Understanding and Improving Platinum Anticancer Drugs

了解和改进铂类抗癌药物

基本信息

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
项目类别：
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

项目摘要

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）：本研究的长期目标是改进铂类癌症治疗。近一半接受化疗的癌症患者服用铂类药物。尽管这些治疗方法有效，但耐药性、毒副作用和肿瘤复发是下一代铂类化疗药物需要解决的关键障碍。克服这些障碍需要更好地了解稳定铂化合物进入肿瘤的途径的因素，发明更好的选择性药物摄取和保留策略，以及设计根除癌组织的结构。拟议研究的三个具体目标旨在解决这些目标。第一个目标是通过针对癌细胞独特的生物学特性，部署将铂类药物引导至癌细胞的方法。实现这一目标的策略包括通过细胞表面的癌症特异性受体进行程序化递送以及双重威胁构建体的合成和评估。后者利用 Pt-DNA 加合物的力量来阻止转录并引发细胞凋亡，同时禁用破坏功效的因素，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凋亡增强因子与铂（II）药物或铂（IV）前药连接起来当铂在癌细胞中还原时，它将释放这种成分，并将铂和辅助模块包装在可生物降解的纳米颗粒中。该提案的第二个目标是了解和改进菲铂，这是一种最近发现的独特有效的阳离子铂络合物，通过用菲啶取代其一个氯化物配体而衍生自顺铂。菲铂在癌细胞谱中具有高度分化性，与任何其他铂类药物相比，它的目标表明它有可能规避限制传统铂类化疗的机制。这些方法包括研究菲铂的 DNA 相互作用及其对细胞功能的影响、探索和刺激其诱导细胞死亡机制的实验，以及对其进行化学修饰以安装类似于顺铂药物家族最终计划建立的双重威胁功能。菲铂在体内的用途。最终目标是提供高向癌细胞注射铂以改善治疗反应。这一目标将通过合成基于 Pt(II) 中心的自组装超分子结构来实现，该结构形成具有疏水空腔的球形笼，可容纳 Pt(IV) 前药的额外有效负载。总的来说，这三个目标提出的研究将加深对传统和非传统铂类抗癌药物的了解，提供信息来指导新型和更有效的化疗候选药物的产生。这些调查的结果对于该领域的其他调查人员也有价值。金属药物领域迅速扩展，预计这里介绍的用于理解和改进铂抗癌药物的创新概念可以很容易地适用于其他治疗性 DNA 结合金属复合物。