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.