Conjugation to polyethylene glycol polymer promotes aptamer biodistribution to healthy and inflamed tissues
Conjugation to polyethylene glycol polymer promotes aptamer biodistribution to healthy and inflamed tissues
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DOI：
10.1089/oli.2005.15.183
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发表时间：
2005-01-01
期刊：
影响因子：
--
通讯作者：
McCauley, TG
中科院分区：
文献类型：
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作者：
Boomer, RM;Lewis, SD;McCauley, TG
在此，我们检查了放射性标记的适体的生物分布，并评估了不同的稳定化适体组合物（混合的2-F/2 '-O-Me;完全2'-O-Me修饰的）在鼠炎症模型中接近发炎组织的相对能力。在施用后3小时使用定量全身放射自显影术（QWBA）评估H-3标记的适体（包括聚乙二醇化和未聚乙二醇化的组合物）的生物分布。还通过显微放射自显影在定性水平上检查了肾脏和肝脏中细胞的适体渗透。为了评估适体在患病组织中的分布，通过在适体给药之前用角叉菜胶处理在动物后肢中局部诱导炎症。检查的适体组合物在器官和组织中的分布水平表现出显著变化。在所有动物的肾脏和膀胱内容物中观察到全身组织中放射性浓度最高。脑、脊髓和脂肪组织的放射性相对较少。总体而言，20-kDa PEG缀合物在全身组织中的总放射性水平显著高于其他适体。在灌注良好的器官和组织中观察到相对高水平的20-kDa缀合物，包括肝、肺、脾、骨髓和心肌。完全2 '-O-Me组成的适体在全身组织中具有最低水平的放射性，但相对于其他适体在胃肠道内容物中分布至更高的浓度。有趣的是，20-kDa PEG-缀合的适体显示出比未缀合的或完全2 '-O-Me-修饰的适体显著更高水平的分布到发炎的爪组织。
Here, we examine biodistribution of radiolabeled aptamers and assess the relative ability of different stabilized aptamer compositions (mixed 2-F/2'-O-Me; fully 2'-O-Me modified) to access inflamed tissues in a murine inflammation model. Biodistribution of H-3-labeled aptamers, including pegylated and unpegylated compositions, was assessed 3 hours postadministration using quantitative whole body autoradiography (QWBA). Aptamer penetration of cells in kidney and liver was also examined at a qualitative level by microautoradiography. To evaluate aptamer distribution to diseased tissues, inflammation was induced locally in animal hind limbs by treatment with carrageenan just prior to aptamer dosing. Aptamer compositions examined exhibited significant variation in distribution levels among organs and tissues. Highest concentrations of radioactivity in whole body tissues for all animals were observed in the kidney and urinary bladder contents. Relatively little radioactivity was associated with brain, spinal cord, and adipose tissue. Overall, the total level of radioactivity in whole body tissues was significantly higher for a 20-kDa PEG conjugate than for other aptamers. Comparatively high levels of the 20-kDa conjugate were seen in well-perfused organs and tissues, including liver, lungs, spleen, bone marrow, and myocardium. A fully 2'-O-Me composition aptamer had the lowest level of radioactivity in whole body tissues but distributed to higher concentrations in the gastrointestinal tract contents relative to other aptamers. Interestingly, the 20-kDa PEG-conjugated aptamer showed significantly higher levels of distribution to inflamed paw tissues than did either unconjugated or fully 2'-O-Me-modified aptamers.