Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre Amrita, Vishwa Vidyapeetham University, Cochin 682 041 Kerala, India.
Nanoscale. 2011 Oct 5;3(10):4150-61. doi: 10.1039/c1nr10591d. Epub 2011 Aug 18.
We report the development of a novel magnetic nano-contrast agent (nano-CA) based on Gd(3+) doped amorphous TiO(2) of size ∼25 nm, exhibiting enhanced longitudinal relaxivity (r(1)) and magnetic resonance (MR) contrasting together with excellent biocompatibility. Quantitative T1 mapping of phantom samples using a 1.5 T clinical MR imaging system revealed that the amorphous phase of doped titania has the highest r(1) relaxivity which is ∼2.5 fold higher than the commercially used CA Magnevist™. The crystalline (anatase) samples formed by air annealing at 250 °C and 500 °C showed significant reduction in r(1) values and MR contrast, which is attributed to the loss of proton-exchange contribution from the adsorbed water and atomic re-arrangement of Gd(3+) ions in the crystalline host lattice. Nanotoxicity studies including cell viability, plasma membrane integrity, reactive oxygen stress and expression of pro-inflammatory cytokines, performed on human primary endothelial cells (HUVEC), human blood derived peripheral blood mononuclear cells (PBMC) and nasopharyngeal epidermoid carcinoma (KB) cell line showed excellent biocompatibility up to relatively higher doses of 200 μg ml(-1). The potential of this nano-CA to cause hemolysis, platelet aggregation and plasma coagulation were studied using human peripheral blood samples and found no adverse effects, illustrating the possibility of the safe intravenous administration of these agents for human applications. Furthermore, the ability of these agents to specifically detect cancer cells by targeting molecular receptors on the cell membrane was demonstrated on folate receptor (FR) positive oral carcinoma (KB) cells, where the folic acid conjugated nano-CA showed receptor specific accumulation on cell membrane while leaving the normal fibroblast cells (L929) unstained. This study reveals that the Gd(3+) doped amorphous TiO(2) nanoparticles having enhanced magnetic resonance contrast and high biocompatibility is a promising candidate for molecular receptor targeted MR imaging.
我们报告了一种新型磁性纳米对比剂（nano-CA）的开发，该对比剂基于尺寸约为 25nm 的掺钆（Gd）非晶态 TiO2，具有增强的纵向弛豫率（r1）和磁共振（MR）对比能力，同时具有优异的生物相容性。使用 1.5T 临床磁共振成像系统对体模样品进行定量 T1 映射显示，掺杂 TiO2 的非晶相具有最高的 r1弛豫率，约为商用 CA MagnevistTM 的 2.5 倍。在 250°C 和 500°C 下通过空气退火形成的结晶（锐钛矿）样品，r1 值和 MR 对比显著降低，这归因于吸附水中质子交换贡献的损失和结晶宿主晶格中 Gd（3+）离子的原子重排。包括人原代内皮细胞（HUVEC）、人血来源外周血单核细胞（PBMC）和鼻咽表皮样癌细胞（KB）细胞系的细胞活力、质膜完整性、活性氧应激和促炎细胞因子表达在内的纳米毒性研究表明，在相对较高剂量 200μg/ml 时，具有优异的生物相容性。使用人外周血样本研究了这种纳米 CA 引起溶血、血小板聚集和血浆凝固的潜力，未发现不良反应，说明这些药物有可能安全地静脉给药用于人体应用。此外，在叶酸受体（FR）阳性口腔癌（KB）细胞上通过细胞膜上的分子受体特异性检测癌细胞的能力也得到了证明，其中叶酸偶联的纳米 CA 显示出对细胞膜的受体特异性积累，而未染色正常成纤维细胞（L929）。这项研究表明，具有增强磁共振对比和高生物相容性的 Gd（3+）掺杂非晶态 TiO2 纳米粒子是一种有前途的分子受体靶向磁共振成像候选物。
