Immunomodulating Ruthenium Metal Complexes for Melanoma PhotodynamicTherapy

这一提议旨在开发一种新型的Ru化合物，这种化合物可以用光激活来 消除原发肿瘤，抑制播散性疾病，防止复发。据推测，光- 具有这些能力的响应性前药将在光动力疗法(Pdt)的发展中发挥作用。 治疗黑色素瘤。PDT是一种未得到充分利用的利基癌症治疗方式，它结合了光和 光敏剂(PS)，用于产生细胞毒性单线态氧，用于破坏肿瘤和肿瘤血管。虽然 人们通常认为光动力疗法是一种局部治疗方法，众所周知，它可以刺激抗肿瘤免疫，这是 对于控制转移性疾病和随后的肿瘤再生长至关重要。PDT严重依赖于存在 氧发挥其抗肿瘤作用，而被批准用于PDT的PSS通常是有机化合物， 都是红灯激活的。为了使PDT对黑色素瘤最有效，它将是 有利地开发能够在低氧组织中很好地发挥作用的PSS，其中光的波长最小 色素性黑色素瘤的黑色素减弱(650-850 nm)。如果这样的代理可以被合并到 激发抗肿瘤免疫的方案，PDT可能为高度复发的患者提供新的治疗选择 癌症，如黑色素瘤，化疗和放射治疗都不起作用。我们之前开发了 非常有效的基于金属的PSS，它将Ru和π-膨胀配体结合在一起，产生产生细胞毒性的系统 即使在低氧压下，由于其长的激发态寿命和大的 双分子猝灭速率。另外，我们开发了基于Os(Os)的PSS，可以在 波长长于800 nm，即使在 缺氧组织。这项建议将结合Ru(效力)和Os(激活&gt；800 nm)的最佳功能 PSS将产生新的Ru金属络合物，旨在通过近红外光诱导强烈的PDT效应 低氧组织使用越来越复杂的黑色素瘤模型。配位化学将被用来 生成模块化3D化合物的库，随后可以对其进行修改以产生结构多样化的化合物 家人。这些新化合物的光物理和光化学性质将得到充分的探索，并 将使用2D细胞和3D肿瘤球体评估它们的诊断潜力和PDT效应 黑色素瘤模型。有希望的候选人将被选为MTD测定和PDT研究的两个阶段 小鼠黑色素瘤模型。对小鼠无毒的PDT活性的PSS将被检测它们的能力 通过肿瘤再激发实验诱导抗肿瘤免疫。最后，在免疫学方面， 将使用体外和体内技术来研究小鼠对PDT的有利反应，以及PDT 将探索和优化治疗方案，以最大化局部肿瘤控制和刺激抗肿瘤 豁免权。该项目将介绍用于黑色素瘤PDT的新型PSS，并将扩展基础知识 金属络合物化学、光物理和治疗特性。

This proposal seeks to develop a novel class of ruthenium (Ru) compounds that can be activated with light to eliminate primary tumors, inhibit disseminated disease, and prevent recurrence. It is hypothesized that light- responsive prodrugs with these capabilities will be of use in the development of photodynamic therapy (PDT) for treating melanoma. PDT is an underutilized, niche cancer treatment modality that combines light and a photosensitizer (PS) to create cytotoxic singlet oxygen for destroying tumors and tumor vasculature. Although commonly thought of as a local treatment, PDT has been known to stimulate anti-tumor immunity, which is crucial for controlling metastatic disease and subsequent tumor regrowth. PDT relies heavily on the presence of oxygen to exert its antitumor effects, and the PSs approved for PDT are generally organic compounds that are activated with red light. In order for PDT to be maximally effective toward melanoma, it would be advantageous to develop PSs that can function well in hypoxic tissue with wavelengths of light that are least attenuated by the melanin in pigmented melanomas (650-850 nm). If such agents could be incorporated into regimens that stimulate antitumor immunity, PDT might offer new treatment options for highly recurrent cancers such as melanoma, where chemotherapy and radiotherapy do not work. We previously developed very potent metal-based PSs that combine Ru and π-expansive ligands to yield systems that create cytotoxic reactive oxygen species even at low oxygen tension due to their long excited state lifetimes and large bimolecular quenching rates. Separately, we developed osmium (Os)-based PSs that absorb light at wavelengths longer than 800 nm and can generate a modest PDT effect with this low-energy light even in hypoxic tissue. This proposal will combine the best features of the Ru (potency) and Os (activation >800 nm) PSs to yield new Ru metal complexes that are designed to elicit a strong PDT effect with near-infrared light in hypoxic tissue using increasingly more sophisticated melanoma models. Coordination chemistry will be used to generate a library of modular 3D compounds that can be subsequently modified to produce structurally diverse families. The photophysical and photochemical properties of these new compounds will be fully explored, and they will be assessed for their diagnostic potential and PDT effects using 2D cell and 3D tumor spheroid melanoma models. Promising candidates will be selected for MTD determination and PDT studies in two mouse melanoma models. PSs that are PDT-active and nontoxic to mice will be probed for their abilities to induce antitumor immunity through tumor rechallenge experiments. Finally, the immunological aspects of favorable PDT responses in mice will be investigated using both in vitro and in vivo techniques, and the PDT regimen will be explored and optimized for maximizing both local tumor control and stimulating antitumor immunity. This project will introduce novel PSs for melanoma PDT and will expand fundamental knowledge of metal complex chemistry, photophysics, and therapeutic properties.