In Vivo Intrathecal Tracer Dispersion in Cynomolgus Monkey Validates Wide Biodistribution Along Neuraxis
In Vivo Intrathecal Tracer Dispersion in Cynomolgus Monkey Validates Wide Biodistribution Along Neuraxis
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DOI：
10.1109/tbme.2019.2930451
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发表时间：
2020-04
影响因子：
4.6
通讯作者：
K. Tangen;I. Nestorov;A. Verma;Jenna M. Sullivan;Robert W Holt;A. Linninger
中科院分区：
文献类型：
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作者：
K. Tangen;I. Nestorov;A. Verma;Jenna M. Sullivan;Robert W Holt;A. Linninger
目的：人们普遍认为鞘内给药时，药物分布局限于靠近注射部位的狭窄区域，从而影响了该方法的有效性。方法：为了验证这一说法，采用多模态体内成像技术，通过观察脑脊液流动、解剖和放射性标记示踪剂的分散，实验观察了IT输注对食食猴的影响。结果：在高滴注速率下，示踪剂仅2 h即可到达宫颈，且分布迅速、广泛。同样的非人类灵长类动物体内成像数据也为预测IT注射后药物分布的计算流体动力学模型提供了证据。在两个样品中预测了与正电子发射断层扫描（PET）获得的分布相匹配的示踪色散。对于第三个标本，示踪剂分散模拟作为盲法研究进行：在体内生物分布数据已知之前进行预测。在所有情况下，计算流体动力学（CFD）预测的IT给药后药物分散度与体内示踪剂的生物分布在时空上密切一致。结论：体内非人灵长类动物数据的验证证实了我们能够从第一性原理预测中枢神经系统特定模型中鞘内给药药物的生物分布。意义：当分子靶向整个脊柱或大脑时，实验恢复了IT递送作为一种可行的给药方法。提出的计算方法能够合理设计神经系统疾病的新疗法，这些疗法需要可靠、有效和安全的将治疗剂输送到中枢神经系统的特定靶点。
Objective: It is commonly believed that in intrathecal (IT) drug delivery, agent distribution is confined to a narrow region close to the injection site, thereby undermining the efficacy of the method. Methods: To test the claim, multimodal in vivo imaging was used to experimentally observe the effects of IT infusion in cynomolgus monkey, looking at cerebrospinal fluid flow, anatomy, and dispersion of a radiolabeled tracer. Results: At high infusion rates, the tracer reached the cervical region after only 2 h, demonstrating rapid and wide distribution. The same in vivo nonhuman primate imaging data also provided evidence in support of a computational fluid dynamic model for the prediction of drug distribution following IT injection. Tracer dispersion was predicted in two specimens matching the distribution acquired with positron emission tomography (PET). For the third specimen, tracer dispersion simulations were conducted as a blind study: predictions were made before in vivo biodistribution data was known. In all cases, the computational fluid dynamics (CFD) predictions of drug dispersion after IT administration showed close spatio-temporal agreement with tracer biodistribution in vivo. Conclusion: Validation by in vivo nonhuman primate data confirms our ability to predict the biodistribution of intrathecally administered agents in subject-specific models of the central nervous system from first principles. Significance: The experiments reinstate IT delivery as a viable administration method when targeting molecules to the whole spine or the brain. The proposed computational methodology enables rational design of novel therapies for neurological diseases that require reliable, efficient, and safe delivery of therapeutic agents to specific target sites in the central nervous system.