Efficiency and Safety of β-CD-(D₃)₇ as siRNA Carrier for Decreasing Matrix Metalloproteinase-9 Expression and Improving Wound Healing in Diabetic Rats

Abstract

Overexpression of matrix metalloproteinase-9 (MMP-9) is critical for diabetic chronic wounds involved in the refractory wound healing process. We aimed to develop a strategy through RNAi to decrease MMP-9 expression and improve diabetic wound healing. We had explored β-CD-(D) as a gene carrier to take siRNA and effectively interfere with MMP-9 expression. It has been proven that β-CD-(D) could be used as an effective siRNA delivery system. In this study, we want to know about the efficiency and safety of β-CD-(D)/MMP-9 siRNA for improving wound healing in diabetic rats. β-CD-(D3)7/MMP-9 siRNA treated animals show lower levels of MMP-9 expression, which induce faster wound-close rates. Histological evaluation indicates that β-CD-(D3)7/MMP-9 siRNA significantly increases the content of collagen around the injured tissues. The number of neutrophilic ganulocytes was significantly decreased through treatment of β-CD-(D3)7/MMP-9 siRNA. In vivo fluorescence imaging assessment shows that β-CD-(D3)7/MMP-9 siRNA could not cause organ damage and organ accumulation. The results suggest that β-CD-(D)/MMP-9 siRNA might be developed as a novel topical agent for the diabetic wounds treatment.

MicroRNA-129 and -335 Promote Diabetic Wound Healing by Inhibiting Sp1-Mediated MMP-9 Expression

“…The gradual decline of MMP-9 levels during the dynamic observation of the wound healing process further verified the essential role of MMP-9 in diabetic wound healing. In support of this, we and others (10,11) have shown that MMP-9 inhibition promotes wound healing. We then provided mechanistic details showing that MMP-9 is activated in the skin of patients with diabetes.…”

“…Sprague-Dawley rats (200-250 g each) were obtained from the Laboratory Animal Center of Sun Yat-Sen University. A diabetic wound was made as previously described (11). miR-129 and/or -335 agomirs (500 mL of a 1-nmol/L agomir solution in PBS) were injected intradermally into the wound edges of the rats immediately and 4, 7, and 10 days after wounding.…”

“…Elevated MMP-9 levels are present in various chronic nonhealing wounds, including diabetic foot ulcers (DFUs) (7)(8)(9). Our previous studies show that abnormally high MMP-9 expression contributes to delayed wound healing because of the imbalance between ECM synthesis and degradation, and reducing MMP-9 expression promotes diabetic wound healing (10,11).…”

Immune Regulation of Skin Wound Healing: Mechanisms and Novel Therapeutic Targets

“…163 MMP-9 siRNA delivered by b-CD-(D3)7, a cationic, star-shaped polymer, to diabetic rat wounds also accelerated wound closure rate by decreasing MMP-9 expression. 164 Though not yet tested in the context of chronic wounds, delivering MMP-9 siRNA using liposomes may be more effective as they have higher rates of interference. 165 Overall, miRNAs and siRNAs have shown promising potential to modulate the immune system and accelerate wound healing, though none have reached clinical trials.…”

Targeting MMP-9 in Diabetic Foot Ulcers

“…It was demonstrated to be effectively taken up by fibroblast cells, reducing MMP-9 gene expression, and to significantly improve wound healing in a rat model of diabetic ulcers [110]. A follow-up study looked at toxicity in the liver and kidney, finding only a transient effect for the naked siRNA and none in the β-CD-(D 3 ) 7 /MMP-9-siRNA [111]. More recently, there was a report of microRNA(miRNA)-129 and miR-335 as an inhibitor of MMP-9 expression in a diabetic mouse model, which results in a commensurate improvement in wound healing [112].…”