Improved Efficacy of Temozolomide (Temodar) Against Glioma by Nanotargeting Using Tetraiodothyroacetic acid (Tetrac)
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Issue Date
2016
Authors
McCallion, Conor Smith '16
Degree
MS in Pharmaceutical Sciences
Advisor
El-Fawal, Hassan A. N.
Mousa, Shaker A.
Mousa, Shaker A.
Committee Members
Musteata, Marcel
Gallo, James M.
Gallo, James M.
Journal Title
Journal ISSN
Volume Title
Abstract
Malignant gliomas [glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA)] have a combined incidence of 5-8/100,000 people and represent the most common primary central nervous system tumors. The treatment outcomes, even with aggressive approaches, are poor. More recently, the alkylating agent temozolomide (TMZ), sold as Temodar, has been approved as the drug of choice for treating these forms of glioma. Gliomas are characterized by the increased expression of \316\261v\316\2623 integrin receptors, an adhesion molecule that promotes angiogenesis and tumor proliferation. This receptor has been shown to be effectively blocked by tetraiodothyroacetic acid (tetrac) and nano-diaminopropane tetrac (nDAT), trade name Nano-Tetrac, in vitro and in vivo, in several tumor cell lines and tumor types, thereby preventing proliferation and angiogenesis. Based on this, we hypothesized that DAT-coated poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) could be used to improve the efficacy and/or potency of TMZ against glioma cells, via tetrac\342\200\231s own antineoplastic effects. Following synthesis of PLGANPs, with and without encapsulated TMZ, the hypothesis was tested in vitro in U87MG glioma cells using the quantification of cytotoxicity in glioma in response to non-NP TMZ alone, nDAT alone, nDAT with free TMZ, encapsulated TMZ (nTMZ) and nDAT with encapsulated nDAT [TMZ] using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. NP averaged 110 nm with a 4.2% w/w loading of TMZ. The use of nTMZ and nDAT [TMZ] were significantly superior to bulk TMZ, both in terms of AUC and IC50 U87MG cells, as measured by MTT assay. The improved efficacy and potency of nTMZ of free TMZ suggests that it may be an effective treatment against GBM, and the improved potency of nDAT [TMZ] makes it a promising means to deliver the TMZ payload.
Citation
McCallion, CS. Improved efficacy of temozolomide (Temodar) against glioma by nanotargeting using tetraiodothyroacetic acid (Tetrac) [thesis]. Ann Arbor (MI): Proquest LLC; 2016. 70 p.
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