ROS Targeted Therapy for Lethal Prostate Cancer

项目总结 前列腺癌(PC)是美国男性癌症死亡的第二大原因。现代治疗学 仅表现出边际疗效，通常与严重的副作用和耐药性有关 病人的死亡率。癌症耐药性是需要解决的最具挑战性的困难之一 具有创新的机械知识和战术应用能力。活性氧物种(ROS)，如 超氧阴离子(O2−)、单线态氧(1O2)和羟基自由基(·OH)是高度活跃的代谢副产物， 其动态平衡是通过氧化还原调节来维持的。高水平的ROS会导致组织损伤，甚至 细胞死亡。通过提高细胞内ROS的小分子活性氧生成剂(Rsg) 因此可作为抗肿瘤治疗药物，这些化合物在癌症治疗中的体内疗效是 由于其不良的药代动力学特性、生物利用度低和靶向性差而严重受阻 属性特定于肿瘤细胞。在这方面，我们发现某些特定的近红外 (NIR)七甲基碳菁染料(HMCD)可通过有机阴离子高选择性进入癌细胞 运输多肽(OATP)家族的载体蛋白，它们在癌细胞中差异表达，而 肿瘤内低氧可通过上调转录因子HSP70的表达进一步增强其表达。 缺氧诱导因子(HIF-1)α。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，用于肿瘤细胞的靶向和输送。这 创新的项目将使我们能够测试将小分子rosg直接传递给癌症的潜在影响。 诱导细胞凋亡。我们假设hmcd-rosg在体外可以杀死癌细胞，并且也是有效的。 体内靶向治疗致命的个人计算机。这种独特的作用机制是由体内ROS的产生所介导的 癌细胞亚细胞器，扰乱重要的生物功能，诱导细胞凋亡。我们的初步结果 研究表明，与激素治疗和化疗相比，PC细胞可以更有效地被杀死 HMCD-ROSSG。将进行HMCD-ROSG偶联物的合成和表征，并 这些新的化学物质的生物活性将在体外进行药物敏感和耐药测试 PC细胞系和体内用小鼠模型。我们将使用近红外和生物发光成像方法 检测工具评估HMCD-rosg结合物进入肿瘤的特异性并研究其有效性 其中作为抗癌治疗和增敏剂的这些新化合物对预防癌症具有高效的作用 PC进展和转移。拟议的项目将由以下机构之间的科学合作执行 化学家和癌症科学家。该提案将为ROS调解的 治疗作为对晚期和抗去势的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.