Cell-mediated delivery of glucocorticoids from thiol-ene hydrogels

JOURNAL OF CONTROLLED RELEASE

卷:162

Article

Yang, Chun³  Mariner, Peter D.^1,2  Nahreini, Jhenya N.^1,2  Anseth, Kristi S.^1,2,4 

[1] Univ Colorado, Dept Chem & Biol Engn, Boulder, CO 80303 USA

[2] Univ Colorado, BioFrontier Inst, Boulder, CO 80303 USA

[3] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA

[4] Univ Colorado, Howard Hughes Med Inst, Boulder, CO 80303 USA

关键词: Hydrogel;    Dexamethasone;    Mesenchymal stem cells;    Glucocorticoid;    Poly(ethylene glycol);   

DOI  :  10.1016/j.jconrel.2012.08.002

来源: Elsevier

【 摘 要 】

Thiol-ene-based poly(ethylene glycol) (PEG) hydrogels provide a unique functional platform for the sustained and localized delivery of bioactive small molecules like glucocorticoids. As a proof of concept, the synthetic glucocorticoid Dexamethasone (Dex) was conjugated to the N-terminus of a matrix metalloproteinase(MMP)-degradable peptide, which was then easily co-polymerized into PEG gel scaffolds by a thiol-ene polymerization mechanism. The conjugated Dex was locally sequestered until released by cleavage of the MMP-degradable peptide tether triggered by cell-secreted MMPs, and was only available for uptake by local co-encapsulated cells. Elevated alkaline phosphatase (ALP) activities and calcium deposition levels were observed for human mesenchymal stem cells (hMSCs) that were encapsulated in PEG hydrogels functionalized with 10 mu M of a Dexamethasone-conjugated peptide (Dex-peptide). The cellular responses stimulated by the tethered Dex lasted for over 21 days. Using co-culture experiments, hMSCs encapsulated in hydrogels with the MMP-degradable Dex-peptides had elevated levels of ALP activity and calcium deposition, whereas no elevated cellular responses were observed in co-cultured hMSCs surrounding the gel. Moreover, modifying the peptide sequence to alter its susceptibility to cleavage and/or changing the Dex-peptide loading further regulated the hMSC response to Dex at different levels and on different time scales. Collectively, these results demonstrate a tunable system for the delivery of glucocorticoids in a localized and cell-dictated manner. Published by Elsevier B.V.

【 授权许可】

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