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.

项目摘要 卵巢癌（OC）是女性癌症死亡率的第五位，也是所有类型中最致命的 妇科癌症，主要影响绝经后妇女。在80%的情况下， 诊断为III期和IV期，存活率为28%。OC的护理标准是 减瘤手术后进行铂类化疗。FDA批准的铂（II） 化合物（顺铂、卡铂和奥沙利铂）对OC存在主要缺点，其为：a） 治疗后癌细胞的获得性抗性，和B）缺乏选择性， 由于剂量限制效应导致的不希望的二次效应。对于多达62%的患者， 接受化疗后会复发，需要维持治疗。改性Pt（IV） 化合物有可能成为Pt（II）基药物的替代品，特别是OC， 对治疗的耐药性是一个主要问题，而一线化疗 治疗可能仍然是多年来最负担得起的选择。该提案旨在开发铂金 （IV）-具有潜在的双重或多重药物作用的金抗癌剂， FDA批准的Pt（II）化合物的药理学特征。我们的假设是 OC细胞内的异金属Pt（IV）化合物的还原不仅会释放出 传统的Pt（II）抗癌剂，但也有高度细胞毒性的金衍生物， 不同的生物分子在肿瘤中，并有利于免疫原性细胞死亡，压倒性的阻力。的 该提案的具体目标是：目标1。新型铂（IV）的合成及体外评价 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，并研究它们的稳定性和与DNA的相互作用（Pt（II）的目标） 化合物）。我们将评估它们对一组上皮性卵巢癌细胞系的作用， 不同程度的遗传复杂性，以及非致瘤细胞系。为选定 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）、对细胞死亡和细胞周期的影响，以及抑制金化合物的靶标。目标二。 优化所选Pt-Au化合物的配方和靶向特性。初步的 体内研究。我们将把性能最好的Pt-Au化合物封装到脂质体中， 免疫脂质体，以进一步改善这些衍生物的安全递送。此外，我们将 评估用两种选择的Pt-Au化合物及其两种制剂处理的小鼠的存活率 （Pt-Au-Lip和Pt-Au-ImmunoLip）对小鼠转移性原位模型（卵巢细胞系）的作用 顺铂耐药，C200），并将其与顺铂和卡铂治疗的患者进行比较。