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Cationic star-shaped polymer as an siRNA carrier for reducing MMP-9 expression in skin fibroblast cells and promoting wound healing in diabetic rats

Authors Li N, Luo H, Yang C, Deng J, Ren M, Xie X, Lin D, Yan L, Zhang L

Received 17 April 2014

Accepted for publication 2 June 2014

Published 15 July 2014 Volume 2014:9(1) Pages 3377—3387


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Na Li,1,* Heng-Cong Luo,1,* Chuan Yang,1 Jun-Jie Deng,2 Meng Ren,1 Xiao-Ying Xie,1 Diao-Zhu Lin,1 Li Yan,1 Li-Ming Zhang2

1Department of Endocrinology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 2DSAPM Lab and PCFM Lab, Institute of Polymer Science, Department of Polymer and Materials Science, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou, People’s Republic of China

*These authors contributed equally to this work

Background: Excessive expression of matrix metalloproteinase-9 (MMP-9) is deleterious to the cutaneous wound-healing process in the context of diabetes. The aim of the present study was to explore whether a cationic star-shaped polymer consisting of ß-cyclodextrin (ß-CD) core and poly(amidoamine) dendron arms (ß-CD-[D3]7) could be used as the gene carrier of small interfering RNA (siRNA) to reduce MMP-9 expression for enhanced diabetic wound healing.
Methods: The cytotoxicity of ß-CD-(D3)7 was investigated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MMT) method in the rat CRL1213 skin fibroblast cell line. The transfection efficiency of ß-CD-(D3)7/MMP-9-small interfering RNA (siRNA) complexes was determined by confocal microscopy and flow cytometry. Quantitative real time (RT) polymerase chain reaction was performed to measure the gene expression of MMP-9 after the transfection by ß-CD-(D3)7/MMP-9-siRNA complexes. The ß-CD-(D3)7/MMP-9-siRNA complexes were injected on the wounds of streptozocin-induced diabetic rats. Wound closure was measured on days 4 and 7 post-wounding.
Results: ß-CD-(D3)7 exhibited low cytotoxicity in fibroblast cells, and easily formed the complexes with MMP-9-siRNA. The ß-CD-(D3)7/MMP-9-siRNA complexes were readily taken up by fibroblast cells, resulting in the downregulation of MMP-9 gene expression (P<0.01). Animal experiments revealed that the treatment by ß-CD-(D3)7/MMP-9-siRNA complexes enhanced wound closure in diabetic rats on day 7 post-wounding (P<0.05).
Conclusion: ß-CD-(D3)7 may be used as an efficient carrier for the delivery of MMP-9-siRNA to reduce MMP-9 expression in skin fibroblast cells and promote wound healing in diabetic rats.

Keywords: gene carrier, small interfering RNAs, matrix metalloproteinase-9, diabetic foot ulceration

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