Nanoparticulate Tetrac Inhibits Growth and Vascularity of Glioblastoma Xenografts

Thangirala Sudha,Dhruba J Bharali,Stewart Sell,Noureldien H E Darwish,Shaker A Mousa,Paul J Davis

doi:10.1007/s12672-017-0293-6

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 T4 on 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 T4 action 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.

Highlights

Glioblastoma multiforme (GBM) is an aggressive central nervous system tumor with high mortality [1, 2]
We subsequently showed in a variety of xenografts that a formulation of tetrac covalently linked to a nanoparticle (Nanotetrac, Nano-diamino-tetrac, NDAT)—an agent restricted to the extracellular space and to action at the integrin—effectively slowed tumor growth and reduced vascularity [17,18,19,20,21]
Hemoglobin Assay For a measurement of tumor vascularity, the hemoglobin content of cell extracts of xenografts revealed that NDAT treatment resulted in a 50% loss of tumor blood vessel content (Fig. 1b)

Summary

Introduction

Glioblastoma multiforme (GBM) is an aggressive central nervous system tumor with high mortality [1, 2]. The cancer is highly vascular, causing the evaluation of anti-angiogenesis in its management [7] Against this background, it is understandable that a number of novel therapeutic approaches are under investigation [8,9,10]. We reported that thyroid hormone, L-thyroxine (T4), was a proliferative factor in vitro in rat C6 and F98 cells and mouse GL261 cell line models for glioblastoma [12]. This effect was mediated by the cell surface thyroid hormone receptor we described on plasma membrane integrin αvβ3 [13, 14]. The deaminated T4 derivative, tetraiodothyroacetic acid (tetrac), blocked the proliferative action nongenomically initiated by T4 on these cells [12]

Methods

Results

Conclusion