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.

中文翻译：

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食蟹猴体内鞘内示踪剂分散验证了沿神经轴的广泛生物分布

目的：人们普遍认为，在鞘内 (IT) 药物递送中，药物分布仅限于靠近注射部位的狭窄区域，从而削弱了该方法的功效。方法：为了测试该声明，使用多模态体内成像实验观察 IT 输注对食蟹猴的影响，观察脑脊液流动、解剖结构和放射性标记示踪剂的分散。结果：在高输注速率下，示踪剂仅在 2 小时后到达宫颈区域，分布迅速且广泛。相同的体内非人类灵长类动物成像数据也提供了支持计算流体动力学模型的证据，用于预测 IT 注射后的药物分布。在与正电子发射断层扫描 (PET) 获得的分布相匹配的两个样本中预测示踪剂分散。对于第三个样本，示踪剂分散模拟作为盲研究进行：在体内生物分布数据已知之前进行预测。在所有情况下，IT 给药后药物分散的计算流体动力学 (CFD) 预测显示与体内示踪剂生物分布的时空一致。结论：通过体内非人类灵长类动物数据的验证证实了我们能够根据第一原理预测鞘内给药的药物在中枢神经系统特定模型中的生物分布。意义：当将分子靶向整个脊柱或大脑时，这些实验将 IT 递送恢复为一种可行的给药方法。