Delivery of H2S: Supramolecular and Enzyme-Triggered Strategies for Controlled Release

项目总结/摘要 尽管硫化氢（H2S）是一种有毒和恶臭的气体，但它是一种重要的信号 这种分子几乎在身体的每一个器官中都起着作用。H2S疗法是一个不断发展的研究领域， 在许多疾病动物模型中显示疗效的研究，包括心血管疾病、神经系统疾病、 疾病和癌症。然而，结果似乎在很大程度上取决于H2S输送的持续时间和速率。 充分了解H2S的生理作用，测量其对不同器官和系统的影响， 为了实现其治疗潜力，本发明提供了用于递送H2S并控制其时机、位置、速率 和交付时间。该项目的长期目标是通过提供 外源H2S;然而，必须首先开发能够控制输送的化学工具。这些 工具，这将提供方法来探测H2S生理在各种疾病，包括酶， 触发的释放H2S的前药（控制递送的时间和位置）和释放H2S的胶束 可调释放速率（控制速率和递送持续时间）。通过以下具体目标， 新的化学工具将在H2S在癌症治疗中的生物相关应用中进行制备和测试： 1.合成具有高特异性的酶触发H2S前药 这一目标将集中在合成的小分子，释放H2S只有在存在特定的 酶，包括蛋白酶、酯酶和偶氮还原酶，所有这些酶都响应于 可能受益于H2S治疗的特定疾病。 2.开发释放速率可调的可生物降解的H2S释放聚合物胶束 在这个目标中，将使用聚合物胶束平台控制H2S释放速率。选择胶束是因为 到可以控制以调整H2S释放动力学的许多因素，包括尺寸、形状、临界 胶束浓度和单聚物交换速率。 3.使用这些工具来回答有争议的生物学问题，关于H2S在 抑制/促进癌细胞增殖 H2S在癌症中的作用是复杂的-它可以抑制或促进癌细胞的生长，这取决于它的浓度。 释放速率、剂量和持续时间。前药和胶束将作为抗癌剂进行测试， 测量释放速率如何影响毒性和对癌细胞的选择性超过正常细胞。 这里提出的H2S输送方法将增加我们对信号作用的理解， 内源性H2S在哺乳动物生物学中的作用。同时，我们希望这些控制时间的策略， H2S输送的位置、速率和持续时间将启发用于其它信号的受控输送的新方法 气.总之，本文提出的研究将提高H2S的治疗潜力，进一步促进 研究计划，可能导致H2S疗法具有低毒性，副作用少，疗效高。

PROJECT SUMMARY/ABSTRACT Despite its reputation as a toxic and foul-smelling gas, hydrogen sulfide (H2S) is an important signaling molecule that plays a role in nearly every organ in the body. H2S therapy is a growing area of research, with studies showing efficacy in many animal models of disease, including cardiovascular disease, neurological diseases, and cancer. However, outcomes appear to depend heavily on the duration and rate of H2S delivery. To fully understand the physiological roles of H2S, to measure its effects on different organs and systems, and to achieve its therapeutic potential, novel methods for delivering H2S with control over the timing, location, rate, and duration of delivery are needed. The long-term goal of this project is to treat diseases by delivery of exogenous H2S; however, chemical tools must first be developed that will enable controlled delivery. These tools, which will provide methods to probe H2S physiology in a variety of diseases, include both enzyme- triggered H2S-releasing prodrugs (control over timing and location of delivery) and H2S releasing micelles with tunable release rates (control over rate and duration of delivery). Through the following specific aims these new chemical tools will be prepared and tested in a biologically relevant application of H2S in cancer therapy: 1. Synthesize enzyme-triggered H2S prodrugs with high specificity This aim will focus on synthesis of small molecules that release H2S only in the presence of specific enzymes, including proteases, esterases, and azoreductases, all of which are upregulated in response to specific diseases that may benefit from H2S treatment. 2. Develop biodegradable H2S-releasing polymer micelles with tunable release rates In this aim H2S release rate will be controlled using a polymer micelle platform. Micelles were chosen due to the many factors that can be controlled to tune H2S release kinetics, including size, shape, critical micelle concentration, and unimer exchange rates. 3. Use these tools to answer controversial biological questions regarding the roles of H2S in the inhibition/promotion of cancer cell proliferation The role of H2S in cancer is complex—it can either inhibit or promote cancer cell growth depending on the rate, dose, and duration of release. The prodrugs and micelles will be tested as anti-cancer agents to measure how release rate affects toxicity and selectivity toward cancer cells over normal cells. The H2S delivery methods proposed here will increase our understanding of the signaling roles that endogenous H2S plays in mammalian biology. Also, we expect that these strategies for controlling timing, location, rate, and duration of H2S delivery will inspire new methods for controlled delivery of other signaling gases. In summary, the studies proposed here will elevate the therapeutic potential of H2S, furthering a research program that may lead to H2S therapies with low toxicity, few side effects, and high efficacy.