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Convection-enhanced delivery of maghemite nanoparticles: Increased efficacy and MRI monitoring

Department of Chemistry, Bar-Ilan University, Ramat-Gan (B.P., S.M.); Department of Neurosurgery, Tel-Aviv Medical Center, Tel-Aviv (Z.R.); Advanced Technology Center, Sheba Medical Center, Tel-Hashomer, Ramat-Gan (D.D., A.O., Y.R., Y.M.); Israel

Address correspondence to Yael Mardor, Chief Scientist, Advanced Technology Center Sheba Medical Center, Tel-Hashomer, 52621, Israel (yael.mardor{at}sheba.health.gov.il).

Convection-enhanced drug delivery (CED) is a novel approach to delivering drugs into brain tissue. Drugs are delivered continuously via a catheter, enabling large volume distributions of high drug concentrations with minimum systemic toxicity. Previously we demonstrated that CED formation/extent of small molecules may be significantly improved by increasing infusate viscosities. In this study we show that the same methodology can be applied to monodispersed maghemite nanoparticles (MNPs). For this purpose we used a normal rat brain model and performed CED of MNPs over short infusion times. By adding 3% sucrose or 3%-6% polyethylene glycol (PEG; molecular weight 400) to saline containing pristine MNPs, we increased infusate viscosity and obtained increased CED efficacy. Further, we show that CED of dextran-coated MNPs (dextran-MNPs) resulted in increased efficacy over pristine MNPs (p < 0.007). To establish the use of MRI for reliable depiction of MNP distribution, CED of fluorescent dextran-MNPs was performed, demonstrating a significant correlation between the distributions as depicted by MRI and spectroscopic images (r² = 0.74, p < 0.0002). MRI follow-up showed that approximately 80%-90% of the dextran-MNPs were cleared from the rat brain within 40 days of CED; the rest remained in the brain for more than 4 months. MNPs have been tested for applications such as targeted drug delivery and controlled drug release and are clinically used as a contrast agent for MRI. Thus, combining the CED method with the advantages of MNPs may provide a powerful tool to treat and monitor brain tumors.

Key Words: brain tumors • convection-enhanced drug delivery • drug delivery • magnetic resonance imaging • nanoparticles