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

项目总结 卵巢癌(OC)是女性癌症死亡率的第五位，也是所有类型中死亡率最高的 妇科癌症，主要影响绝经后妇女。在80%的情况下， 确诊为III期和IV期，存活率为28%。业主立案法团的关怀标准是 手术后进行以铂为基础的化疗。FDA批准的铂金(II) 化合物(顺铂、卡铂和奥沙利铂)是OC的主要缺点：a) 治疗后癌细胞的获得性耐药，以及b)缺乏选择性，导致 由于剂量限制效应而产生的不受欢迎的二次效应。对于多达62%的患者来说，这种疾病 在接受化疗后会复发，需要进行维持治疗。改性铂(IV) 化合物有可能成为基于铂(II)的药物的替代品，特别是对于OC，用于 对哪种药物的耐药性是主要问题，对哪种一线化疗 多年来，治疗可能仍然是最负担得起的选择。这项提议旨在开发铂金 (Iv)-具有潜在双药或多药作用的黄金抗癌剂，并经改进 FDA批准的铂(II)化合物的药理概况。我们的假设是 OC细胞内异金属铂(IV)化合物的还原不仅会释放 传统的铂(II)抗癌剂，但也有高度细胞毒性的金衍生物 肿瘤中不同的生物分子有利于免疫原性细胞死亡，凌驾于耐药性之上。这个 本方案的具体目标是：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。我们将合成新的铂(IV)-Au(I)和铂(IV)- Au(III)化合物及其与DNA(靶标铂)的相互作用及其稳定性研究 化合物)。我们将评估它们对一组上皮性卵巢癌细胞株的影响 不同程度的遗传复杂性，以及在非致瘤细胞系上。对于选定的 化合物，我们将研究它们对其他癌症特征(迁移、侵袭和 血管生成)，对细胞死亡和细胞周期的影响，以及对金化合物靶标的抑制。目标2. 优化选定铂-金化合物的配方和靶向性能。初步入站 活体调查。我们将把性能最好的铂-金化合物封装到脂质体中并 进一步提高这些衍生物的安全性。此外，我们还将 两种铂-金化合物及其制剂对小鼠存活率的影响 (PT-Au-Lip和铂-Au-免疫Lip)对小鼠卵巢癌细胞系原位转移模型的影响 耐顺铂，C200)，并将其与顺铂和卡铂治疗的药物进行比较。

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.