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Glutathione Conjugated Hydrogels: Simple, Flexible Vehicles For Local Therapy
Karol Sokolowski, Hai Pham, Eric R. Wenzler, Richard A. Gemeinhart.
University of Illinois at Chicago, Chicago, IL, USA.

BACKGROUND: Chronic wounds present a complex disease environment for which optimal treatment remains elusive. Development of a versatile delivery vehicle for small molecule and protein therapeutics could provide a personalized option over conventional systemic therapies and rigid, predetermined topical dressings.
METHODS: Polyethylene glycol (PEG) hydrogels were prepared through UV-polymerization of aqueous solution containing PEGDA (Mn 575), 0.05% Irgacure 2959 (w/v), and in the absence or presence of 60 mM glutathione (GSH-PEG). Loading of selected antibiotics, vancomycin and meropenem, occurred through incubation post-polymerization with washing prior to use. Drug solutions were prepared at concentrations of 0.16, 1.6, 16 and 0.256, 2.56, 25.6 mg/mL for meropenem and vancomycin, respectively. Drug influence on protein loading was assayed using fluorescent glutathione-S-transferase (GST) fusion protein. Antimicrobial activity of loaded hydrogels was tested using time-kill technique against Pseudomonas aeruginosa. Toxicity of hydrogel delivery was examined in vitro using primary human dermal fibroblasts.
RESULTS: Incorporation of GSH improved deliverable drug quantity as compared to PEG-only hydrogels while permitting simultaneous delivery of GST-fusion proteins. Vancomycin and meropenem loading were time- and concentration-dependent. After one-hour incubation in meropenem [0.16 mg/mL], significant differentiation between GSH-PEG and PEG loading was observed (51.98.6 and 4.3511.6 g meropenem loaded respectively; p=0.037). Varying meropenem concentrations for incubation [0.16-16 mg/mL] was shown to influence deliverable quantity (GSH-PEG, 21.4-311.5 g; PEG, 0-124.1 g). Concurrent loading of protein and antibiotics was demonstrated in GSH-PEG, with superior protein loading observed when protein preceded antibiotic loading (40.628.1 and 82.911.9 g, respectively; p=0.027). GSH-PEG meropenem [16 mg/mL] achieved bactericidal activity against meropenem-resistant carbapenemase-producing P. aeruginosa (MIC 128 g/mL). Deliverable concentrations of meropenem and vancomycin (up to 1.28 and 12.8 mg/mL respectively) did not negatively influence fibroblast proliferation over 24 hours (p>0.05 all).
CONCLUSIONS: GSH-PEG hydrogels demonstrate the capacity to passively load and deliver small molecule agents alone and in combination with GST-fusion proteins. The flexible, multi-functional hydrogels exhibit favorable drug delivery properties to address the variable needs of chronic wound environments.


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