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Nat Chem Biol. 2019 Feb;15(2):151-160. doi: 10.1038/s41589-018-0190-5. Epub 2018 Dec 31.

Targeted delivery of nitric oxide via a 'bump-and-hole'-based enzyme-prodrug pair.

Author information

1
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
2
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, PR China.
3
State key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Science, Nankai University, Tianjin, China.
4
School of Medicine, Nankai University, Tianjin, China.
5
Department of Genitourinary Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
6
Center for Research and Development of Chinese Medicine, Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
7
Spine Department, Tianjin Hospital, Tianjin, China.
8
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China. jiansongcheng@nankai.edu.cn.
9
Department of Chemistry and Center for Therapeutics and Diagnostics, Georgia State University, Atlanta, GA, USA.
10
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China. jieshen@nankai.edu.cn.
11
State key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Science, Nankai University, Tianjin, China. qiangzhao@nankai.edu.cn.
12
Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China. qiangzhao@nankai.edu.cn.

Abstract

The spatiotemporal generation of nitric oxide (NO), a versatile endogenous messenger, is precisely controlled. Despite its therapeutic potential for a wide range of diseases, NO-based therapies are limited clinically due to a lack of effective strategies for precisely delivering NO to a specific site. In the present study, we developed a novel NO delivery system via modification of an enzyme-prodrug pair of galactosidase-galactosyl-NONOate using a 'bump-and-hole' strategy. Precise delivery to targeted tissues was clearly demonstrated by an in vivo near-infrared imaging assay. The therapeutic potential was evaluated in both rat hindlimb ischemia and mouse acute kidney injury models. Targeted delivery of NO clearly enhanced its therapeutic efficacy in tissue repair and function recovery and abolished side effects due to the systemic release of NO. The developed protocol holds broad applicability in the targeted delivery of important gaseous signaling molecules and offers a potent tool for the investigation of relevant molecular mechanisms.

PMID:
30598545
DOI:
10.1038/s41589-018-0190-5
[Indexed for MEDLINE]

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