabah S De Vrieze Jana J Pieszka Michaela M Ng David Yuen W DYW David Sunil A SA De Geest Bruno G BG Nuhn Lutz L

Biomacromolecules 20200416 6

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 ret ...[more]

PMID: 32255626

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Project description:Liver fibrosis is a hard-to-treat disease with liver transplantation as only effective curation to this date. During disease progression, immune suppressive macrophages dominate and support fibrosis formation by replacement of functional parenchyma with collagen-dominating scare tissue. To alter the macrophage behavior, a pH-degradable, nanogel-based delivery system was developed for the covalent conjugation of the clinically approved bisphosphonate alendronate. The nanocarrier mediates the drugs’ delivery into hepatic nonparenchymal cells after intravenous administration and, thereby, triggers a macrophage repolarization against fibrosis progression. This approach may provide a significant contribution to establish further nanotherapeutic delivery strategies to effectively treat liver fibrosis. Immune suppressive macrophages contribute to the progression of several diseases including cancer and fibrosis. Especially in chronically damaged liver tissues they trigger the replacement of functional parenchyma by collagen-dominating scare tissue. In this study, we aimed to intervene into this cascade by repolarizing the macrophage phenotype via a pH-degradable, squaric ester-based nanogel carrier system. This nanotechnology platform enables a selective covalent conjugation of the highly water-soluble bisphosphonate alendronate and, thus, its safe and efficient delivery to hepatic nonparenchymal cells of fibrotic livers after intravenous administration. The bisphosphonate triggers a reprogramming of profibrotic M2- towards antifibrotic M1-phenotype macrophages affording an fibrolytic outcome, as verified both on mRNA and protein level. Further insights by genomic and proteomic studies confirm the macrophages’ repolarization and thus corroborate the virtue of the nanogels as biocompatible nanocarrier platform for hepatotropic bisphosphonate delivery. Beyond preventing liver fibrosis progression, these nanogels may therefore represent an attractive device for further nanotherapeutic interventions in M2-type macrophage dominating diseases.

Dataset Information

Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels.

Publications

Control over Imidazoquinoline Immune Stimulation by pH-Degradable Poly(norbornene) Nanogels.

Similar Datasets

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