Abstract. Metallodrugs are commonly prescribed to treat cancer, but they have significant off target effects
because they kill all quickly dividing cells, including healthy cells. There is a need for new targeted therapies.
Light activated ruthenium (Ru) based drugs are promising because they allow for spatial and temporal control of
drug activation using the FDA approved technique of photodynamic therapy (PDT). One light-activated Ru
complex, TLD-1433 has shown promising results for treatment of bladder cancer in Phase II clinical trials,
showing the promise of this approach. Herein, new protic Ru complexes have been synthesized and studied
which demonstrate light activation and selective toxicity towards breast cancer cells vs. normal cells. This
application aims to determine the influence of pi expansive ligands, electron withdrawing groups, and hydroxy
bearing pyridinol ligands on PDT. This can determine the factors leading to an ideal PDT agent with favorable
uptake, localization within appropriate cellular targets, and a high yield of toxic singlet oxygen. The long-term
goal of this work is to design highly cytotoxic and selective prodrugs that are initially inert but generate cytotoxic
species (singlet oxygen) in the presence of tissue penetrating red light. These prodrugs can target cancer cells
due to a combination of enhanced uptake and high levels of oxidative stress present in cancerous cells. Three
hypotheses motivate this work. First, hydroxy substituted ligands can enhance the uptake of Ru(II) compounds
due to the formation of neutral species via ligand deprotonation at physiological pH which leads to improved
uptake. Second, hydroxy groups appear to enhance singlet oxygen formation once they are deprotonated in a
series of Ru(II) complexes. This application probes the generality of this trend with new scaffolds. Third, the use
pi extended co-ligands can enhance both uptake and singlet oxygen formation. New synthetic targets are
proposed to test these hypotheses and to look for synergistic enhancements of phototoxicity index values. Three
specific aims will probe these hypotheses. Aim 1 involves the design new PDT agents to maximize
photocytotoxicity using ligands to enhance lipophilicity, red shift light absorption, and increase singlet oxygen
production. Aim 2 involves investigations into the photocytotoxicity and uptake of these novel protic Ru
compounds in both cancerous and normal cells. Aim 3 will involve measuring singlet oxygen and reactive oxygen
species formation in solution and in cells as well as probing for DNA binding. The proposed research will establish
a new generation of Ru PDT agents with selective toxicity towards breast cancer cells and other susceptible cell
types. There is potentially a high impact for drug developers beyond the oncology field, in that we are elucidating
how protic ligands impact uptake and singlet oxygen formation, and this can be used to target other diseases
including potentially bacterial infections. This project will be used to train a diverse group of undergraduate and
graduate students in collaborative anticancer research with students in chemistry and in biological engineering.
The work from this project will be disseminated via publications and presentations at conferences.
