The Institute of Nanotechnology and Advanced Materials, Department of Chemistry, Bar-Ilan University, Ramat-Gan.
Int J Nanomedicine. 2011;6:1595-602. doi: 10.2147/IJN.S23025. Epub 2011 Aug 3.
Convection-enhanced delivery (CED) is a novel approach for delivering drugs directly into brain tumors by intracranial infusion, enabling the distribution of high drug concentrations over large tissue volumes. This study was designed to present a method for binding methotrexate (MTX) to unique crystalline, highly ordered and superparamagnetic maghemite nanoparticles via human serum albumin (HSA) coating, optimized for CED treatments of gliomas. Naked nanoparticles and HSA- or polyethylene glycol (PEG)-coated nanoparticles with/without MTX were studied. In vitro results showed no toxicity and a similar cell-kill efficacy of the MTX-loaded particles via HSA coating to that of free MTX, while MTX-loaded particles via PEG coating showed low efficacy. In vivo, the PEG-coated nanoparticles provided the largest distributions in normal rat brain and long clearance times, but due to their low efficacy in vitro, were not considered optimal. The naked nanoparticles provided the smallest distributions and shortest clearance times. The HSA-coated nanoparticles (with/without MTX) provided good distributions and long clearance times (nearly 50% of the distribution volume remained in the brain 3 weeks post treatment). No MTX-related toxicity was noted. These results suggest that the formulation in which HSA was bound to our nanoparticles via a unique precipitation method, and MTX was bound covalently to the HSA, could enable efficient and stable drug loading with no apparent toxicity. The cell-kill efficacy of the bound MTX remained similar to that of free MTX, and the nanoparticles presented efficient distribution volumes and slow clearance times in vivo, suggesting that these particles are optimal for CED.
经颅输注增强传递（CED）是一种通过颅内输注将药物直接递送至脑肿瘤的新方法，可使高浓度药物分布于大体积组织中。本研究旨在提出一种通过人血清白蛋白（HSA）涂层将甲氨蝶呤（MTX）结合到独特的结晶、高度有序和超顺磁磁铁矿纳米粒子上的方法，该方法经优化后可用于治疗脑胶质瘤的 CED。研究了裸纳米粒子以及通过 HSA 或聚乙二醇（PEG）涂层包裹的载有 MTX 的纳米粒子。体外结果表明，通过 HSA 涂层载有 MTX 的纳米粒子对细胞的杀伤效果与游离 MTX 相似，且无毒性，而通过 PEG 涂层载有 MTX 的纳米粒子效果较差。在体内，PEG 涂层的纳米粒子在正常大鼠脑中分布最大，清除时间最长，但由于其体外效果不佳，因此不被认为是最佳选择。裸纳米粒子的分布最小，清除时间最短。HSA 涂层的纳米粒子（载有或未载 MTX）具有良好的分布和较长的清除时间（治疗后 3 周，近 50%的分布体积仍保留在大脑中）。未观察到与 MTX 相关的毒性。这些结果表明，通过独特的沉淀方法将 HSA 结合到我们的纳米粒子上，并将 MTX 共价结合到 HSA 上的制剂可以实现高效且稳定的药物加载，而无明显毒性。结合的 MTX 的细胞杀伤效果与游离 MTX 相似，并且纳米粒子在体内具有有效的分布体积和缓慢的清除时间，表明这些粒子是 CED 的理想选择。
