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Issue 12, 2018
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An E-selectin targeting and MMP-2-responsive dextran–curcumin polymeric prodrug for targeted therapy of acute kidney injury

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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 the targeting group to the inflamed vascular endothelial cells for enhanced therapeutic outcomes. An MMP-2-responsive peptide, PVGLIG, was used to endow the polymeric prodrug with the ability to rapidly release the anti-inflammatory drug, curcumin (CUR), after the targeted site is reached and to improve the drug concentration in the 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 the polymeric prodrug and was approximately 23-fold higher than that of free CUR. The in vitro drug release results showed that the release rate of SA-DEX-PVGLIG-CUR was significantly enhanced compared to that of SA-DEX-CUR in a dissolving medium containing the MMP-2 enzyme, suggesting that SA-DEX-PVGLIG-CUR had rapid drug release characteristics in an inflammatory environment. A cellular uptake test confirmed that SA-DEX-PVGLIG-CUR was effectively internalized by inflamed vascular endothelial cells in comparison with 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 the rapid drug release in renal tissue, SA-DEX-PVGLIG-CUR effectively ameliorated the pathological progression of AKI compared with free CUR and SA-DEX-CUR, as reflected by the improved renal functions, histopathological changes, pro-inflammatory cytokine production, oxidative stress and expression of apoptosis related proteins. Altogether, this study provided a new therapeutic strategy for the treatment of AKI.

Graphical abstract: An E-selectin targeting and MMP-2-responsive dextran–curcumin polymeric prodrug for targeted therapy of acute kidney injury

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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., 2018,6, 3397-3409
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    An E-selectin targeting and MMP-2-responsive dextran–curcumin polymeric prodrug for targeted therapy of acute kidney injury

    J. Hu, D. Liu, J. Qi, K. Lu, F. Jin, X. Ying, J. You and Y. Du, Biomater. Sci., 2018, 6, 3397
    DOI: 10.1039/C8BM00813B

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