Cell-mediated delivery of glucocorticoids from thiol-ene hydrogels.
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 μM 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.
Department of Chemistry and Biochemistry, University of Colorado at Boulder, 215 UCB, Boulder, CO 80309-0215, USA.
Chun
C
Yang
Peter D
PD
Mariner
Jhenya N
JN
Nahreini
Kristi S
KS
Anseth
D000469:Alkaline Phosphatase / Q000378:metabolism; D002478:Cells, Cultured; D003907:Dexamethasone / Q000008:administration & dosage* / Q000737:chemistry; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000737:chemistry; D006801:Humans; D020100:Hydrogels / Q000008:administration & dosage / Q000737:chemistry; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D013438:Sulfhydryl Compounds / Q000737:chemistry
D005938:Glucocorticoids; D020100:Hydrogels; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; D011092:Polyethylene Glycols; D003907:Dexamethasone; D000469:Alkaline Phosphatase; D020782:Matrix Metalloproteinases