Dataset Information

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size.

ABSTRACT: Therapeutic immunomodulation in the skin, its draining lymph nodes, or both tissues simultaneously using an intradermal administration scheme is desirable for a variety of therapeutic scenarios. To inform how drug carriers comprising engineered biomaterials can be leveraged to improve treatment efficacy by enhancing the selective accumulation or retention of payload within these target tissues, we analyzed the influence of particle versus macromolecule hydrodynamic size on profiles of retention in the site of dermal injection as well as the corresponding extent of accumulation in draining lymph nodes and systemic off-target tissues. Using a panel of fluorescently labeled tracers comprising inert polymers that are resistant to hydrolysis and proteolytic degradation that span a size range of widely used drug carrier systems, we find that macromolecule but not rigid particle retention within the skin is size-dependent, whereas the relative dermal enrichment compared to systemic tissues increases with size for both tracer types. Additionally, macromolecules 10 nm in hydrodynamic size and greater accumulate in draining lymph nodes more extensively and selectively than particles, suggesting that intra- versus extracellular availability of delivered payload within draining lymph nodes may be influenced by both the size and form of engineered drug carriers. Our results inform how biomaterial-based drug carriers can be designed to enhance the selective exposure of formulated drug in target tissues to improve the therapeutic efficacy as well as minimize off-target effects of locoregional immunotherapy.

SUBMITTER: Rohner NA

PROVIDER: S-EPMC5990040 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size.

Rohner Nathan Andrew NA Thomas Susan Napier SN

ACS biomaterials science & engineering 20161118 2

Therapeutic immunomodulation in the skin, its draining lymph nodes, or both tissues simultaneously using an intradermal administration scheme is desirable for a variety of therapeutic scenarios. To inform how drug carriers comprising engineered biomaterials can be leveraged to improve treatment efficacy by enhancing the selective accumulation or retention of payload within these target tissues, we analyzed the influence of particle versus macromolecule hydrodynamic size on profiles of retention ...[more]

PMID: 29888321

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Project description:Tumor-draining lymph nodes (TDLNs) are the first organs where the metastatic spread of different types of cancer, including head and neck cancer (HNC), occurs and have therefore high prognostic relevance. Moreover, first anti-cancer immune responses have been shown to be initiated in such LNs via tumor-educated myeloid cells. Among myeloid cells present in TDLNs, neutrophils represent a valuable population and considerably participate in the activation of effector lymphocytes there. Tumor-supportive or tumor-inhibiting activity of neutrophils strongly depends on the surrounding microenvironment. Thus, type I interferon (IFN) availability has been shown to prime anti-tumor activity of these cells. In accordance, mice deficient in type I IFNs show elevated tumor growth and metastatic spread, accompanied by the pro-tumoral neutrophil bias. To reveal the mechanism responsible for this phenomenon, we have studied here the influence of defective type I IFN signaling on the immunoregulatory activity of neutrophils in TDLNs. Live imaging of such LNs was performed using two-photon microscopy in a transplantable murine HNC model. CatchupIVM-red and Ifnar1-/- (type I IFN receptor- deficient) CatchupIVM-red mice were used to visualize neutrophils and to assess their interaction with T-cells in vivo. We have evaluated spatiotemporal patterns of neutrophil/T-cell interactions in LNs in the context of type I interferon receptor (IFNAR1) availability in tumor-free and tumor-bearing animals. Moreover, phenotypic and functional analyses were performed to further characterize the mechanisms regulating neutrophil immunoregulatory capacity. We demonstrated that inactive IFNAR1 leads to elevated accumulation of neutrophils in TDLNs. However, these neutrophils show significantly impaired capacity to interact with and to stimulate T-cells. As a result, a significant reduction of contacts between neutrophils and T lymphocytes is observed, with further impairment of T-cell proliferation and activation. This possibly contributes to the enhanced tumor growth in Ifnar1-/- mice. In agreement with this, IFNAR1-independent activation of downstream IFN signaling using IFN-λ improved the immunostimulatory capacity of neutrophils in TDLNs and contributed to the suppression of tumor growth. Our results suggest that functional type I IFN signaling is essential for neutrophil immunostimulatory capacity and that stimulation of this signaling may provide a therapeutic opportunity in head and neck cancer patients.

Dataset Information

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size.

Publications

Flexible Macromolecule versus Rigid Particle Retention in the Injected Skin and Accumulation in Draining Lymph Nodes Are Differentially Influenced by Hydrodynamic Size.

Similar Datasets

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