This is a year -25 renewal request that addresses a recognized challenge in medicinal inorganic chemistry, namely moving beyond platinum in oncology. To do this, a set of texaphyrin-gold conjugates is proposed. These systems will help overwhelm the antioxidant defense network essential to tumor growth via two overlapping mechanisms. They will also build on progress made in recent years under this grant that has led to very promising texaphyrin-platinum conjugates that display improved efficacy and reduced toxicity relative to FDA-approved agents, such as oxaliplatin. However, this proposal addresses a new challenge, namely using texaphyrins to deliver gold(I) N-heterocyclic carbene complexes to tumors. There is a strong mechanistic rationale for doing so. We have recently shown that uniquely designed, N-hetrocyclic carbene Au(I) complexes give rise to enhanced inhibition of antioxidant activity in cancer models as a result of thioredoxin reductase (TrxR) inhibition. On the other hand, texaphyrins are known to increase oxidative stress through redox cycling. This complementarity is unique and exciting. It should allow us to target the antioxidant protective network from two different directions and do so in a tumor-selective manner. To test the promise inherent in this hypothesis, we will pursue the following specific aims:
Aim 1. Synthesize texaphyrin-Au(I) conjugates containing both labile and non-labile linkages. Use N- heterocyclic carbenes to control gold complexation.
Aim 2. Assess the ability of the texaphyrin-Au conjugates to affect the antioxidant network. Use MTT assays to assess anti-proliferation activity in well-studied cancer cell lines and use flow cytometry to screen for oxidative stress response.
Aim 3. Study texaphyrin-Au conjugate cellular uptake and compartmentalization in vitro. Use analyses of metal content (Gd, Au) and LCMS measurements of texaphyrin concentration in cellular and organ digests to confirm whole cell uptake and subcellular localization.
Aim 4. Begin studies of toxicity and efficacy in vivo. Use murine models to determine the tolerability and biodistribution of the most promising texaphyrin-Au conjugates and their ability to localize to solid tumors and inhibit tumor growth in vivo.
This ongoing project addresses a major challenge in medicinal inorganic chemistry, namely going beyond platinum in oncology. Building off success with platinum constructs, new gold-texaphyrin conjugates are proposed. They target the antioxidant defense systems of cancer.
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