Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109-1065, USA.
Biomaterials. 2011 Mar;32(8):2183-93. doi: 10.1016/j.biomaterials.2010.11.040. Epub 2010 Dec 21.
While successful magnetic tumor targeting of iron oxide nanoparticles has been achieved in a number of models, the rapid blood clearance of magnetically suitable particles by the reticuloendothelial system (RES) limits their availability for targeting. This work aimed to develop a long-circulating magnetic iron oxide nanoparticle (MNP) platform capable of sustained tumor exposure via the circulation and, thus, potentially enhanced magnetic tumor targeting. Aminated, cross-linked starch (DN) and aminosilane (A) coated MNPs were successfully modified with 5 kDa (A5, D5) or 20 kDa (A20, D20) polyethylene glycol (PEG) chains using simple N-Hydroxysuccinimide (NHS) chemistry and characterized. Identical PEG-weight analogues between platforms (A5 & D5, A20 & D20) were similar in size (140-190 nm) and relative PEG labeling (1.5% of surface amines - A5/D5, 0.4% - A20/D20), with all PEG-MNPs possessing magnetization properties suitable for magnetic targeting. Candidate PEG-MNPs were studied in RES simulations in vitro to predict long-circulating character. D5 and D20 performed best showing sustained size stability in cell culture medium at 37 °C and 7 (D20) to 10 (D5) fold less uptake in RAW264.7 macrophages when compared to previously targeted, unmodified starch MNPs (D). Observations in vitro were validated in vivo, with D5 (7.29 h) and D20 (11.75 h) showing much longer half-lives than D (0.12 h). Improved plasma stability enhanced tumor MNP exposure 100 (D5) to 150 (D20) fold as measured by plasma AUC(0-∞). Sustained tumor exposure over 24 h was visually confirmed in a 9L-glioma rat model (12 mg Fe/kg) using magnetic resonance imaging (MRI). Findings indicate that a polyethylene glycol modified, cross-linked starch-coated MNP is a promising platform for enhanced magnetic tumor targeting, warranting further study in tumor models.
虽然已经在许多模型中成功实现了氧化铁纳米颗粒的磁性肿瘤靶向，但网状内皮系统（RES）对磁性合适颗粒的快速血液清除限制了它们用于靶向的可用性。本工作旨在开发一种长循环磁性氧化铁纳米颗粒（MNP）平台，该平台能够通过循环持续暴露于肿瘤，从而潜在地增强磁性肿瘤靶向。用简单的 N-羟基琥珀酰亚胺（NHS）化学成功地用 5 kDa（A5、D5）或 20 kDa（A20、D20）聚乙二醇（PEG）链修饰氨化交联淀粉（DN）和氨基硅烷（A）涂层的 MNPs，并对其进行了表征。平台之间相同 PEG 重量类似物（A5&D5、A20&D20）的粒径（140-190nm）和相对 PEG 标记（表面胺的 1.5%-A5/D5，0.4%-A20/D20）相似，所有 PEG-MNP 都具有适合磁性靶向的磁化性能。在体外 RES 模拟中研究了候选 PEG-MNP，以预测长循环特性。D5 和 D20 在 37°C 的细胞培养基中表现出最佳的持续尺寸稳定性，与之前靶向的未修饰淀粉 MNPs（D）相比，RAW264.7 巨噬细胞的摄取量低 7（D20）至 10（D5）倍。体外观察结果在体内得到了验证，D5（7.29h）和 D20（11.75h）的半衰期明显长于 D（0.12h）。通过血浆 AUC（0-∞）测量，改善的血浆稳定性使肿瘤 MNP 暴露增加了 100（D5）至 150（D20）倍。在 9L 胶质细胞瘤大鼠模型（12mg Fe/kg）中使用磁共振成像（MRI），可在 24 小时内持续观察到肿瘤暴露。研究结果表明，聚乙二醇修饰的交联淀粉涂层 MNP 是一种有前途的增强磁性肿瘤靶向的平台，值得在肿瘤模型中进一步研究。
