Controlling the Release of Small, Bioactive Proteins via Dual Mechanisms with Therapeutic Potential

Abstract

Injectable drug delivery systems that respond to biologically relevant stimuli present an attractive strategy for tailorable drug delivery. Here, we report the design and synthesis of unique polymers for the creation of hydrogels that are formed in situ and degrade in response to clinically relevant endogenous and exogenous stimuli, specifically reducing microenvironments and externally applied light. Hydrogels were formed with polyethylene glycol and heparin-based polymers using a Michael-type addition reaction. The resulting hydrogels were investigated for the local controlled release of low molecular weight proteins (e.g., growth factors and cytokines), which are of interest for regulating various cellular functions and fates in vivo yet remain difficult to deliver. Incorporation of reduction-sensitive linkages and light-degradable linkages afforded significant changes in the release profiles of fibroblast growth factor-2 (FGF-2) in the presence of the reducing agent glutathione or light, respectively. The bioactivity of the released FGF-2 was comparable to pristine FGF-2, indicating the ability of these hydrogels to retain the bioactivity of cargo molecules during encapsulation and release. Further, in vivo studies demonstrated degradation-mediated release of FGF-2. Overall, our studies demonstrate the potential of these unique stimuli-responsive chemistries for controlling the local release of low molecular weight proteins in response to clinically relevant stimuli.

Materials for Immunotherapy

“…The authors used both viral and nonviral vectors to deliver antigens and effectively promote antitumor immunity. Afterward, Kiick and co‐workers developed a PEG hydrogel with heparin crosslinks for the slow release of growth factors and cytokines as a general strategy for immunotherapy and regenerative medicine . In spite of the ubiquitous application of PEG hydrogels, concerns linger over its long term efficacy and translational potential compared to other hydrogel materials.…”

Tunable hydrogels for mesenchymal stem cell delivery: Integrin-induced transcriptome alterations and hydrogel optimization for human wound healing

“…With this in mind, we have focused our energy on designing tunable 3D matrices, ideal to produce reproducible effects on stem cell phenotype. 28,[63][64][65] In the current study, we have functionalized PEG norbornene (PEG-8-Nb) hydrogels, using monocysteine-tethered integrin-binding small molecules to investigate their effects on MSC gene expression and using MSCs cultured in untethered 3D hydrogels and on plain tissue culture 2D surfaces as controls. Our 3D culture systems were also engineered to contain MMP-cleavable cross-links for cell-driven remodeling in vitro and in vivo with predictable degradation kinetics.…”

Injectable Hydrogel-Based Nanocomposites for Cardiovascular Diseases

“…Obviously, the application of injectable hydrogel probably significantly improved the biological activity of small molecule protein. An injectable hydrogel with a light-sensitive bond and photoresolvability, including polyethylene glycol and heparin-based polymers, successfully wrapped fibroblast growth factor 2 (FGF-2), whose activity was comparable to that before embedding and significantly altered the release profile of FGF-2 (Kharkar et al, 2017). It is worth noting that some researchers attempted to embed horseradish peroxidase (HRP) with a bioactive peptide with a phenolic hydroxyl group into hydrogel to cause a coupling reaction to enhance the function of the active peptide (Wang L. S. et al, 2014).…”