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Inflammation. 2019 Feb;42(1):170-184. doi: 10.1007/s10753-018-0882-8.

Application of Deacetylated Poly-N-Acetyl Glucosamine Nanoparticles for the Delivery of miR-126 for the Treatment of Cecal Ligation and Puncture-Induced Sepsis.

Author information

1
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 173 Ashley Ave., MSC 908, CRI Room 610, Charleston, SC, 29425, USA.
2
Department of Biopharmaceutics College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210000, China.
3
Department of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.
4
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
5
Marine Polymer Technologies, Inc., Burlington, MA, 01803, USA.
6
Department of Cell & Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC, 29425, USA.
7
Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.
8
Department of Pharmacology, Medical University of South Carolina, Charleston, SC, 29425, USA.
9
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 173 Ashley Ave., MSC 908, CRI Room 610, Charleston, SC, 29425, USA. fanhong@musc.edu.
10
Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, 29425, USA. fanhong@musc.edu.

Abstract

Sepsis is an acute inflammatory syndrome in response to infection. In some cases, excessive inflammation from sepsis results in endothelial dysfunction and subsequent increased vascular permeability leading to organ failure. We previously showed that treatment with endothelial progenitor cells, which highly express microRNA-126 (miR-126), improved survival in mice subjected to cecal ligation and puncture (CLP) sepsis. miRNAs are important regulators of gene expression and cell function, play a major role in endothelial homeostasis, and may represent an emerging therapeutic modality. However, delivery of miRNAs to cells in vitro and in vivo is challenging due to rapid degradation by ubiquitous RNases. Herein, we developed a nanoparticle delivery system separately combining deacetylated poly-N-acetyl glucosamine (DEAC-pGlcNAc) polymers with miRNA-126-3p and miRNA-126-5p and testing these combinations in vitro and in vivo. Our results demonstrate that DEAC-pGlcNAc polymers have an appropriate size and zeta potential for cellular uptake and when complexed, DEAC-pGlcNAc protects miRNA from RNase A degradation. Further, DEAC-pGlcNAc efficiently encapsulates miRNAs as evidenced by preventing their migration in an agarose gel. The DEAC-pGlcNAc-miRNA complexes were taken up by multiple cell types and the delivered miRNAs had biological effects on their targets in vitro including pERK and DLK-1. In addition, we found that delivery of DEAC-pGlcNAc alone or DEAC-pGlcNAc:miRNA-126-5p nanoparticles to septic animals significantly improved survival, preserved vascular integrity, and modulated cytokine production. These composite studies support the concept that DEAC-pGlcNAc nanoparticles are an effective platform for delivering miRNAs and that they may provide therapeutic benefit in sepsis.

KEYWORDS:

Endothelial dysfunction; Inflammation; Organ dysfunction; Polymicrobial sepsis; miRNA delivery

PMID:
30244405
PMCID:
PMC6380957
[Available on 2020-02-01]
DOI:
10.1007/s10753-018-0882-8

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