Combined Antioxidant–Antibiotic Treatment for Effectively Healing Infected Diabetic Wounds Based on Polymer Vesicles

Abstract

Infected diabetic wounds are difficult to heal due to high reactive oxygen species (ROS) concentrations and recurrent infections. Such wounds can easily deteriorate into a diabetic ulcer, a chronic diabetic complication with a very high mortality rate. Herein, we propose a combined antioxidant–antibiotic therapy based on poly­(ε-caprolactone)-block-poly­(glutamic acid) polymer vesicle to treat infected diabetic wounds. This was realized by in situ decoration of stable, well-dispersed ceria nanoparticles onto ciprofloxacin (CIP)-loaded polymer vesicles. These resulting CIP-loaded and ceria-decorated polymer vesicles (CIP-Ceria-PVs) exhibited high superoxide dismutase mimetic activity to inhibit superoxide free radicals (the inhibition rate reached ∼50% at an extremely low cerium concentration of 1.25 μg/mL). When the cerium content is in the range of 5–20 μg/mL, the CIP-Ceria-PVs showed the highest protective capability to normal L02 cells from damage of superoxide free radicals. In addition, the CIP-Ceria-PVs exhibited enhanced antibacterial activity (the dosage of CIP in CIP-Ceria-PVs was reduced by 25–50% compared to free CIP). In vivo treatment of infected diabetic wounds was performed on a diabetic mice model. The CIP-Ceria-PVs could effectively cure infected diabetic wounds within 14 days. Overall, a combined antioxidant–antibiotic therapy was proposed by introducing ceria nanoparticles and CIP into polymer vesicles for the treatment of infected diabetic wounds.

Polymeric Nanomaterials for Efficient Delivery of Antimicrobial Agents

“…Very recently, polymer vesicles loaded with antimicrobials have been explored as dressings in promoting wound healing by spraying onto wounds [167,[171][172][173]. Du and coworkers [173] reported bifunctional polymer vesicles loaded with antimicrobials and antioxidant for healing infected diabetic wounds, as presented in Figure 13.…”

Polymer Vesicles for Antimicrobial Applications

“…Taking advantage of the unique structural property of vesicles in drug delivery systems, the antimicrobial polymer vesicles also showed potential in tissue engineering and wound healing with the encapsulation of functional molecules [107,114,115]. For instance, Du and coworkers [114] designed a series of antibacterial peptide-mimetic alternating copolymers (PMACs) with different repeating units, and the PMAC with repeating unit of 14 exhibited the best antibacterial activity against both of E. coli and S. aureus with ultralow MICs of 8.0 µg mL −1 .…”

“…Very recently, the same group [115] designed antioxidant-antibiotic co-loaded polymer vesicle to cure the infected diabetic wounds, which usually caused a diabetic ulcer due to the high local concentration of reactive oxygen species (ROS). As illustrated in Figure 10, a biodegradable polymer PCL-b-PGA was designed to self-assemble into vesicles and encapsulate ciprofloxacin into the hydrophilic cavity.…”

“…Figure10. Illustration of the preparation of ciprofloxacin and ceria loaded polymer vesicles and the combined antioxidant-antibiotic treatment of infected diabetic wounds[115] (Reprinted with permission from[115]). …”

Oxygen-Releasing Composites: A Promising Approach in the Management of Diabetic Foot Ulcers

“…Recent advanced biomaterials for regenerative medicine have also been applied to increase the potential efficacy of wound dressing materials for DFUs. For example, a variety of nanoparticles containing growth factors (e.g., vascular endothelial growth factor; VEGF and basic fibroblast growth factor; bFGF), microRNA (miRNA), and antibacterial agents (e.g., ciprofloxacin) showed improved healing potential in diabetic in vivo models [ 6 , 7 , 8 , 9 ]. In addition to these typical bioactive agents, antioxidants have also been incorporated into multiple functional composites for chronic wounds, including diabetic wounds [ 10 , 11 , 12 ].…”