title: Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts.
abstract: Thyroid hormone as L-thyroxine (T4) stimulates proliferation of glioma cells in vitro and medical induction of hypothyroidism slows clinical growth of glioblastoma multiforme (GBM). The proliferative action of T4on glioma cells is initiated nongenomically at a cell surface receptor for thyroid hormone on the extracellular domain of integrin αvβ3. Tetraiodothyroacetic acid (tetrac) is a thyroid hormone derivative that blocks T4action at αvβ3 and has anticancer and anti-angiogenic activity. Tetrac has been covalently bonded via a linker to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT) that increases the potency of tetrac and broadens the anticancer properties of the drug. In the present studies of human GBM xenografts in immunodeficient mice, NDAT administered daily for 10 days subcutaneously as 1 mg tetrac equivalent/kg reduced tumor xenograft weight at animal sacrifice by 50%, compared to untreated control lesions (p < 0.01). Histopathological analysis of tumors revealed a 95% loss of the vascularity of treated tumors compared to controls at 10 days (p < 0.001), without intratumoral hemorrhage. Up to 80% of tumor cells were necrotic in various microscopic fields (p < 0.001 vs. control tumors), an effect attributable to devascularization. There was substantial evidence of apoptosis in other fields (p < 0.001 vs. control tumors). Induction of apoptosis in cancer cells is a well-described quality of NDAT. In summary, systemic NDAT has been shown to be effective by multiple mechanisms in treatment of GBM xenografts.
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, 12144, USA.
authors.forename: Thangirala
authors.initials: T
authors.lastname: Sudha
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, 12144, USA.
authors.forename: Dhruba J
authors.initials: DJ
authors.lastname: Bharali
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, NY, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Sell
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, 12144, USA.|Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt.
authors.forename: Noureldien H E
authors.initials: NHE
authors.lastname: Darwish
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, 12144, USA. pdavis.ordwayst@gmail.com.|Department of Medicine, Albany Medical College, Albany, NY, USA. pdavis.ordwayst@gmail.com.|NanoPharmaceuticals LLC, Rensselaer, NY, USA. pdavis.ordwayst@gmail.com.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Davis
authors.affiliation: Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, 1 Discovery Drive, Rensselaer, NY, 12144, USA.|NanoPharmaceuticals LLC, Rensselaer, NY, USA.
authors.forename: Shaker A
authors.initials: SA
authors.lastname: Mousa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007037:Hypothyroidism / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D039302:Integrin alphaVbeta3 / Q000235:genetics; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000235:genetics; D013974:Thyroxine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D039302:Integrin alphaVbeta3; D011956:Receptors, Cell Surface; C011126:tetraiodothyroacetic acid; D013974:Thyroxine