Understanding and Improving Platinum Anticancer Drugs

描述(申请人提供)：这项研究的长期目标是改进基于铂的癌症治疗。在所有接受化疗的癌症患者中，有近一半接受了铂类药物的治疗。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在通往肿瘤的过程中稳定铂化合物的因素，发明更好的选择性药物摄取和保留策略，以及设计根除癌症组织的结构。拟议研究的三个具体目标涉及这些目标。第一个目标是部署通过靶向癌细胞独特的生物学来将铂制剂定向到癌细胞的方法。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传递，以及合成和评估双重威胁结构。后者利用铂-DNA加合物的力量来阻止转录和触发细胞凋亡，同时禁用破坏疗效的因素，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位或促凋亡因子与铂(II)药物或铂(IV)前药联系起来 这将在癌细胞中铂减少时释放这种成分，并将铂和辅助模块包装在可生物降解的纳米颗粒中。这项建议的第二个目的是了解和改进菲三铂，这是一种最近发现的唯一有效的阳离子铂络合物，通过用菲来取代它的一个氯化配体来从顺铂中衍生出来。苯三铂在癌细胞光谱中高度分化， 与任何其他铂类药物相比，它具有靶向性，表明它有可能绕过限制传统铂化疗的机制。这些方法包括研究苯三铂的DNA相互作用及其对细胞功能的影响，实验探索和刺激其诱导细胞死亡的机制，以及对其进行化学修饰以安装类似于顺铂药物家族计划的双重威胁特征，最终确定苯三铂在体内的效用。最终的目标是提供一个高 将铂推注给癌细胞，以提高治疗反应。这一目标将通过合成基于铂(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子，可以容纳额外的铂(IV)前体药。综上所述，这三个目标中提出的研究将使人们更好地了解传统和非传统的铂抗癌药物，提供指导产生新的和更有效的化疗候选药物的信息。这些调查的结果也将对其他调查人员有价值 快速扩展的金属药物领域，预计这里介绍的用于了解和改进铂抗癌剂的创新概念可以很容易地适用于其他治疗性DNA结合金属络合物。

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.