Tetraiodothyroacetic acid (tetrac), nanotetrac and anti-angiogenesis

Tetraiodothyroacetic acid (tetrac) is a naturally occurring derivative of thyroid hormone, T₄. In the absence or presence of L-T4 or L-T3, tetrac has been found to disrupt a number of functions or events that are important to cancer cells via the known thyroid hormone-tetrac receptor on the plasma membrane integrin αvβ3. These functions include regulation of cell division, local stimulation of angiogenesis, chemo-resistance and resistance to radiation. It is desirable to reformulate tetrac as a nanoparticle whose activity is exclusively at the cell surface integrin. Nanotetrac has been designed to limit tetrac to the extracellular space on the basis of the size of the nanoparticle and to provide optimized exposure of the biphenyl structure and acetic acid side chain of its inner ring to the receptor site on αvβ3. Tetrac and its novel nanoparticulate formulation have anti-angiogenesis activity that transcends the inhibition of thyroid hormone-binding at the integrin. Restriction of nanotetrac to the extracellular space has been verified, and nanotetrac has been shown to be up to 10-fold more potent than unmodified tetrac at its integrin target. Nanotetrac formulations have potential applications as inhibitors of tumor-related angiogenesis and of angiogenesis that is unrelated to malignancy, including clinically significant disorders ranging from skin diseases to vascular proliferation in the retina and neovascularization associated with inflammatory states.