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

H2S 的传递：超分子和酶触发的控释策略

• 批准号: 10092182
• 负责人: John B Matson
• 金额: $ 29.38万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10092182
• 关键词: Affect; Animal Disease Models; Animal Model; Antineoplastic Agents; Area; Biological; Biology; Cancer Cell Growth; Cardiovascular Diseases; Cell Proliferation; Cellular biology; Chemicals; Complex; Data; Development; Disease; Dose; Drug Delivery Systems; Enzymes; Gases; Gel; Goals; Hydrogen Sulfide; Investigation; Kinetics; Lead; Location; Malignant Neoplasms; Measures; Methods; Micelles; Normal Cell; Organ; Organic Chemistry; Outcome; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Physiological; Physiology; Play; Polymer Chemistry; Polymers; Prodrugs; Publishing; Research; Research Personnel; Role; Shapes; Signal Transduction; Signaling Molecule; Site; Smell Perception; Specificity; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Work; azoreductase; body system; cancer cell; cancer therapy; controlled release; copolymer; design; esterase; nervous system disorder; novel; programs; response; self assembly; side effect; small molecule; tool

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.

项目摘要/摘要 尽管硫化氢（H2S）是有毒和臭气的声誉，但是一个重要的信号 在体内几乎每个器官中都起作用的分子。 H2S治疗是一个越来越多的研究领域， 研究表明，许多疾病动物模型的效率，包括心血管疾病，神经系统 疾病和癌症。但是，结果似乎在很大程度上取决于H2S递送的持续时间和速度。 充分了解H2S的身体作用，衡量其对不同器官和系统的影响以及 为了获得其治疗潜力，用于控制时间，位置，速率， 需要交货时间。该项目的长期目标是通过交付来治疗疾病 外源H2S；但是，必须首先开发化学工具，以实现受控的交付。这些 工具将提供各种疾病中H2S生理学的方法，包括两种酶 - 触发了H2S释放前药（控制时间和交付的位置）和H2S释放胶束 可调释放率（控制速率和交付持续时间）。通过以下特定目的 将在H2在癌症治疗中的生物学相关应用中准备和测试新的化学工具： 1。合成酶触发的H2S前药 该目标将重点放在仅在特定存在下释放H2s的小分子的合成 酶，包括蛋白酶，酯酶和氮杂酶，所有这些酶都响应于 可能受益于H2S治疗的特定疾病。 2。开发具有可调释放速率的可生物降解的H2S释放聚合物胶束 在此目标中，H2S释放率将使用聚合物胶束平台控制。选择了胶束 对于可以控制H2S的许多因素，包括尺寸，形状，关键 胶束浓度和单聚合物汇率。 3。使用这些工具回答有关H2在 抑制/促进癌细胞增殖 H2在癌症中的作用很复杂 - 它可以抑制或促进癌细胞的生长 释放的速率，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正常细胞对癌细胞的毒性和选择性。 这里提出的H2S交付方法将增加我们对信号传导作用的理解 内源性H2S在哺乳动物生物学中发挥作用。另外，我们希望这些控制时机的策略， H2S交付的位置，费率和持续时间将激发用于控制其他信号传递的新方法 气体。总而言之，此处提出的研究将提高H2S的治疗潜力，进一步 可能导致H2S疗法低毒性，几乎没有副作用和高效性的研究计划。