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Immunomodulating Ruthenium Metal Complexes for Melanoma PhotodynamicTherapy

Award Number: R01CA222227
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/06/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Immunomodulating Ruthenium Metal Complexes for Melanoma PhotodynamicTherapy - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$9,011 )
2024	2022	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	000	6	7/9/2024	NON-COMPETING CONTINUATION	-$9,011
														Subtotal = -$9,011

Issue Date FY: 2022 ( Subtotal = $511,023 )
2022	2022	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	001	6	5/23/2022	NON-COMPETING CONTINUATION	$41,717
2022	2022	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	000	6	2/28/2022	NON-COMPETING CONTINUATION	$469,306
														Subtotal = $511,023

Issue Date FY: 2021 ( Subtotal = $521,452 )
2021	2021	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	001	5	2/23/2021	NON-COMPETING CONTINUATION	$521,452
2021	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Cancer Treatment Research	000	2	12/16/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $521,452

Issue Date FY: 2020 ( Subtotal = $534,709 )
2020	2020	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	001	4	2/25/2020	NON-COMPETING CONTINUATION	$534,709
2020	2019	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	000	3	11/22/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Cancer Treatment Research	002	2	3/17/2020	NON-COMPETING CONTINUATION	$18,296
2020	2019	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	003	3	3/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$18,296
														Subtotal = $534,709

Issue Date FY: 2019 ( Subtotal = $527,762 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Cancer Treatment Research	000	2	2/15/2019	NON-COMPETING CONTINUATION	$483,572
2019	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Cancer Treatment Research	001	2	9/4/2019	NON-COMPETING CONTINUATION	-$243,413
2019	2019	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Cancer Treatment Research	002	3	9/5/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$287,603
														Subtotal = $527,762

Issue Date FY: 2018 ( Subtotal = $521,279 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Cancer Treatment Research	000	1	3/6/2018	NEW	$521,279
														Subtotal = $521,279

Grand Total All Awards = $2,607,214

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Immunomodulating Ruthenium Metal Complexes for Melanoma PhotodynamicTherapy

Award Number: R01CA222227

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/06/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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