State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.
State Key Laboratory of Fine Chemicals, Shenzhen University, Shenzhen 518071, China.
J Am Chem Soc. 2022 Sep 21;144(37):16799-16807. doi: 10.1021/jacs.2c03669. Epub 2022 Sep 7.
Ultrasound-triggered remote control of biomolecular functions in cells provides unique advantages for us to interrogate nature. However, strategies to design therapeutic ultrasound-responsive functional molecules remain elusive, and rare ultrasound-cleavable chemical bonds have been developed to date. Herein, therapeutic ultrasound (1 MHz)-induced scission of urea bonds for drug release is demonstrated for the first time. Such a transformation has been verified to be initiated by hydroxyl radicals generated in the interior of cavitation bubbles, occurring specifically at the cavitation bubble-liquid interface. A series of urea-bond-containing prodrugs based on methylene blue (MB), namely MBUs, are designed. Upon sonication with low-intensity therapeutic ultrasound, the urea bonds linked with primary amines can be selectively cleaved, and free MB is released in a physiologically relevant environment, accompanied by recovered absorbance, fluorescence, and photosensitivity. Moreover, an FDA-approved alkylating agent (i.e., melphalan) bearing urea bond is also developed (MBU-Mel), successfully achieving ultrasound-triggered drug release in deep-seated cancer cells (mimic with 1 cm pigskin), showing the scalability of our ultrasound-responsive molecule platform in bioactive molecules release. This may set the starting point for therapeutic ultrasound-induced drug release, making a forward step in "sonopharmacology".
超声触发细胞内生物分子功能的远程控制为我们探究自然提供了独特的优势。然而，设计治疗超声响应性功能分子的策略仍然难以捉摸，到目前为止，仅开发了很少的超声可裂解化学键。本文首次证明了治疗超声（1 MHz）诱导的尿素键断裂用于药物释放。这种转变被证实是由空化泡内部产生的羟基自由基引发的，仅在空化泡-液体界面处发生。设计了一系列基于亚甲基蓝（MB）的含尿素键的前药，即 MBUs。用低强度治疗超声进行超声处理时，与伯胺相连的尿素键可以选择性地断裂，在生理相关的环境中释放游离的 MB，并伴随着恢复的吸光度、荧光和光敏性。此外，还开发了一种带有尿素键的已获 FDA 批准的烷化剂（即美法仑）（MBU-Mel），成功地在深部癌细胞（用 1 cm 猪皮模拟）中实现了超声触发的药物释放，展示了我们在生物活性分子释放方面的超声响应分子平台的可扩展性。这可能为治疗超声诱导的药物释放奠定了基础，在“声药理学”方面迈出了重要一步。
