ROS Targeted Therapy for Lethal Prostate Cancer

项目摘要 前列腺癌（PC）是美国男性癌症死亡的第二大原因。当前治疗 仅显示出边际疗效，并且通常与严重的副作用和耐药性有关， 病人死亡率的癌症耐药性是需要解决的最具挑战性的困难之一 创新的机械知识和战术应用。活性氧物质（ROS），例如 超氧阴离子（O2-）、单线态氧（1 O2）和羟基自由基（·OH）是高活性代谢副产物， 其体内平衡由氧化还原调节维持。高水平的ROS会导致组织损伤， 细胞死亡虽然小分子活性氧产生剂（ROSG），提高细胞内ROS 因此，尽管这些化合物的水平可以用作抗肿瘤治疗剂，但是这些化合物在癌症治疗中的体内功效是 由于其不利的药代动力学特性、低生物利用度和靶向性差， 对肿瘤细胞的特异性。在这方面，我们已经发现，某些特定的近红外 (NIR)七甲川碳菁染料（HMCD）可通过有机阴离子高选择性地进入癌细胞 转运多肽（OATP）家族的载体蛋白，其在癌细胞中差异表达， 肿瘤内缺氧可通过上调转录因子 缺氧诱导因子（HIF-1α）。为了提高ROS介导的癌症治疗的疗效，我们试图 将小分子ROSG与癌症特异性HMCD偶联用于癌细胞靶向和递送。这 一个创新的项目将使我们能够测试将小分子ROSG直接递送到癌症的潜在影响 细胞诱导凋亡。我们假设HMCD-ROSG在体外杀死癌细胞;并且也将有效 用于致死PC的靶向治疗。其独特的作用机制是由细胞内ROS的产生介导的。 癌细胞亚细胞器，破坏重要的生物功能，引发凋亡。我们的初步结果 表明，与激素治疗和化疗相比，PC细胞可以被更有效地杀死， HMCD-ROSG。将进行HMCD-ROSG缀合物的合成和表征，并且将进行HMCD-ROSG缀合物的合成和表征。 这些新的化学实体的生物活性将在体外进行药物敏感和耐药试验。 PC细胞系和体内小鼠模型。我们将采用近红外和生物发光成像方式， 用于评估HMCD-ROSG缀合物对肿瘤的特异性并研究其有效性的检测工具 这些新化合物作为抗癌治疗剂和增敏剂， PC进展和转移。拟议的项目将由一个科学合作， 化学家和癌症科学家该提案将为ROS介导的 作为晚期和去势抵抗性PC和转移的有效治疗干预。

PROJECT SUMMARY Prostate cancer (PC) is the second leading cause of cancer mortality in American men. Current therapeutics only show marginal efficacy and are often associated with serious side effects and drug resistance that contribute to patient mortality. Cancer drug resistance is one of the most challenging difficulties that needs to be addressed with innovative mechanistic knowledge and tactical application. Reactive oxygen species (ROS), such as superoxide anion (O2−), singlet oxygen (1O2) and hydroxyl radical (·OH), are highly active metabolic by-products, whose homeostasis is maintained by redox regulation. High levels of ROS can cause tissue damages and even cell death. Though small molecule reactive oxygen generating agents (ROSG) that enhance intracellular ROS levels may thus serve as anti-tumor therapeutics, the in vivo efficacy of these compounds in cancer therapy is severely impeded by their unfavorable pharmacokinetic properties, low bioavailability, and their poor targeting property specifically to tumor cells. In this regard, we have discovered that certain some specified near infrared (NIR) heptamethine carbocyanine dye (HMCD) can enter cancer cells with high selectivity via organic anion transporting polypeptide (OATP) family of carrier proteins, which are differentially expressed in cancer cells while the expression can be further enhanced by intra-tumoral hypoxia through upregulation of transcription factor of the hypoxia inducible factor (HIF-1α). To improve the efficacy of ROS-mediated cancer therapy, we sought to conjugate small molecule ROSG with cancer-specific HMCD for cancer cell targeting and delivery. This innovative project will allow us to test the potential impact of delivering small molecule ROSG directly to cancer cells to induce apoptosis. We hypothesize that HMCD-ROSG kills cancer cells in vitro; and will also be effective in vivo for targeted treatment of lethal PCs. The unique mechanism of action is mediated by ROS production in cancer cell subcellular organelles, disrupting vital biologic function to elicit apoptosis. Our preliminary results indicated that, compared with hormonal therapy and chemotherapy, PC cells could be killed more effectively by HMCD-ROSG. The synthesis and characterization of HMCD-ROSG conjugates will be performed and the biological activities of these new chemical entities will be tested in vitro with drug-sensitive and drug-resistant PC cells lines and in vivo with mouse models. We will employ NIR and bioluminescence imaging modalities as detection tools to assess specificity of the HMCD-ROSG conjugates into tumors and to study the effectiveness of these novel compounds as anti-cancer therapeutic and sensitizing agents for high efficacy on prevention of PC progression and metastasis. The proposed project will be performed by a scientific collaboration between a chemist and cancer scientist. The proposal will provide a solid foundation and new aspect to the ROS-mediated therapy as a potent therapeutic intervention for advanced and castration-resistant PC and metastasis.