Malignant glioma accounts for approximately one-third of all primary brain tumors in adults or 18400 new cases in the United States annually. Despite advances in recent conventional therapeutic regimen of surgery, radiation and anticancer chemotherapies, the clinical outcome in treating malignant brain tumors remains disappointing. The resistance of glioma to the conventional therapeutic regimen of surgery, radiation therapy, and chemotherapy is still not well understood. Successful malignant glioma treatment is highly dependent on the ability to diagnose patients at early stages of disease and to identify which therapy might respond. One approach that is beginning to succeed clinically is to exploit the dependence of most tumors on increased angiogenesis through neovascularization. Targeting the endothelial cells lining the tumor neovascularization has been found to impact cancers in a broad manner, with growing clinical success of this approach. Cilengitide is a highly selective integrin inhibitor targeting the tumor and its vasculature. We will apply Cilengitide therapy to rat models of U87MG brain tumors, and apply our MRI methods to measure longitudinal changes in extracellular pHe, v3 integrin expression and tumor vascular permeability before and after therapy. To achieve these goals, we are proposing to develop multifunctional denritic MRI contrast agents that will target multiple cancer biomarkers which are specific to tumor microenvironment. We will incorporate pH-responsive GdDOTA-4Amp, T1 relaxation agents and pH-unresponsive NdDOTA-4AmC, PARACEST agents in the same dendrimer molecule in order to measure extracellular pHe of malignant glioma accurately with high resolution and high sensitivity. We will use same nano-sized dendrimer-based pH-responsive contrast agent to measure tumor vascular permeability. In order to target v3 integrin, we will conjugate cyclic-RGD peptides to the PARACEST dendrimers. Finally, we will use these dendrimeric MRI contrast agents to measure extracellular pHe, v3 integrin expression and tumor vascular permeability in single MRI scan session before and after therapy. Therefore, our multifunctional nano-sized dendrimeric MRI nanoprobes have great potential for future clinical applications in measuring in vivo pH non-invasively as well as to assess multiple biomarkers of malignant brain tumor during a single MRI session.

Public Health Relevance

The results of this project will provide a direct method to measure in vivo pH non-invasively. Thus, the extracellular pH (pHe) within tumor tissues will be used as a diagnostic biomarker to determine the prognosis of pathology, to evaluate the efficacy of pHe-altering therapies and to predict the efficacy of pHe-dependent chemotherapies. Besides, multifunctional nano-sized MRI probes will be used to assess multiple, tumor specific, biomarkers in a single MRI scan session and this novel technology will significantly enhance in the early diagnosis and treatment of brain cancer.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-SBIB-J (90))
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Fountain, Jane W
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Henry Ford Health System
United States
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Varma, Nadimpalli Ravi S; Shankar, Adarsh; Iskander, Asm et al. (2013) Differential biodistribution of intravenously administered endothelial progenitor and cytotoxic T-cells in rat bearing orthotopic human glioma. BMC Med Imaging 13:17
Ali, Meser M; Bhuiyan, Mohammed Pi; Janic, Branislava et al. (2012) A nano-sized PARACEST-fluorescence imaging contrast agent facilitates and validates in vivo CEST MRI detection of glioma. Nanomedicine (Lond) 7:1827-37
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Varma, Nadimpalli Ravi S; Janic, Branislava; Iskander, A S M et al. (2012) Endothelial progenitor cells (EPCs) as gene carrier system for rat model of human glioma. PLoS One 7:e30310
Ali, Meser M; Janic, Branislava; Babajani-Feremi, Abbas et al. (2010) Changes in vascular permeability and expression of different angiogenic factors following anti-angiogenic treatment in rat glioma. PLoS One 5:e8727