Journal of Stem Cell Research & Therapy

Nanotetrac targets the thyroid hormone receptor on integrin αvβ3 on tumor cells to promote apoptosis, disorder cell defense pathways and block angiogenesis

3^rd International Conference and Exhibition on Cell & Gene Therapy

October 27-29, 2014 Embassy Suites Las Vegas, USA

Paul J Davis and Shaker A Mousa

Scientific Tracks Abstracts: J Stem Cell Res Ther

Abstract:

We have described a cell surface receptor for thyroid hormone and hormone analogues on the extracellular domain of integrin αvβ3. The receptor has no structural analogies to nuclear thyroid hormone receptors (TRs) involved in genomic actions of thyroid hormone. The integrin is expressed primarily by cancer cells and rapidly-dividing endothelial cells. Thyroid hormone as L-thyroxine (T4) and 3,5,3?-triiodo-L-thyronine (T3) non-genomically supports cancer cell proliferation and anti-apoptosis at this receptor site. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that has undesirable thyromimetic actions inside cells, but at the cell exterior inhibits binding and actions of T4 and T3 at αvβ3. We covalently bound tetrac to a biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticle which restricts action of the hormone analogue to the receptor on αvβ3 and prohibits cell uptake. Nanoparticulate tetrac (Nanotetrac) is ten-fold more potent than unmodified tetrac as an anti-proliferative/anti-angiogenic agent at αvβ3. In addition, Nanotetrac has anti-angiogenic and pro-apoptotic actions lacking in unmodified tetrac. The anti-angiogenic qualities of Nanotetrac include inhibition by several mechanisms of the activities of VEGF, bFGF, PDGF and EGF. Targeted to its receptor on the integrin, Nanotetrac also disorders gene transcription relevant to six cancer cell survival pathways and blocks tumor cell repair of double-stranded DNA breaks that are induced by γ-radiation. The agent has been shown to be highly effective against ten human cancer xenograft models, including pancreas, lung, kidney, prostate and breast. The function of the 200 nm PLGA tail on Nanotetrac is to restrict its tetrac probe to the cell exterior and αvβ3. However, the cassette of tetrac-directed PLGA may be used to deliver a traditional chemotherapeutic agent-adsorbed to the nanoparticle locally to tumor cells and tumor-relevant endothelial cells. In summary, Nanotetrac is a highly-selective chemotherapeutic/anti-angiogenic agent targeted to a novel small molecule receptor on integrin αvβ3. At this receptor, Nanotetrac is capable of 1) activating pro-apoptotic systems suppressed in cancer cells, 2) suppressing anti-apoptotic mechanisms that are ordinarily activated in such cells, 3) disabling a number of cell survival pathways and 4) inhibiting by several mechanisms the actions of multiple vascular growth factors. Nanotetrac is restricted to the extracellular space and its integrin target is primarily expressed by cancer cells and rapidly-dividing blood vessel cells.

Biography :

Paul J Davis is Professor of Medicine at Albany Medical College and Professor of Pharmacy at the Albany College of Pharmacy and Health Sciences. He is former Chair of the Department of Medicine at the Medical College. He obtained his medical training at Harvard Medical School, Albert Einstein College of Medicine and the NIH. He is a Past President of the American Thyroid Association, a former Director of the American Board of Internal Medicine and is a Master and former Governor of the American College of Physicians. He is Head, U.S. Endocrinology and Metabolism panel of the Faculty of 1000 Medicine. He has co-authored more than 200 scientific publications, 25 textbook chapters and multiple editorials. He is Associate Editor at Endocrine Research (Informa) and on the Editorial Boards of Hormones and Cancer (Springer Publishing) and of Imunnology, Endocrine and Metabolic Agents in Medicinal Chemistry (Bentham). His research group was the first to identify a receptor or target for thyroid hormone on the outside of cancer cells that allows the hormone to be a growth factor for certain cancers and for the blood supply of malignancies. He has also been involved in the development of drugs to salvage nerve cells at the time of stroke and heart cells in the setting of reduced coronary artery blood flow.