ROS Targeted Therapy for Lethal Prostate Cancer

ROS 靶向治疗致命性前列腺癌

• 批准号: 10112557
• 负责人: RUOXIANG WANG
• 金额: $ 19.52万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10112557
• 关键词: Address; American; Androgen Antagonists; Antimalarials; Antineoplastic Agents; Apoptosis; Apoptotic; Artemisinins; Biological; Biological Availability; Biological Process; Blood; Cancer Etiology; Carbocyanines; Carrier Proteins; Castration; Cause of Death; Cell Death; Cell model; Cessation of life; Chemicals; Chemoresistance; Collaborations; Conjugating Agent; Detection; Development; Disease; Drug Delivery Systems; Drug Kinetics; Drug Sensitization; Drug resistance; Dyes; Family; Foundations; Future; Goals; Growth; Homeostasis; Hour; Hydroxyl Radical; Hypoxia Inducible Factor; In Vitro; Isotopes; Knowledge; Label; Lead; Ligand Binding; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Mitochondria; Modeling; Mus; Near-infrared optical imaging; Neoplasm Metastasis; Normal tissue morphology; OATP Transporters; Organ; Organelles; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; Patients; Pharmaceutical Preparations; Positron-Emission Tomography; Primary Neoplasm; Production; Property; Prostate Cancer therapy; Radio; Reactive Oxygen Species; Regulation; Reporting; Resistance; Scientist; Singlet Oxygen; Solid; Specific qualifier value; Specificity; Structure-Activity Relationship; Superoxides; Surface; Testing; Therapeutic; Therapeutic Intervention; Tissues; Treatment Efficacy; Up-Regulation; advanced prostate cancer; anti-cancer therapeutic; bioluminescence imaging; cancer cell; cancer diagnosis; cancer drug resistance; cancer therapy; castration resistant prostate cancer; chemical property; chemotherapy; comparative; design; differential expression; drug-sensitive; effective therapy; effectiveness evaluation; effectiveness study; hormone therapy; image guided; imaging modality; improved; in vitro testing; in vivo; innovation; men; molecular imaging; mortality; mouse model; neoplastic cell; novel; prostate cancer cell; prostate cancer cell line; prostate cancer metastasis; prostate cancer prevention; prostate cancer progression; receptor binding; refractory cancer; side effect; small molecule; targeted delivery; targeted treatment; tool; transcription factor; tumor; tumor growth; tumor hypoxia; uptake

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.

项目概要 前列腺癌 (PC) 是美国男性癌症死亡率的第二大原因。 仅显示出边际疗效，并且通常与严重的副作用和耐药性相关，从而导致 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，例如活性氧（ROS）。 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， 其体内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，甚至导致组织损伤。 小分子活性氧发生剂（ROSG）可增强细胞内的活性氧（ROS）。 因此，这些化合物可以作为抗肿瘤治疗剂，但这些化合物在癌症治疗中的功效是 由于其不利的药代动力学特性、低生物利用度和较差的靶向性而受到阻碍 在这方面，我们发现某些特定的近红外特性。 (NIR) 七次甲基碳花青染料 (HMCD) 可通过有机阴离子高选择性进入癌细胞 转运多肽（OATP）家族的载体蛋白，其在癌细胞中差异表达，而 通过上调转录因子，肿瘤内缺氧可以进一步增强表达 为了提高 ROS 介导的癌症治疗的疗效，我们试图研究缺氧诱导因子 (HIF-1α)。 将小分子 ROSG 与癌症特异性 HMCD 结合，用于癌细胞靶向和递送。 创新项目将使我们能够测试将小分子 ROSG 直接输送到癌症的潜在影响 我们认为HMCD-ROSG在体外也能有效杀死癌细胞； 体内针对致命PC的独特作用机制是由ROS产生介导的。 我们的初步结果显示，癌细胞的亚细胞器会破坏重要的生物功能，从而引发细胞凋亡。 表明，与激素疗法和化疗相比，通过以下方法可以更有效地杀死 PC 细胞： 将进行 HMCD-ROSG 缀合物的合成和表征。 这些新化学实体的生物活性将在体外进行药物敏感性和耐药性测试 PC 细胞系和体内小鼠模型我们将采用 NIR 和生物发光成像方式。 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 这些新型化合物作为抗癌治疗剂和敏化剂，可高效预防癌症 PC 的进展和转移将由科学家之间的科学合作进行。 该提案将为 ROS 介导提供坚实的基础和新的方面。 疗法作为晚期和去势抵抗性 PC 和转移的有效治疗干预措施。