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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：
10358644
负责人：
Shashi Gujar
金额：
$ 51.1万
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 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358644
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 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 Persons Phase 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 Surgeon Survival Rate System T-Lymphocyte Techniques Testing Therapeutic Tissues Treatment Efficacy Tumor Immunity Woman anti-melanoma immunity 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 innovation ipilimumab melanoma metal complex mouse model multidisciplinary novel novel strategies prevent professor targeted treatment treatment response 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.

该提案寻求开发一类新型钌（Ru）化合物，其可以用光活化，消除原发性肿瘤，抑制播散性疾病，防止复发。假设光- 具有这些功能的反应性前药将用于光动力疗法（PDT）的开发治疗黑色素瘤PDT是一种未被充分利用的利基癌症治疗方式，它结合了光和生物相容性。光敏剂（PS）产生细胞毒性单线态氧以破坏肿瘤和肿瘤血管。虽然 PDT通常被认为是一种局部治疗，已知它能刺激抗肿瘤免疫，对于控制转移性疾病和随后的肿瘤再生长至关重要。PDT严重依赖于的氧来发挥其抗肿瘤作用，并且批准用于PDT的PS通常是有机化合物，会被红灯激活为了使PDT对黑色素瘤最大限度地有效，有利的是开发可以在缺氧组织中良好地发挥作用的PS，其中光的波长最小在色素性黑色素瘤中被黑色素减弱（650-850 nm）。如果这些物质可以被加入到刺激抗肿瘤免疫的治疗方案，PDT可能为高度复发性肿瘤提供新的治疗选择。癌症，如黑色素瘤，化疗和放疗都不起作用。我们之前开发了非常有效的基于金属的PS，其结合联合收割机Ru和π-膨胀配体以产生产生细胞毒性的系统活性氧物质，即使在低氧张力下，由于其长的激发态寿命和大的双分子猝灭速率另外，我们开发了基于锇（Os）的PS，其吸收的光为波长长于800 nm，并且可以用这种低能量光产生适度的PDT效应，缺氧组织该提议将联合收割机的Ru（效力）和Os（激活>800 nm）的最佳特征结合起来。 PS产生新的Ru金属络合物，其被设计为在近红外光下引发强PDT效应。缺氧组织中使用越来越复杂的黑色素瘤模型。配位化学将用于生成模块化3D化合物库，这些化合物可以随后进行修饰以产生结构多样的家庭这些新化合物的光物理和光化学性质将得到充分研究，将使用2D细胞和3D肿瘤球体评估它们的诊断潜力和PDT效果黑素瘤模型。有前途的候选人将被选为MTD确定和PDT研究在两个小鼠黑素瘤模型。将探测具有PDT活性且对小鼠无毒的PS的能力，通过肿瘤再攻击实验诱导抗肿瘤免疫。最后，免疫学方面，将使用体外和体内技术研究小鼠中有利的PDT应答，将探索和优化方案，以最大限度地提高局部肿瘤控制和刺激抗肿瘤免疫力该项目将介绍用于黑色素瘤PDT的新型PS，并将扩展金属络合物化学、生物物理学和治疗性质。

项目成果

期刊论文数量（37）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Discovery of immunogenic cell death-inducing ruthenium-based photosensitizers for anticancer photodynamic therapy.

DOI：
10.1080/2162402x.2020.1863626
发表时间：
2020-12-29
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Konda P;Lifshits LM;Roque JA 3rd;Cole HD;Cameron CG;McFarland SA;Gujar S
通讯作者：
Gujar S

Breaking the barrier: an osmium photosensitizer with unprecedented hypoxic phototoxicity for real world photodynamic therapy.

DOI：
10.1039/d0sc03008b
发表时间：
2020-09-28
期刊：
Chemical science
影响因子：
8.4
作者：
Roque JA 3rd;Barrett PC;Cole HD;Lifshits LM;Shi G;Monro S;von Dohlen D;Kim S;Russo N;Deep G;Cameron CG;Alberto ME;McFarland SA
通讯作者：
McFarland SA

Anticancer Agent with Inexplicable Potency in Extreme Hypoxia: Characterizing a Light-Triggered Ruthenium Ubertoxin.

DOI：
10.1021/jacs.1c09010
发表时间：
2022-06-08
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Cole, Houston D.;Roque, John A.;Shi, Ge;Lifshits, Liubov M.;Ramasamy, Elamparuthi;Barrett, Patrick C.;Hodges, Rachel O.;Cameron, Colin G.;McFarland, Sherri A.
通讯作者：
McFarland, Sherri A.

Insights into enantioselective separations of ionic metal complexes by sub/supercritical fluid chromatography.

通过亚/超临界流体色谱法对离子金属复合物的对映选择性分离的见解。

DOI：
10.1016/j.aca.2022.340156
发表时间：
2022-10-02
期刊：
ANALYTICA CHIMICA ACTA
影响因子：
6.2
作者：
Handlovic, Troy T.;Wahab, M. Farooq;Cole, Houston D.;Alatrash, Nagham;Ramasamy, Elamparuthi;MacDonnell, Frederick M.;McFarland, Sherri A.;Armstrong, Daniel W.
通讯作者：
Armstrong, Daniel W.

Intraligand Excited States Turn a Ruthenium Oligothiophene Complex into a Light-Triggered Ubertoxin with Anticancer Effects in Extreme Hypoxia.

DOI：
10.1021/jacs.2c02475
发表时间：
2022-05-11
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Roque, John A., III;Cole, Houston D.;Barrett, Patrick C.;Lifshits, Liubov M.;Hodges, Rachel O.;Kim, Susy;Deep, Gagan;Frances-Monerris, Antonio;Alberto, Marta E.;Cameron, Colin G.;McFarland, Sherri A.
通讯作者：
McFarland, Sherri A.