State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, PR China.
Nat Chem Biol. 2019 Feb;15(2):151-160. doi: 10.1038/s41589-018-0190-5. Epub 2018 Dec 31.
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.
一氧化氮（NO）是一种多功能的内源性信使，其时空生成受到精确控制。尽管其在治疗多种疾病方面具有潜在的疗效，但由于缺乏将 NO 精确递送到特定部位的有效策略，基于 NO 的治疗方法在临床上受到限制。在本研究中，我们通过使用“凹凸”策略对半乳糖苷酶-半乳糖基-NONO 酸盐的酶前药对进行修饰，开发了一种新型的 NO 传递系统。通过体内近红外成像测定，明确证明了对靶向组织的精确递送。在大鼠后肢缺血和小鼠急性肾损伤模型中评估了其治疗潜力。NO 的靶向递送明显增强了其在组织修复和功能恢复方面的治疗效果，并消除了由于 NO 的全身释放而导致的副作用。所开发的方案在重要气体信号分子的靶向传递中具有广泛的适用性，并为相关分子机制的研究提供了有力的工具。
