Bartlett Derek W, Su Helen, Hildebrandt Isabel J, Weber Wolfgang A, Davis Mark E
Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, MC 210-41, Pasadena, CA 91125, USA.
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15549-54. doi: 10.1073/pnas.0707461104. Epub 2007 Sep 17.
Targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. Although macromolecules accumulate nonspecifically in tumors through the enhanced permeability and retention (EPR) effect, previous studies using nanoparticles to deliver chemotherapeutics or siRNA demonstrated that attachment of cell-specific targeting ligands to the surface of nanoparticles leads to enhanced potency relative to nontargeted formulations. Here, we use positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA. Conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to the 5' end of the siRNA molecules allows labeling with (64)Cu for PET imaging. Bioluminescent imaging of mice bearing luciferase-expressing Neuro2A s.c. tumors before and after PET imaging enables correlation of functional efficacy with biodistribution data. Although both nontargeted and transferrin-targeted siRNA nanoparticles exhibit similar biodistribution and tumor localization by PET, transferrin-targeted siRNA nanoparticles reduce tumor luciferase activity by approximately 50% relative to nontargeted siRNA nanoparticles 1 d after injection. Compartmental modeling is used to show that the primary advantage of targeted nanoparticles is associated with processes involved in cellular uptake in tumor cells rather than overall tumor localization. Optimization of internalization may therefore be key for the development of effective nanoparticle-based targeted therapeutics.
靶向递送是一种很有前景的方法，可用于开发更安全、更有效的肿瘤学治疗药物。尽管大分子通过增强的渗透和滞留（EPR）效应在肿瘤中发生非特异性积累，但先前使用纳米颗粒递送化疗药物或小干扰RNA（siRNA）的研究表明，将细胞特异性靶向配体连接到纳米颗粒表面会导致相对于非靶向制剂而言药效增强。在此，我们使用正电子发射断层扫描（PET）和生物发光成像来量化由含环糊精的聚阳离子和siRNA形成的纳米颗粒的体内生物分布和功能。将1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸缀合到siRNA分子的5'端，可实现用（64）Cu进行PET成像标记。对荷有表达荧光素酶的Neuro2A皮下肿瘤的小鼠在PET成像前后进行生物发光成像，能够将功能疗效与生物分布数据相关联。尽管非靶向和转铁蛋白靶向的siRNA纳米颗粒通过PET显示出相似的生物分布和肿瘤定位，但转铁蛋白靶向的siRNA纳米颗粒在注射后1天相对于非靶向siRNA纳米颗粒可使肿瘤荧光素酶活性降低约50%。房室模型用于表明靶向纳米颗粒的主要优势与肿瘤细胞中细胞摄取所涉及的过程相关，而非与整体肿瘤定位相关。因此，优化内化可能是开发基于纳米颗粒的有效靶向治疗药物的关键。
