Understanding and Improving Platinum Anticancer Drugs

了解和改进铂类抗癌药物

• 批准号: 8829151
• 负责人: Stephen J. Lippard
• 金额: $ 67.47万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-01-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829151
• 关键词: Address; Adverse effects; Amines; Antineoplastic Agents; Apoptosis; Autophagocytosis; Base Sequence; Binding; Biology; Blood; Blood Circulation; Bolus Infusion; Bypass; Cancer Patient; Cancerous; Carboplatin; Cell Death; Cell membrane; Cell physiology; Cell surface; Cells; Chemistry; Chloride Ion; Chlorides; Cisplatin; Clinical; Complex; DNA; DNA Adducts; DNA Binding; DNA Binding Agent; DNA Damage; DNA Repair; DNA-Directed DNA Polymerase; Drug resistance; Eating; Elements; Ethylene Glycols; Evaluation; Event; FDA approved; Family; Generations; Genetic Transcription; Glycolates; Goals; Grant; Health; Hybrids; Investigation; Kinetics; Knowledge; Lead; Left; Ligands; Link; Malignant Neoplasms; Mediating; Medicine; Metals; Methods; NBL1 gene; Necrosis; Normal Cell; Nuclear; Pathway interactions; Penetration; Pharmaceutical Preparations; Phenanthridines; Platinum; Platinum Compounds; Process; Prodrugs; Property; Recurrence; Recurrent disease; Research; Research Personnel; Rotation; Route; Staging; Structure; Testing; Therapeutic; Tissues; Topoisomerase II; Toxic effect; Translations; Treatment Efficacy; Work; anticancer activity; base; cancer cell; cancer stem cell; cancer therapy; chemotherapeutic agent; chemotherapy; crosslink; design; design and construction; drug candidate; ds-DNA; enhancing factor; ethylene glycol; fundamental research; gene function; improved; in vivo; inhibitor/antagonist; innovation; meetings; metal complex; nanoparticle; next generation; novel; oxaliplatin; preference; programs; receptor; repaired; research study; resistance mechanism; response; secretase; self assembly; therapeutic DNA; tumor; tumor microenvironment; tumor specificity; uptake

DESCRIPTION (provided by applicant): The long-term goal of this research is to improve platinum-based cancer therapy. Platinum drugs are administered to nearly half of all cancer patients receiving chemotherapy. Despite the efficacy of these treatments, drug resistance, toxic side effects, and tumor recurrence are critical barriers that need to be addressed for the next generation of platinum chemotherapeutics. Overcoming these obstacles requires improved understanding of factors that stabilize platinum compounds en route to the tumor, the invention of better strategies for selective drug uptake and retention, and the design of constructs that eradicate cancerous tissue. The three specific aims of the proposed research address these objectives. The first aim is to deploy methods for directing platinum agents to cancer cells by targeting their unique biology. Tactics for achieving this goal include programmed delivery through cancer-specific receptors on the cell surface and the synthesis and evaluation of dual-threat constructs. The latter capitalize on the power of Pt-DNA adducts to arrest transcription and trigger apoptosis while simultaneously disabling factors that undermine efficacy, such as cancer stem cells in the tumor microenvironment. The approaches include linking cancer cell-targeting units or apoptosis-enhancing factors to a platinum(II) drug, or to a platinum(IV) prodrug that will release such a component upon platinum reduction in the cancer cell, as well as packaging the platinum and auxiliary modules in biodegradable nanoparticles. The second aim of this proposal is to understand and improve phenanthriplatin, a recently discovered, uniquely potent cationic platinum complex derived from cisplatin by replacing one of its chloride ligands with phenanthridine. Phenanthriplatin is highly differentiated in the spectrum of cancer cells that it targets compared to any other platinum drug, indicating its potential to circumvent mechanisms that limit conventional platinum chemotherapy. The approaches include investigating the DNA interactions of phenanthriplatin and their effects on cellular function, experiments to probe and stimulate its mechanisms of inducing cell death, and chemically modifying it to install dual-threat features similar to those planned for the cisplatin drug family ultimately to establish the utility of phenanthriplatin in vivo. The final aim is to deliver a high bolus of platinum to cancer cells to improve the therapeutic response. This goal will be met by the synthesis of self-assembled supramolecular constructs based on Pt(II) centers that form a spherical cage with hydrophobic cavities that can accommodate an additional payload of Pt(IV) prodrugs. Taken together, research proposed in the three aims will give rise to a greater understanding of conventional and non-traditional platinum anticancer agents, providing information that will guide the generation of novel and more effective chemotherapeutic candidates. The results of these investigations will also be of value to other investigators in the rapidly expanding field of metal-based medicines, and it is expected that the innovative concepts introduced here for understanding and improving platinum anticancer agents can be readily adapted for other therapeutic DNA-binding metal complexes.

描述（由申请人提供）：这项研究的长期目标是改善基于铂的癌症治疗。铂药物均接受接受化疗的所有癌症患者中的一半。尽管这些治疗有效，但耐药性，有毒副作用和肿瘤复发是下一​​代铂化学治疗需要解决的关键障碍。克服这些障碍需要提高人们对稳定铂金化合物的因素的理解，在肿瘤的途中，发明了更好的选择性药物摄取和保留率的更好策略，以及消除癌组织的构建体的设计。拟议的研究的三个特定目的解决了这些目标。第一个目的是通过针对其独特的生物学来部署将铂剂引导到癌细胞的方法。实现此目标的策略包括通过细胞表面上的癌症特异性受体进行编程的分娩以及对双重威胁构建体的合成和评估。后者利用了PT-DNA加合物对阻止转录和触发凋亡的能力，同时破坏了破坏疗效的因素，例如肿瘤微环境中的癌症干细胞。这些方法包括将癌细胞靶向单元或细胞凋亡因子与铂（II）药物联系起来，或将铂（IV）前药联系起来 这将在癌细胞的铂减少以及可生物降解纳米颗粒中的铂和辅助模块包装时释放这种成分。该提案的第二个目的是理解和改善菲哲素，这是一种最近发现的，有效的阳离子铂络合物，它通过用苯鞭打蛋白代替其一种氯化物配体来衍生自顺铂。在癌细胞的频谱中高度分化的苯th思汀 它与任何其他白金药物相比，其靶向，表明其可能绕过限制常规铂化疗的机制。这些方法包括研究妥智能蛋白的DNA相互作用及其对细胞功能的影响，实验，以探测和刺激其诱导细胞死亡的机制，以及化学修改其以安装类似于顺铂药物家族类似的双重威胁特征，以最终确定eNanthriptin in vivo InVivo的现象。最终目标是提供高 铂向癌细胞的注料以改善治疗反应。基于PT（II）中心的自组装超分子构建体的合成将实现该目标，该中心形成带有疏水腔的球形笼子，可以容纳额外的有效载荷PT（IV）前药。综上所述，这三个目标中提出的研究将使人们对常规和非传统铂抗癌剂有了更深入的了解，从而提供了指导新颖和更有效的化学治疗候选者的信息。这些调查的结果也对其他研究人员具有价值 基于金属的药物的快速扩展领域，可以预期，此处引入的创新概念可以理解和改善铂抗癌剂，因此很容易适应其他治疗性DNA结合金属络合物。