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Overcoming Temozolomide Resistance in Glioblastoma Multiforme with MGMT-Targeting Spherical Nucleic Acids.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Overcoming Temozolomide Resistance in Glioblastoma Multiforme with MGMT-Targeting Spherical Nucleic Acids./
Author:	Sita, Timothy L.
Description:	1 online resource (128 pages)
Notes:	Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
Subject:	Nanoscience. -
Online resource:	click for full text (PQDT)
ISBN:	9781369679434

Overcoming Temozolomide Resistance in Glioblastoma Multiforme with MGMT-Targeting Spherical Nucleic Acids.
Sita, Timothy L.

Overcoming Temozolomide Resistance in Glioblastoma Multiforme with MGMT-Targeting Spherical Nucleic Acids. - 1 online resource (128 pages)

Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.

Thesis (Ph.D.)--Northwestern University, 2017.

Includes bibliographical references

Glioblastoma multiforme (GBM) is the most prevalent primary central nervous system malignancy. Due to the aggressive nature of these tumors and our inability to adequately treat them, only 3-5% of patients survive longer than 3 years post-diagnosis. The standard of care for newly diagnosed GBM is surgical resection followed by concomitant and adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. TMZ cytotoxicity is mediated primarily through methylation of the O 6 -position of guanine. In the majority of patients, this methyl group is rapidly removed by the enzyme O6 -methylguanine-DNA methyltransferase (MGMT), conferring resistance to the chemotherapy. However, in a small subset of GBM patients, the promoter region for MGMT is methylated over the course of tumor development. This epigenetic silencing of MGMT activity allows TMZ to induce apoptosis in glioblastoma cells and drastically increases survival in GBM patients. The following work seeks to recapitulate this improved survival phenotype by combining TMZ with a novel nanoconstruct capable of silencing MGMT expression. The nanoconstruct consists of gold nanoparticles densely conjugated with either an MGMT-targeting ribozyme (ribozyme-Spherical Nucleic Acids (SNAs)), or small interfering RNA (siRNA) duplexes designed against MGMT (siMGMT-SNAs), and has been found to have unique characteristics, including (1) the rapid internalization by all glioma cell types studied including glioma initiating cells (GICs), (2) the capacity to potently silence MGMT expression, (3) increased apoptotic response in GBM cells, (4) the ability to cross the blood-brain barrier (BBB), blood-tumor barrier (BTB), and accumulate in GBM xenografts, and (5) no observable acute toxicity at high doses in animal models. In summary, preliminary data suggest ribozyme-SNA and siMGMT-SNAs sensitize GBM cells in vitro and in vivo, enhancing the therapeutic response to TMZ.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2018

Mode of access: World Wide Web

ISBN: 9781369679434Subjects--Topical Terms:

632473
Nanoscience.
Index Terms--Genre/Form:

554714
Electronic books.

Overcoming Temozolomide Resistance in Glioblastoma Multiforme with MGMT-Targeting Spherical Nucleic Acids.
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500 $a Source: Dissertation Abstracts International, Volume: 78-08(E), Section: B.
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502 $a Thesis (Ph.D.)--Northwestern University, 2017.
504 $a Includes bibliographical references
520 $a Glioblastoma multiforme (GBM) is the most prevalent primary central nervous system malignancy. Due to the aggressive nature of these tumors and our inability to adequately treat them, only 3-5% of patients survive longer than 3 years post-diagnosis. The standard of care for newly diagnosed GBM is surgical resection followed by concomitant and adjuvant radiotherapy and temozolomide (TMZ) chemotherapy. TMZ cytotoxicity is mediated primarily through methylation of the O 6 -position of guanine. In the majority of patients, this methyl group is rapidly removed by the enzyme O6 -methylguanine-DNA methyltransferase (MGMT), conferring resistance to the chemotherapy. However, in a small subset of GBM patients, the promoter region for MGMT is methylated over the course of tumor development. This epigenetic silencing of MGMT activity allows TMZ to induce apoptosis in glioblastoma cells and drastically increases survival in GBM patients. The following work seeks to recapitulate this improved survival phenotype by combining TMZ with a novel nanoconstruct capable of silencing MGMT expression. The nanoconstruct consists of gold nanoparticles densely conjugated with either an MGMT-targeting ribozyme (ribozyme-Spherical Nucleic Acids (SNAs)), or small interfering RNA (siRNA) duplexes designed against MGMT (siMGMT-SNAs), and has been found to have unique characteristics, including (1) the rapid internalization by all glioma cell types studied including glioma initiating cells (GICs), (2) the capacity to potently silence MGMT expression, (3) increased apoptotic response in GBM cells, (4) the ability to cross the blood-brain barrier (BBB), blood-tumor barrier (BTB), and accumulate in GBM xenografts, and (5) no observable acute toxicity at high doses in animal models. In summary, preliminary data suggest ribozyme-SNA and siMGMT-SNAs sensitize GBM cells in vitro and in vivo, enhancing the therapeutic response to TMZ.
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538 $a Mode of access: World Wide Web
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