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E-selectin-targeting, inflammatory microenvironment-responsive dextran-curcumin polymeric prodrug for acute kidney injury

Abstract

Based on the overproduction of matrix metalloproteinase-2 (MMP-2) in renal tissue during acute kidney injury (AKI) occurrence, we developed a MMP-2 enzyme-triggered polymeric prodrug with sialic acid (SA) as targeting group to the inflamed vascular endothelial cells for enhanced therapeutic outcomes. The MMP-2-responsove peptide, PVGLIG, was used to afford the polymeric prodrug the ability to rapidly release anti-inflammatory drug, curcumin (CUR), after the targeted site has been reached and improve drug concentration in target tissue. The sialic acid-dextran-PVGLIG-curcumin (SA-DEX-PVGLIG-CUR) polymeric prodrug was successfully synthesized via multi-step chemical reactions and characterized by 1H NMR. The water solubility of CUR was significantly increased in polymeric prodrug and approximately 23-fold higher than that of free CUR. In vitro drug release results showed that the release rate of SA-DEX-PVGLIG-CUR was significantly enhanced than that of SA-DEX-CUR in dissolve medium containing MMP-2 enzyme, suggesting SA-DEX-PVGLIG-CUR had rapid drug release characteristics under inflammatory environment. Cellular uptake test confirmed that SA-DEX-PVGLIG-CUR was effectively internalized by inflamed vascular endothelial cells in comparison to that by normal cells, and the mechanism was associated with the specific interaction between SA and E-selectin receptors specifically expressed on inflamed vascular endothelial cells. Bio-distribution results further demonstrated the rapid and increased renal accumulation of SA-DEX-PVGLIG-CUR in AKI mice. Benefiting from rapid drug release in renal tissue, SA-DEX-PVGLIG-CUR effectively ameliorated pathological progression of AKI compared with free CUR and SA-DEX-CUR, as reflected by the improved renal functions, histopathological changes, pro-inflammatory cytokines, oxidative stress and expression of apoptotic related proteins. Taken together, this study provided a new therapeutic strategy for the treatment of AKI.

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Publication details

The article was received on 17 Jul 2018, accepted on 07 Oct 2018 and first published on 09 Oct 2018


Article type: Paper
DOI: 10.1039/C8BM00813B
Citation: Biomater. Sci., 2018, Accepted Manuscript
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    E-selectin-targeting, inflammatory microenvironment-responsive dextran-curcumin polymeric prodrug for acute kidney injury

    J. Hu, D. Liu, J. Qi, K. Lu, F. Jin, X. Ying, J. You and Y. Du, Biomater. Sci., 2018, Accepted Manuscript , DOI: 10.1039/C8BM00813B

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