Perlstein Benny, Ram Zvi, Daniels Dianne, Ocherashvilli Aharon, Roth Yiftach, Margel Shlomo, Mardor Yael
Department of Chemistry, Bar-Ilan University, Ramat-Gan, Israel.
Neuro Oncol. 2008 Apr;10(2):153-61. doi: 10.1215/15228517-2008-002. Epub 2008 Mar 3.
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 (r(2) = 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.
对流增强药物递送（CED）是一种将药物递送至脑组织的新方法。药物通过导管持续递送，能够以最小的全身毒性实现高药物浓度的大体积分布。此前我们证明，通过增加输注液粘度可显著改善小分子的CED形成/范围。在本研究中，我们表明相同的方法可应用于单分散磁赤铁矿纳米颗粒（MNP）。为此，我们使用正常大鼠脑模型，并在短输注时间内进行MNP的CED。通过向含有原始MNP的盐水中添加3%蔗糖或3%-6%聚乙二醇（PEG；分子量400），我们提高了输注液粘度并获得了更高的CED疗效。此外，我们表明葡聚糖包被的MNP（葡聚糖-MNP）的CED比原始MNP具有更高的疗效（p < 0.007）。为了确定MRI用于可靠描绘MNP分布的用途，进行了荧光葡聚糖-MNP的CED，结果表明MRI和光谱图像所描绘的分布之间存在显著相关性（r(2) = 0.74，p < 0.0002）。MRI随访显示，在CED后40天内，约80%-90%的葡聚糖-MNP从大鼠脑中清除；其余的在脑中保留超过4个月。MNP已被测试用于靶向药物递送和控释药物等应用，并在临床上用作MRI的造影剂。因此，将CED方法与MNP的优势相结合可能为治疗和监测脑肿瘤提供一个强大的工具。
