|MRI-guided Magnetic Targeting and Therapy of Brain Tumors|
|05-26-16 Hit 504|
Victor C. Yang, Ph.D. Albert B. Prescott Professor of Pharmaceutical Sciences
Date: 07.16. (Thur) 13:00 Place: Pine Room, Hoam Faculty House (Kwanak Campus)
MRI-Guided Magnetic Targeting and Therapy of Brain Tumors
B. Chertok1, A. David1,3, F. Yu1 and V. Yang1,2,4
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065
- Department of Molecular Medicine & Biopharmaceutical Sciences, Seoul National University, Korea
- Industrial Science and Technology Network, Inc, York, Pennsylvania 17601
- Tianjin Key Laboratory of Modern Drug Delivery and High Efficiency, Tianjin University, Tianjin, China 30007
Approximately 40,000 Americans are diagnosed with brain tumors each year, with 15-35% being glioblastoma multiforme (GBM); the most aggressive primary brain tumor that has defied all existing therapeutic modalities. Treatment of brain tumors normally begins with surgical resection then follows with radiation or chemotherapy. Surgery faces the risks of removing surrounding tissues that may carry vital brain functions, while both radiation and chemotherapy can also harm normal tissues along the treatment pathway. Chemotherapy has been offering very limited applications, due to the palliative response and lack of targeting and selectivity of the drugs.
Proposed herein is a novel drug delivery system (DDS) that will utilize MION (magnetic iron oxide nanoparticles) as the carrier to achieve synchronized MRI and drug therapy of brain tumors. It contains all desirable features within a single DDS including:  MRI,  magnetic targeting,  prodrug, and  intracellular drug uptake, in overriding obstacles in brain drug delivery and achieving MRI-visualized, highly effective tumor therapy with least drug- induced toxic effects. In principle, macromolecular drug (e.g. siRNA) with unmatched glioma specificity and potency will be linked to the non-toxic cell-penetrating LMWP via cytosol-degradable S-S linkage, whereas MION carrying superparamagnetic behavior and superior magnetophoretic mobility will be coated with a bio-compatible dextran polymer containing immobilized heparin. The LMWP-modified drug (LMWP-Drug) and heparin-coated MION (Hep-MION) will automatically group into a complex via electrostatic interaction between the cationic LMWP and anionic heparin. After assembly, LMWP-Drug/Hep-MION shall display a unique prodrug feature during tumor targeting, due to inhibition of the trans-cell activity of LMWP by heparin binding. To prevail over first-pass organ clearance thus maximizing MION accumulation at the tumor, the complexes will be injected via intra-arterial route. Optimized magnetic field topography will be followed to abort possible embolism of arterial vasculature and maximize tumor targeting selectivity. After tumor localization of MION (i.e. via passive EPR- and active magnetic-targeting) is verified by MRI, nasal administration of protamine, a clinical heparin antidote that binds heparin stronger than LMWP, will be followed to trigger an on-command release of the LMWP-Drug conjugates from the Hep-MION carriers. Once inside tumor cells via LMWP-mediated cell-internalization, the drug entity will be detached from LMWP by degradation of the S-S bond via elevated cytosol reductase activity, initiating tumor apoptosis. Since large drugs are cell-impermeable, the cytosol-delivered drugs will not be affected by MDR effect. Preliminary findings have been extremely promising, as they demonstrated by far the first true success of delivering a significant amount of the large (465KDa) β-galactosidase protein selectively into the brain tumor but not the ipsilateral or contralateral normal brain regions. Since components of this DDS are all suitable for clinical translation, it is envisioned that the system would have great potential to effectively combating brain cancers in the future.
This work is supported in part by NIH Grants CA114612, NS066945, the Hartwell Biomedical Research Award, as well as the WCU program through Korea Science and Engineering Program funded by the Ministry of Education, Science and Technology (R31-2008-000-10103-01).