Immunomodulating Ruthenium Metal Complexes for Melanoma PhotodynamicTherapy

用于黑色素瘤光动力疗法的免疫调节钌金属配合物

基本信息

批准号：
9983296
负责人：
Shashi Gujar
金额：
$ 26.93万
依托单位：
UNIVERSITY OF TEXAS ARLINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-06 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9983296
关键词：
3-Dimensional Adjuvant Affect Age Animals Antibodies Area Attention Attenuated BRAF gene Baptist Church Benign Biological Bladder Books Cancer Etiology Cells Cessation of life Chemicals Chemistry Clinic Clinical Trials Colon Combined Modality Therapy Complex Comprehensive Cancer Center Cytotoxic Chemotherapy Data Development Diagnostic Disease Dose Family Fibroblasts Future Goals Health Sciences Human Hypoxia Immune Immunity Immunologics Immunotherapeutic agent In Vitro International Knowledge Lead Libraries Ligands Light Lymphocyte Lymphocyte antigen Malignant Neoplasms Malignant neoplasm of urinary bladder Maximum Tolerated Dose Measures Melanins Melanoma Cell Metals Metastatic Melanoma Metastatic Neoplasm to the Lung Modeling Mus Operative Surgical Procedures Osmium Outcome Study Oxygen PUVA Photochemotherapy Parents Patients Phase Photosensitization Photosensitizing Agents Pigmentation physiologic function Pigments Positioning Attribute Pre-Clinical Model Primary Neoplasm Process Prodrugs Production Property Publications Radiation therapy Reactive Oxygen Species Recurrence Recurrent Malignant Neoplasm Regimen Relapse Reovirus Reporting Resistance Ruthenium Ruthenium Compounds Singlet Oxygen Site Skin Skin Cancer Solid Neoplasm Solubility Spleen Structure Surgeon Survival Rate System T-Lymphocyte Techniques Testing Therapeutic Tissues Treatment Efficacy Tumor Immunity Woman antitumor effect base cancer cell cancer immunotherapy cancer therapy chemotherapy curative treatments cytotoxic cytotoxicity design experience experimental study forest fundamental research human pathogen immunogenic cell death improved improved outcome in vivo inhibitor/antagonist innovation melanoma metal complex mouse model multidisciplinary novel novel strategies prevent professor response targeted treatment tumor tumor growth

项目摘要

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.

该建议旨在开发一种新颖的唯一（ru）化合物，可以用光激活消除原发性肿瘤，抑制传播疾病并防止复发。假设光明具有这些功能的反应前药将用于发育光动力疗法（PDT） PDT是一种未充分利用的利基癌症治疗方式，结合了光和A 光敏剂（PS）创建可破坏肿瘤和肿瘤脉管系统的细胞毒性单线氧。虽然普遍认为是局部治疗，已知PDT刺激抗肿瘤免疫学，这是对于控制转移性疾病和随后的肿瘤后悔至关重要。 PDT严重依赖存在氧气发挥其抗肿瘤作用，并且批准PDT的PSS是有机化合物用红灯激活。为了使PDT对黑色素瘤具有最大有效的效果有利于发展PSS在低氧组织中发挥良好功能的PSS 黑色素在色素黑色瘤（650-850 nm）中减弱。如果可以将这样的代理纳入刺激抗肿瘤免疫的方案，PDT可能会为高度复发提供新的治疗选择黑色素瘤等癌症，化学疗法和放射疗法无效。我们以前开发了将RU和π表达配体结合起来产生细胞毒性的系统的非常潜在的基于金属的PSS 即使在低氧气张力下，由于其长期激发态寿命和大的氧气张力和较大的氧气种类双分子淬火率。另外，我们开发了基于osmium（OS）的PSS，吸收了在波长超过800 nm，即使在这种低能的光中也可以产生适度的PDT效应低氧组织。该建议将结合RU（效力）和操作系统（激活> 800 nm）的最佳功能 PSS产生新的RU金属配合物，旨在引起强烈的PDT效果，并在低氧组织使用越来越复杂的黑色素瘤模型。协调化学将用于生成一个模块化3D化合物库，随后可以修改以产生结构上的潜水家庭。这些新化合物的光学和光化学特性将被充分探索，并且他们将使用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。有希望的候选人将在两个中选择MTD确定和PDT研究小鼠黑色素瘤模型。将对小鼠的PDT活性且无毒的PSS的能力进行探测通过肿瘤补偿实验诱导抗肿瘤免疫学。最后，免疫学方面将使用体外和体内技术和PDT研究小鼠中有利的PDT反应将探索和优化方案，以最大化局部肿瘤控制和刺激抗tuumoror 免疫。该项目将为黑色素瘤PDT介绍新颖的PSS，并将扩大有关的基本知识金属复合物化学，摄影和治疗特性。