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.

这项建议Seeek可以开发一种新型的氟森（RU）化合物，可以用光来激活。消除原发性肿瘤，流离失所的传播疾病并防止复发。具有这些能力的反应前药，与我们一起发展光动力疗法（PDT）对于踩踏黑色素瘤。光敏剂（PS）可创建用于破坏肿瘤和肿瘤脉管系统的冷毒性单线氧。普遍认为是局部治疗，PDT已知可以刺激免疫力，这是对于控制转移性疾病和随后的肿瘤再生至关重要。氧气发挥其抗肿瘤作用，并且批准PDT的PSS是有机化合物用红光激活。有利于发展PSS在低氧组织中发挥良好功能的PSS 黑色素中的黑色素衰减（650-850 nm）。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我们以前开发的化学疗法和放射疗法等黑色素瘤等癌症非常有效的金属PSS，将RU和π表达配体结合起来产生细胞毒性的系统由于其长期激发的寿命和较大的大量氧气而导致的活性氧双分子淬火率分别开发了基于oSmium（OS）的PS 波长超过800 nm，拐弯低毒性组织。 PSS到Yieeld New Ru金属复合物，旨在引起强烈的PDT效应，并在使用更多的黑色素瘤模型的缺氧组织将使化学构成。生成一个模块化3D化合物库，随后可以修改为生产结构多样这些新化合物的光物理和光化学特性将被充分探索他们将使用2D细胞3D肿瘤球体评估它们的征状和PDT效应黑色素瘤模型。小鼠黑色素瘤模型。通过肿瘤再现实验诱导抗肿瘤免疫。使用体外和体内技术研究的小鼠中有利的PDT反应以及PDT 将探索和优化方案，以最大化局部肿瘤控制，刺激和刺激和免疫力。金属复合物化学，光体物理和治疗特性。