In vivo imaging of 64Cu-labeled polymer nanoparticles targeted to the lung endothelium
In vivo imaging of 64Cu-labeled polymer nanoparticles targeted to the lung endothelium
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DOI：
10.2967/jnumed.107.045302
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发表时间：
2008-01-01
影响因子：
9.3
通讯作者：
Schuster, Daniel P.
中科院分区：
文献类型：
--
作者：
Rossin, Raffaella;Muro, Silvia;Schuster, Daniel P.
靶向细胞间粘附分子1（ICAM-1）的纳米颗粒（NP）有望成为急性和慢性呼吸系统疾病患者肺内皮细胞治疗的一种手段。随着这些新材料的出现，需要采取策略来了解它们在体内的行为。我们已经评估了Cu-64和PET的使用，以非侵入性成像的肺吸收和分布的纳米颗粒包被的抗ICAM抗体。研究方法：用抗ICAM抗体（或非特异性IgG）和Cu-64-DOTA-IgG（其中DOTA是1，4，7，10-四氮杂环十二烷-1，4，7，10-四乙酸）的混合物包被模型荧光NP。在健康小鼠和脂多糖（LPS）预处理小鼠中进行生物分布和小动物PET和CT研究。还进行了代谢研究以评价（CU）-C-64标记的NP在体内肺中的稳定性。结果：小鼠肺给予抗ICAM纳米颗粒标记的Cu-64清晰成像的小动物PET后1，4，和24小时。生物分布和小动物成像显示，与对照组相比，注射ICAM靶向纳米颗粒的小鼠肺中的摄取量高3至4倍。用LPS预处理小鼠进一步增强了肺摄取，可能是因为ICAM-1上调。然而，在24小时内，在每个实验组中观察到肺信号降低约2倍。从注射Cu-64标记的抗ICAM NPs的小鼠中收获的肺组织中的代谢研究显示，早在注射后1小时，从NPs开始大量释放小的Cu-64-放射性代谢物。还观察到肺荧光的减少，最可能反映了NP在体内从肺的部分释放。结论：使用小动物PET在体内追踪Cu-64标记的纳米结构显示出作为靶向肺内皮和其他组织的新NP药物递送剂的临床前筛选策略的潜力。未来的设计优化，以延长放射性标记在体内的稳定性将进一步改善这种有前途的方法。
Nanoparticles (NPs) targeting the intercellular adhesion molecule 1 (ICAM-1) hold promise as a mean of delivering therapeutics to the pulmonary endothelium in patients with acute and chronic respiratory diseases. As these new materials become available, strategies are needed to understand their behavior in vivo. We have evaluated the use of Cu-64 and PET to noninvasively image the lung uptake and distribution of NPs coated with an anti-ICAM antibody. Methods: Model fluorescent NPs were coated with a mixture of an anti-ICAM antibody (or nonspecific IgG) and Cu-64-DOTA-IgG (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). Biodistribution and small-animal PET and CT studies were performed in healthy mice and in mice pre-treated with lipopolysaccharides (LPSs). Metabolism studies were also performed to evaluate the stability of (CU)-C-64-labeled NPs in lungs in vivo. Results: The lungs of mice administered anti-ICAM NPs labeled with Cu-64 were clearly imaged by small-animal PET 1, 4, and 24 h after administration. Both biodistribution and small-animal imaging showed a 3- to 4-fold higher uptake in the lungs of mice injected with ICAM-targeted NPs relative to that of the control group. Lung uptake was further enhanced by pretreating the mice with LPS, presumably because of ICAM-1 upregulation. However, an approximately 2-fold decrease in lung signal was observed in each experimental group over 24 h. Metabolism studies in lung tissues harvested from mice injected with Cu-64-labeled anti-ICAM NPs showed considerable release of a small Cu-64-radiometabolite from the NPs beginning as early as 1 h after injection. A decrease in lung fluorescence was also observed, most likely reflecting partial release of NPs from the lungs in vivo. Conclusion: The use of small-animal PET to track Cu-64-labeled nanostructures in vivo shows potential as a strategy for the preclinical screening of new NP drug delivery agents targeting the lung endothelium and other tissues. Future design optimization to prolong the stability of the radiolabel in vivo will further improve this promising approach.