Department of Pharmaceutics, School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China.
Biomaterials. 2011 Aug;32(22):5177-86. doi: 10.1016/j.biomaterials.2011.03.075. Epub 2011 Apr 30.
Clinical diagnosis of cancers using magnetic resonance imaging (MRI) is highly dependent on contrast agents, especially for brain tumors which contain blood-brain barrier (BBB) at the early stage. However, currently mostly used low molecular weight contrast agents such as Gd-DTPA suffer from rapid renal clearance, non-specificity, and low contrast efficiency. The aim of this paper is to investigate the potential of a macromolecular MRI contrast agent based on dendrigraft poly-l-lysines (DGLs), using chlorotoxin (CTX) as a tumor-specific ligand. The contrast agent using CTX-modified conjugate as the main scaffold and Gd-DTPA as the payload was successfully synthesized. The results of fluorescent microscopy showed that the modification of CTX could markedly enhance the cellular uptake in C6 glioma and liver tumor cell lines, but not in normal cell line. Significantly increased accumulation of CTX-modified conjugate within glioma and liver tumor was further demonstrated in tumor-bearing nude mice using in vivo imaging system. The MRI results showed that the signal enhancement of mice treated with CTX-modified contrast reached peak level at 5 min for both glioma and liver tumor, 144.97% ± 19.54% and 158.69% ± 12.41%, respectively, significantly higher than that of unmodified counterpart and commercial control. And most importantly, the signal enhancement of CTX-modified contrast agent maintained much longer compared to that of controls, which might be useful for more exact diagnosis for tumors. CTX-modified dendrimer-based conjugate might be applied as an efficient MRI contrast agent for targeted and accurate tumor diagnosis. This finding is especially important for tumors such as brain glioma which is known hard to be diagnosed due to the presence of BBB.
使用磁共振成像（MRI）进行癌症的临床诊断高度依赖于造影剂，特别是对于早期含有血脑屏障（BBB）的脑肿瘤。然而，目前大多数使用的低分子量造影剂，如 Gd-DTPA，存在快速肾清除、非特异性和低对比度效率等问题。本文旨在研究基于树枝状大分子聚赖氨酸（DGL）的大分子 MRI 造影剂的潜力，使用氯毒素（CTX）作为肿瘤特异性配体。成功合成了以 CTX 修饰的缀合物为主要支架和 Gd-DTPA 为有效载荷的造影剂。荧光显微镜的结果表明，CTX 的修饰可以显著增强 C6 神经胶质瘤和肝癌细胞系的细胞摄取，但对正常细胞系没有影响。在荷瘤裸鼠中使用体内成像系统进一步证明了 CTX 修饰的缀合物在胶质瘤和肝癌中的明显积累。MRI 结果表明，CTX 修饰的造影剂处理的小鼠的信号增强在胶质瘤和肝癌中分别在 5 分钟达到峰值水平，分别为 144.97%±19.54%和 158.69%±12.41%，明显高于未修饰的对照和商业对照。最重要的是，CTX 修饰的造影剂的信号增强保持的时间比对照剂长的多，这可能对肿瘤的更准确诊断有用。CTX 修饰的基于树枝状大分子的缀合物可能被用作针对肿瘤的有效 MRI 造影剂，用于进行准确的肿瘤诊断。这一发现对于脑胶质瘤等由于 BBB 存在而难以诊断的肿瘤尤其重要。
