The long-term goal of the proposed research is to develop a non-viral nanovector that can serve as an imaging marker, targeting agent, and drug delivery carrier for non-invasive diagnosis, staging, treatment, and therapy-response assessment of brain cancers among others. In this proposed research, the effectivity of the engineered nanovector will be demonstrated with the brain cancer, medulloblastoma. Brain tumor therapy is currently severely limited by the inability to non-invasively diagnose and stage disease, and monitor the response to treatment in affected individuals. Like all cancers of the brain, medulloblastoma is difficult to treat because of possible neurotoxicity complications, tumor treatment-resistance, and limited mobility of potential therapeutics across the blood-brain barrier. The proposed nanovector will be composed of a superparamagnetic iron oxide core and a biodegradable polymeric shell, encapsulating or conjugated to tumor targeting ligands and siRNA therapeutic agents. The nanovector is designed to maintain high dispersity and biostability, prolonged blood circulation time, and the ability to safely load and effectively deliver biologies. The nanovector will specifically and efficiently target medulloblastoma, induce endocytosis in the targeted cells, selectively block gene expression, and engage in prolonged residence inside the tissue.
Specific aims of the proposed research are to: (1) synthesize the tumor-targeted core-shell nanoconjugate and validate its MR contrast enhancement capabilities;(2) synthesize the nanovector by encapsulating siRNA in the nanoconjugate developed in aim 1 and demonstrate siRNA delivery and subsequent suppression of the reporter gene in 9L/LacZ cells;and (3) deliver siRNA against Nmyc, a gene necessary for medulloblastoma proliferation, and evaluate the efficacy of nanovector-delivered Nmyc siRNA in medulloblastoma cells in vitro and in vivo using mouse intracranial models of medulloblastoma. The nanovector is designed to be able to target primary cancers of neuroectodermal origin, and thus the research findings can be generalized to treat other cancers such as such as prostate and breast cancers in addition to medulloblastoma. We anticipate that the technology based on this biodegradable, nontoxic nanovector will have significant implications for the diagnosis, prognosis, and effective treatment of medulloblastoma, and consequently offer a new avenue for eliminating the suffering and death of children afflicted with brain cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA134213-03
Application #
7671233
Study Section
Medical Imaging Study Section (MEDI)
Program Officer
Grodzinski, Piotr
Project Start
2007-09-21
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$297,028
Indirect Cost
Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Mu, Qingxin; Jeon, Mike; Hsiao, Meng-Hsuan et al. (2015) Stable and efficient Paclitaxel nanoparticles for targeted glioblastoma therapy. Adv Healthc Mater 4:1236-45
Stephen, Zachary R; Kievit, Forrest M; Veiseh, Omid et al. (2014) Redox-responsive magnetic nanoparticle for targeted convection-enhanced delivery of O6-benzylguanine to brain tumors. ACS Nano 8:10383-95
Phan-Lai, Vy; Kievit, Forrest M; Florczyk, Stephen J et al. (2014) CCL21 and IFN? recruit and activate tumor specific T cells in 3D scaffold model of breast cancer. Anticancer Agents Med Chem 14:204-10

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