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Mater Sci Eng C Mater Biol Appl. 2019 Nov;104:109954. doi: 10.1016/j.msec.2019.109954. Epub 2019 Jul 16.

An in situ slow-releasing H2S donor depot with long-term therapeutic effects for treating ischemic diseases.

Author information

1
Department of Chemical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan, ROC.
2
Medical Administration Department and Cardiovascular Center, Veterans General Hospital Taichung, Taichung, Taiwan, ROC.
3
Department of Nuclear Medicine and Molecular Imaging Center, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan, ROC.
4
Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan, ROC.
5
Cardiovascular Center, Veterans General Hospital Taichung and College of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC. Electronic address: weihaoji@vghtc.gov.tw.
6
Department of Chemical Engineering and Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing Hua University, Hsinchu, Taiwan, ROC. Electronic address: hwsung@mx.nthu.edu.tw.

Abstract

Therapeutic angiogenesis is essential for rescuing necrotic tissues in cases of ischemic disease. The exogenous hydrogen sulfide (H2S) donor, diallyl trisulfide (DATS), has been investigated as a therapeutic agent that promotes angiogenesis. However, the short half-life of generated H2S limits its therapeutic efficacy. In an attempt to overcome this difficulty, a poly(D,L-lactic-co-glycolic acid) microparticle system that contains DATS (DATS@MPs) is prepared as an in situ depot for the controlled release of H2S, providing slow release and long-term effectiveness. The results of in vitro investigations indicate that the slow-released DATS from the DATS@MPs depot yields a longer intracellular production of H2S than that from a free DATS depot. The intracellular generation of H2S favors the translocation of the transcription factor, Nrf2, from the cytosol to nuclei, potentially upregulating the gene expressions of antioxidant enzymes, ultimately increasing cellular resistance to oxidative stress. Intramuscular injection of the slow-releasing H2S donor depot DATS@MPs in an ischemic limb that is experimentally generated in a mouse model promotes therapeutic angiogenesis and protects cells from apoptosis and tissues from necrosis, ultimately salvaging the limb. These analytical results reveal that DATS@MPs is potentially useful in H2S-based therapy for treating ischemic diseases.

KEYWORDS:

Critical limb ischemia; Drug delivery; H(2)S donor; Oxidative stress; Therapeutic angiogenesis

PMID:
31500027
DOI:
10.1016/j.msec.2019.109954

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