Our long-term objective is to develop and validate new nanoprobes serving both as imaging markers and drug carriers for non-invasive diagnosis, staging, and treatment of brain cancers. Brain tumor therapy is currently severely limited by an inability to noninvasively and precisely diagnose and stage disease, selectively target tumor cells, and prompt monitoring of the response to treatment in affected individuals. Like all cancers in brain, medulloblastoma are difficult to treat because of neurotoxicity, tumor resistance to foreign substances, and minimal delivery of potential therapies across the blood-brain barrier. In this research, we propose to develop an integrated multifunctional nanovector for diagnosis and treatment of medulloblastoma, the most common form of pediatric brain cancer. The nanovector consists of a superparamagnetic iron oxide core and a biodegradable polymer shell, encapsulated or conjugated with targeting ligands (chlorotoxin), gene therapeutic agents, and near infrared fluorophore. Chlorotoxin has shown a strong affinity for primary tumors of neuroectodermal origin but not normal brain cells. We have also identified that bone morphogenic protein-2 (BMP-2) induces medulloblastoma cell death in an autocrine and paracrine fashion but does not cause apoptosis in non-neoplastic cells. The nanovector is detectable by both MRI and near infrared fluorescence (NIRF) optical imaging to enable preoperative and intraoperative visualization of tumor margins. The nanovector is designed to have remarkable dispersity and biostability, prolonged circulation time in blood, and unique ability to safely load and effectively deliver drugs. The nanovector will target medulloblastoma with high specificity, be endocytosed by target cells, and retain inside the cells over extended periods of time, which is particularly advantageous for intraoperative imaging and post monitoring of drug response in vivo.
Specific aims of the proposed research are to (1) design, synthesize, characterize the nanovector core-shell structure immobilized with targeting agents, and validate its optical and MR contrast capability;(2) apply the optimal tumor targeted MRI/NIRF nanoconjugate to deliver therapeutic DNA encoding BMP-2 and study its efficacy in gene transfection and inducing apoptosis in vitro;(3) validate and quantify nanovector cell targeting, transfection, apoptosis, toxicity, biodistribution in vivo in mouse flank and intracranial models of medulloblastoma. We anticipate that the technology based on this new injectable and biodegradable nanovector will dramatically advance the diagnosis, prognosis, and evaluation of therapeutic endpoints for medulloblastoma and offer exciting new opportunity for eliminating the suffering and death of children with brain cancer.
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|Kievit, Forrest M; Stephen, Zachary R; Wang, Kui et al. (2015) Nanoparticle mediated silencing of DNA repair sensitizes pediatric brain tumor cells to ?-irradiation. Mol Oncol 9:1071-80|
|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|
|Mok, Hyejung; Zhang, Miqin (2013) Superparamagnetic iron oxide nanoparticle-based delivery systems for biotherapeutics. Expert Opin Drug Deliv 10:73-87|
|Wang, Kui; Park, James O; Zhang, Miqin (2013) Treatment of glioblastoma multiforme using a combination of small interfering RNA targeting epidermal growth factor receptor and *-catenin. J Gene Med 15:42-50|
|Phan-Lai, Vy; Florczyk, Stephen J; Kievit, Forrest M et al. (2013) Three-dimensional scaffolds to evaluate tumor associated fibroblast-mediated suppression of breast tumor specific T cells. Biomacromolecules 14:1330-7|
|Veiseh, Omid; Kievit, Forrest M; Liu, Vicki et al. (2013) In vivo safety evaluation of polyarginine coated magnetic nanovectors. Mol Pharm 10:4099-106|
|Wang, Tingzhong; Kievit, Forrest M; Veiseh, Omid et al. (2013) Targeted cell uptake of a noninternalizing antibody through conjugation to iron oxide nanoparticles in primary central nervous system lymphoma. World Neurosurg 80:134-41|
|Kievit, Forrest M; Cooper, Ashleigh; Jana, Soumen et al. (2013) Aligned chitosan-polycaprolactone polyblend nanofibers promote the migration of glioblastoma cells. Adv Healthc Mater 2:1651-9|
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