Platinum-Gold Compounds as Potential Chemo- and Targeted Agents for Ovarian Cancer

铂金化合物作为卵巢癌的潜在化疗药物和靶向药物

• 批准号: 10627602
• 负责人: Maria Contel
• 金额: $ 16.62万
• 依托单位: BROOKLYN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627602
• 关键词: Advanced Development; Affect; Aftercare; Antibody-drug conjugates; Antineoplastic Agents; Biological; Biological Availability; Cancer cell line; Carboplatin; Cell Cycle; Cell Death; Cell Line; Cisplatin; Clinic; Clinical; Coupling; DNA; Diagnosis; Disease; Dose Limiting; Encapsulated; Epidermal Growth Factor Receptor; Epithelial ovarian cancer; Evaluation; FDA approved; Formulation; Genetic; Geometry; Glutathione S-Transferase; Gold; Gold Compounds; Grant; Health; Human; Immunoliposome; In Vitro; Invaded; Investigation; KDR gene; Ligands; Lip structure; Liposomes; Maintenance Therapy; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Metals; Methods; Modeling; Monoclonal Antibodies; Mus; Newly Diagnosed; Operative Surgical Procedures; Ovarian; Paclitaxel; Parents; Patients; Pharmaceutical Preparations; Platinum; Poly(ADP-ribose) Polymerase Inhibitor; Positioning Attribute; Postmenopause; Property; Public Health; Recurrence; Research; Research Training; Resistance; Solubility; Students; Survival Rate; System; Therapeutic; Time; Trastuzumab; Tumor Debulking; United States; Woman; Work; angiogenesis; anti-PD1 antibodies; anti-cancer; cancer cell; carboxylate; carboxylation; cell growth; chemotherapy; cytotoxic; cytotoxicity; docetaxel; drug development; expectation; immunogenic cell death; improved; in vivo; innovation; insight; intravenous administration; migration; mortality; neoplastic cell; oxaliplatin; pharmacologic; standard of care; targeted agent; targeted delivery; targeted treatment; thioredoxin reductase; tumor; vector

PROJECT SUMMARY Ovarian cancer (OC) is the fifth in cancer mortality for women, and it is the deadliest for all types of gynecological cancers, affecting mainly postmenopausal women. In 80% of the cases the diagnosis comes at stages III and IV with 28% survival rate. The standard of care of OC is debulking surgery followed by platinum-based chemotherapy. FDA-approved platinum (II) compounds (cisplatin, carboplatin and oxaliplatin) present major drawbacks for OC which are: a) the acquired resistance of cancer cells after treatment, and b) the lack of selectivity which causes undesired secondary effects due to dose limiting effects. For as many as 62% patients the disease will recur after receiving chemotherapy, and maintenance therapies are required. Modified Pt(IV) compounds hold the potential to become alternatives to Pt(II)-based drugs, especially for OC, for which resistance to the treatment is a major problem, and for which first-line chemotherapy treatment may still be the most affordable option for years. This proposal aims to develop Platinum (IV)-Gold anticancer agents with potential dual- or multi-drug effects with improved pharmacological profile with respect to FDA-approved Pt(II) compounds. Our hypothesis is that the reduction of the heterometallic Pt(IV) compounds inside OC cells, will release not only conventional Pt(II) anticancer agents, but also highly cytotoxic gold derivatives that will target different biomolecules in the tumors and favor immunogenic cell death, overriding resistance. The specific aims of this proposal are: Aim 1. Synthesis and in vitro Evaluation of New Platinum(IV)- Gold Compounds in Ovarian Cancer Cell Lines. We will synthesize new Pt(IV)-Au(I) and Pt(IV)- Au(III) compounds and study their stability and interactions with DNA (target for Pt(II) compounds). We will evaluate their effects on a panel of epithelial ovarian cancer cell lines with varying degrees of genetic complexity, as well as on non-tumorigenic cell lines. For selected compounds, we will study their effects on other cancer hallmarks (migration, invasion and angiogenesis), on cell death and cell cycle, and inhibition of gold compounds’ targets. Aim 2. Optimize the Formulation and Targeting Properties of Selected Pt-Au Compounds. Preliminary in vivo Investigation. We will encapsulate best performing Pt-Au compounds into liposomes and immunoliposomes to further improve the safe delivery of these derivatives. In addition, we will assess the survival of mice treated with two selected Pt-Au compound and their two formulations (Pt-Au-Lip and Pt-Au-ImmunoLip) on a mouse metastatic orthotopic model (ovarian cell line resistant to cisplatin, C200) and compare it to that of those treated with cisplatin and carboplatin.

项目概要 卵巢癌（OC）在女性癌症死亡率中排名第五，并且是所有类型中最致命的 妇科癌症，主要影响 80% 的绝经后妇女。 诊断为 III 期和 IV 期，存活率为 28%。 OC 的护理标准是。 减瘤手术后进行 FDA 批准的铂类化疗（II）。 OC 化合物（顺铂、卡铂和奥沙利铂）的主要缺点是：a) 治疗后癌细胞的获得性耐药性，以及b）缺乏选择性，导致 由于剂量限制效应，导致多达 62% 的患者出现不良副作用。 接受化疗后会复发，需要改良Pt(IV)维持治疗。 化合物有潜力成为 Pt(II) 基药物的替代品，特别是 OC、 哪种治疗耐药是主要问题，以及哪种一线化疗 多年来，治疗可能仍然是最实惠的选择。该提案旨在开发铂金。 (IV)-具有潜在双药或多药作用且改善的黄金抗癌剂 FDA 批准的 Pt(II) 化合物的药理学特征我们的假设是： OC 电池内异金属 Pt(IV) 化合物的还原不仅会释放 传统的 Pt(II) 抗癌剂，还有高细胞毒性的金衍生物，可靶向 肿瘤中不同的生物分子，有利于免疫原性细胞死亡，压倒耐药性。 该提案的具体目标是： 目标 1. 新铂（IV）的合成和体外评价- 卵巢癌细胞系中的金化合物我们将合成新的 Pt(IV)-Au(I) 和 Pt(IV)-。 Au(III) 化合物并研究其稳定性以及与 DNA 的相互作用（Pt(II) 的靶标） 我们将评估它们对一组上皮性卵巢癌细胞系的影响。 不同程度的遗传复杂性，以及对于选定的非致瘤细胞系。 化合物，我们将研究它们对其他癌症标志（迁移、侵袭和 血管生成）、细胞死亡和细胞周期以及金化合物目标的抑制。 初步优化选定 Pt-Au 化合物的配方和靶向特性。 我们将性能最佳的 Pt-Au 化合物封装到脂质体中并进行体内研究。 此外，我们还将利用免疫脂质体进一步提高这些衍生物的安全递送。 评估用两种选定的 Pt-Au 化合物及其两种制剂治疗的小鼠的存活率 （Pt-Au-Lip 和 Pt-Au-ImmunoLip）在小鼠转移原位模型（卵巢细胞系 对顺铂（C200）耐药）并将其与顺铂和卡铂治疗的患者进行比较。