An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis

Sijia Yi; Nicholas B. Karabin; Jennifer Zhu; Sharan Bobbala; Huijue Lyu; Sophia Li; Yugang Liu; Molly Frey; Michael Vincent; Evan A. Scott

doi:10.3389/fbioe.2020.00542

An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis

Sijia Yi, Nicholas B. Karabin, Jennifer Zhu, Sharan Bobbala, Huijue Lyu, Sophia Li, Yugang Liu, Molly Frey, Michael Vincent, Evan A. Scott^*

^*Corresponding author for this work

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3⁺ Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE^−/− mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy.

Original language	English (US)
Article number	542
Journal	Frontiers in Bioengineering and Biotechnology
Volume	8
DOIs	https://doi.org/10.3389/fbioe.2020.00542
State	Published - Jun 5 2020

Funding

The authors would like to thank Dr. Eric W. Roth for CryoTEM assistance. The CryoTEM made use of the BioCryo facility of Northwestern University's NUANCE Center, which has received support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-1542205); the MRSEC program (NSF DMR-1720139) at the Materials Research Center; the International Institute for Nanotechnology (IIN); and the State of Illinois, through the IIN. It also made use of the CryoCluster equipment, which has received support from the MRI program (NSF DMR-1229693). Funding. This research was supported by the National Science Foundation (CBET-1806007 and CAREER Award No. 1453576) and the National Institutes of Health Director's New Innovator Award (NHLBI 1DP2HL132390-01).

Keywords

atherosclerosis
filament
hydrogel
immunotherapy
nanoparticle
regulatory T cells
sustained delivery

ASJC Scopus subject areas

Bioengineering
Biotechnology
Biomedical Engineering
Histology

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title = "An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis",

abstract = "Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3+ Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE−/− mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy.",

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author = "Sijia Yi and Karabin, {Nicholas B.} and Jennifer Zhu and Sharan Bobbala and Huijue Lyu and Sophia Li and Yugang Liu and Molly Frey and Michael Vincent and Scott, {Evan A.}",

note = "Publisher Copyright: {\textcopyright} Copyright {\textcopyright} 2020 Yi, Karabin, Zhu, Bobbala, Lyu, Li, Liu, Frey, Vincent and Scott.",

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AU - Yi, Sijia

AU - Karabin, Nicholas B.

AU - Zhu, Jennifer

AU - Bobbala, Sharan

AU - Lyu, Huijue

AU - Li, Sophia

AU - Liu, Yugang

AU - Frey, Molly

AU - Vincent, Michael

AU - Scott, Evan A.

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Y1 - 2020/6/5

N2 - Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3+ Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE−/− mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy.

AB - Chronic unresolved vascular inflammation is a critical factor in the development of atherosclerosis. Cardiovascular immunotherapy has therefore become a recent focus for treatment, with the objective to develop approaches that can suppress excessive inflammatory responses by modulating specific immune cell populations. A benefit of such immunomodulatory strategies is that low dosage stimulation of key immune cell populations, like antigen presenting cells, can subsequently propagate strong proliferation and therapeutic responses from effector cells. We have previously demonstrated that intravenous injections of anti-inflammatory nanocarriers provided atheroprotection that was mediated by regulatory T cells (Tregs) upregulated in lymphoid organs and atherosclerotic lesions. Here, we demonstrate an injectable filamentous hydrogel depot (FM-depot) engineered for low dosage, sustained delivery of anti-inflammatory nanocarriers. The bioactive form of vitamin D (aVD; 1, 25-Dihydroxyvitamin D3), which inhibits pro-inflammatory transcription factor NF-κB via the intracellular nuclear hormone receptor vitamin D receptor (VDR), was stably loaded into poly(ethylene glycol)-block-poly(propylene sulfide) (PEG-b-PPS) filomicelles. These aVD-loaded filaments underwent morphological transitions to release monodisperse drug-loaded micelles upon oxidation. This cylinder-to-micelle transition was characterized in vitro by cryogenic transmission electron microscopy (CryoTEM) and small angle X-ray scattering (SAXS). Following crosslinking with multi-arm PEG for in situ gelation, aVD-loaded FM-depots maintained high levels of Foxp3+ Tregs in both lymphoid organs and atherosclerotic lesions for weeks following a single subcutaneous injection into ApoE−/− mice. FM-depots therefore present a customizable delivery platform to both develop and test nanomedicine-based approaches for anti-inflammatory cardiovascular immunotherapy.

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KW - hydrogel

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KW - nanoparticle

KW - regulatory T cells

KW - sustained delivery

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An Injectable Hydrogel Platform for Sustained Delivery of Anti-inflammatory Nanocarriers and Induction of Regulatory T Cells in Atherosclerosis

Abstract

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Keywords

ASJC Scopus subject areas

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