Biomedical Applications of Expanded Porphyrins: Development of Gold-Texaphyrin Conjugates

扩展卟啉的生物医学应用：金-泰克萨菲林缀合物的开发

• 批准号: 9307322
• 负责人: Jonathan L Sessler
• 金额: $ 36.04万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-08-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307322
• 关键词: A549; Acids; Address; Affect; Agonist; Amides; Animal Model; Antineoplastic Agents; Antioxidants; Apoptosis; Biodistribution; Biological Assay; Blood; CASP3 gene; CASP9 gene; Cancer Model; Cancer cell line; Carbamates; Cell Death; Cell Line; Cell Nucleus; Cells; Cellular Membrane; Centrifugation; Chemistry; Complement; Complex; Cyclodextrins; Cytosol; Data; Dependence; Detection; Development; Disulfides; Dose; Doxorubicin; Drug resistance; FDA approved; Flow Cytometry; Formulation; Funding; Gadolinium; Gold; Grant; Heart; Homeostasis; Immunocompromised Host; In Vitro; Inbred BALB C Mice; Individual; Inductively Coupled Plasma Mass Spectrometry; Injection of therapeutic agent; Inorganic Chemistry; Kidney; Laboratories; Link; Lipids; Liquid substance; Liver; Local Therapy; Low-Density Lipoproteins; LysoTracker; Lysosomes; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Maximum Tolerated Dose; Measurement; Membrane Potentials; Metals; Microscopic; Microsomes; Mitochondria; Monitor; Mono-S; Mus; NU/NU Mouse; Necrosis; Organ; Organ Harvestings; Organelles; Oxidation-Reduction; Oxidative Stress; PC3 cell line; Phase; Phenotype; Platinum; Porphyrins; Progress Reports; Proteins; Protocols documentation; Resistance; Series; Serum Proteins; Serum-Free Culture Media; Solid Neoplasm; Spleen; Staining method; Stains; Stress; System; Testing; Texaphyrin; Tissues; Toxic effect; Tumor-Associated Process; Work; Xenograft procedure; annexin A5; anticancer activity; arm; base; biological adaptation to stress; carbene; cell growth; design; improved; in vivo; lipoate; mitochondrial membrane; mouse model; nanoparticle; neoplastic cell; oncology; oxaliplatin; pre-clinical; small molecule; success; surfactant; thioredoxin reductase; time use; tumor; tumor growth; tumor xenograft; uptake

This is a year -25 renewal request that addresses a recognized challenge in medicinal inorganic chemistry, namely moving beyond platinum in oncology. To do this, a set of texaphyrin-gold conjugates is proposed. These systems will help overwhelm the antioxidant defense network essential to tumor growth via two overlapping mechanisms. They will also build on progress made in recent years under this grant that has led to very promising texaphyrin-platinum conjugates that display improved efficacy and reduced toxicity relative to FDA-approved agents, such as oxaliplatin. However, this proposal addresses a new challenge, namely using texaphyrins to deliver gold(I) N-heterocyclic carbene complexes to tumors. There is a strong mechanistic rationale for doing so. We have recently shown that uniquely designed, N-hetrocyclic carbene Au(I) complexes give rise to enhanced inhibition of antioxidant activity in cancer models as a result of thioredoxin reductase (TrxR) inhibition. On the other hand, texaphyrins are known to increase oxidative stress through redox cycling. This complementarity is unique and exciting. It should allow us to target the antioxidant protective network from two different directions and do so in a tumor-selective manner. To test the promise inherent in this hypothesis, we will pursue the following specific aims: Aim 1. Synthesize texaphyrin-Au(I) conjugates containing both labile and non-labile linkages. Use N- heterocyclic carbenes to control gold complexation. Aim 2. Assess the ability of the texaphyrin-Au conjugates to affect the antioxidant network. Use MTT assays to assess anti-proliferation activity in well-studied cancer cell lines and use flow cytometry to screen for oxidative stress response. Aim 3. Study texaphyrin-Au conjugate cellular uptake and compartmentalization in vitro. Use analyses of metal content (Gd, Au) and LCMS measurements of texaphyrin concentration in cellular and organ digests to confirm whole cell uptake and subcellular localization. Aim 4. Begin studies of toxicity and efficacy in vivo. Use murine models to determine the tolerability and biodistribution of the most promising texaphyrin-Au conjugates and their ability to localize to solid tumors and inhibit tumor growth in vivo.

这是一个-25年的续订请求，旨在解决药用无机化学领域公认的挑战， 即在肿瘤学领域超越铂金。为此，提出了一组泰克萨菲林-金缀合物。 这些系统将通过两种方式帮助压垮肿瘤生长所必需的抗氧化防御网络 重叠的机制。他们还将以近年来在这笔赠款下取得的进展为基础，这些进展导致 非常有前途的泰克萨菲林-铂缀合物，相对于其他药物，其功效提高，毒性降低 FDA 批准的药物，例如奥沙利铂。然而，该提案解决了一个新的挑战，即使用 泰克萨菲林将金 (I) N-杂环卡宾配合物递送至肿瘤。有很强的机械性 这样做的理由。我们最近展示了独特设计的 N-杂环卡宾 Au(I) 配合物 由于硫氧还蛋白还原酶，在癌症模型中增强抗氧化活性的抑制 (TrxR) 抑制。另一方面，已知泰克萨菲林通过氧化还原循环增加氧化应激。 这种互补性是独特且令人兴奋的。它应该让我们能够针对抗氧化保护 从两个不同的方向网络并以肿瘤选择性的方式进行。测试承诺 根据这一假设，我们将追求以下具体目标： 目标 1. 合成含有不稳定和不稳定键的泰克萨菲林-Au(I) 缀合物。使用N- 杂环卡宾控制金络合。 目标 2. 评估泰克萨菲林-金缀合物影响抗氧化网络的能力。使用 MTT 检测 评估经过充分研究的癌细胞系的抗增殖活性，并使用流式细胞术筛选氧化 应激反应。 目标 3. 研究 texaphyrin-Au 缀合物的体外细胞摄取和区室化。金属的用途分析 细胞和器官消化物中泰克萨菲林浓度（Gd、Au）和 LCMS 测量，以确认 全细胞摄取和亚细胞定位。 目标 4. 开始体内毒性和功效研究。使用小鼠模型来确定耐受性和 最有前途的泰克萨弗瑞-金缀合物的生物分布及其定位于实体瘤和 抑制体内肿瘤生长。