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

项目摘要/摘要 尽管硫化氢被认为是有毒和难闻的气体，但它是一个重要的信号 在人体几乎每一个器官中都起作用的分子。硫化氢治疗是一个不断增长的研究领域， 研究显示在许多疾病动物模型中有效，包括心血管疾病、神经学 疾病和癌症。然而，结果似乎在很大程度上取决于硫化氢输送的持续时间和速度。 充分了解硫化氢的生理作用，测量其对不同器官和系统的影响，以及 为了实现其治疗潜力，提供硫化氢的新方法通过控制时机，位置，速度， 和交付的持续时间是需要的。这个项目的长期目标是通过交付 外源硫化氢；然而，必须首先开发能够实现受控输送的化学工具。这些 将提供方法来探索各种疾病中的硫化氢生理的工具，包括酶- 触发硫化氢释放前体药物(控制给药时间和位置)和硫化氢释放胶束 可调节的释放率(控制递送速率和持续时间)。通过以下具体目标： 将准备新的化学工具，并在与生物相关的硫化氢在癌症治疗中的应用中进行测试： 1.高特异性酶促硫化氢前体药物的合成 这一目标将集中在合成只有在特定条件下才能释放硫化氢的小分子。 酶，包括蛋白水解酶、酯酶和偶氮还原酶，所有这些酶都被上调以响应 可能受益于硫化氢治疗的特定疾病。 2.开发释放速率可调的可生物降解的硫化氢释放聚合物胶束 为此，将使用聚合物胶束平台来控制硫化氢的释放速率。胶束的选择是由于 对于可以控制以调整硫化氢释放动力学的许多因素，包括大小、形状、临界 胶束浓度和单体汇率。 3.使用这些工具回答有关硫化氢在环境中的作用的有争议的生物学问题 抑制/促进癌细胞增殖 硫化氢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 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，以 与正常细胞相比，测量释放率如何影响对癌细胞的毒性和选择性。 这里提出的硫化氢传递方法将增加我们对信号作用的理解， 内源性硫化氢在哺乳动物生物学中发挥作用。另外，我们预计这些控制时机的策略， 硫化氢传递的位置、速率和持续时间将启发其他信令的受控传递的新方法 毒气。总之，这里提出的研究将提高硫化氢的治疗潜力，进一步 可能导致低毒、副作用少和高效的硫化氢疗法的研究计划。

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.