背景:实现向中枢神经系统(CNS)的有效药物递送仍然是治疗神经系统疾病的挑战。鞘内(IT)输送,直接注射到脑脊液(CSF)中,提出了一个有前途的战略。大型动物研究对于评估大多数药物和治疗的安全性和有效性以及将数据转化为人类非常重要。了解IT注射参数对CNS内溶质分布的影响对于优化临床前研究至关重要。这可能有助于设计人体临床研究。
方法:食蟹猴的三维(3D)体外模型,根据核磁共振数据,开发了腰椎注射参数对鞘内溶质分散的影响。评估的参数是(A)注射位置,(b)丸剂体积,(c)冲洗量。(d)推注率,和(e)冲洗率。为了模拟蛛网膜下腔(SAS)内的CSF流动,将具有心脏和呼吸诱导成分的理想化CSF流量波形输入到模型中.在填充有去离子水的3D体外模型的腰部区域中施用荧光素药物替代示踪剂的溶液。注射示踪剂后,使用高分辨率相机每30秒对CSF系统宽溶质弥散成像,持续3小时.为了确保可重复性,每个注射方案重复三次。对于每个协议,注射后三小时的平均时空分布,曲线下面积(AUC),并测定三小时轴外CSF(eaCSF)的注射剂量百分比(%ID)。
结果:腰椎注射参数的变化导致溶质沿神经轴分布的变化。具体来说,注射位置显示出最大的影响,在注射后三小时,将向eaCSF的递送增强至+10.5%ID(p=0.0282)。以1ml/min的速度添加1.5ml的注射后冲洗液,使溶质向eaCSF的输送增加了+6.5%ID(p=0.0218),而较大的推注量导致+2.3%ID(p=0.1910)增加。分析的推注率和冲洗率最小,统计学上无显著影响。
结论:这些结果预测了腰椎注射参数对NHPs鞘内间隙溶质分布的影响。具体来说,注射位置的选择,flush,和推注体积显着改善了溶质向eaCSF的递送。体外NHPCSF模型和结果提供了一个系统来帮助预测和优化临床前NHP研究的IT递送方案。
BACKGROUND: Achieving effective drug delivery to the central nervous system (CNS) remains a challenge for treating neurological disorders. Intrathecal (IT) delivery, which involves direct injection into the cerebrospinal fluid (CSF), presents a promising strategy. Large animal studies are important to assess the safety and efficacy of most drugs and treatments and translate the data to humans. An understanding of the influence of IT injection parameters on solute distribution within the CNS is essential to optimize preclinical research, which would potentially help design human clinical studies.
METHODS: A three-dimensional (3D) in vitro model of a cynomolgus monkey, based on MRI data, was developed to evaluate the impact of lumbar injection parameters on intrathecal solute dispersion. The parameters evaluated were (a) injection location, (b) bolus volume, (c) flush volume, (d) bolus rate, and (e) flush rate. To simulate the CSF flow within the subarachnoid space (SAS), an idealized CSF flow waveform with both cardiac and respiratory-induced components was input into the model. A solution of fluorescein drug surrogate tracer was administered in the lumbar region of the 3D in vitro model filled with deionized water. After injection of the tracer, the CSF system wide-solute dispersion was imaged using high-resolution cameras every thirty seconds for a duration of three hours. To ensure repeatability each injection protocol was repeated three times. For each protocol, the average spatial-temporal distribution over three hours post-injection, the area under the curve (AUC), and the percent injected dose (%ID) to extra-axial CSF (eaCSF) at three hours were determined.
RESULTS: The changes to the lumbar injection parameters led to variations in solute distribution along the neuro-axis. Specifically, injection location showed the most impact, enhancing the delivery to the eaCSF up to + 10.5%ID (p = 0.0282) at three hours post-injection. Adding a post-injection flush of 1.5 ml at 1 ml/min increased the solute delivery to the eaCSF by + 6.5%ID (p = 0.0218), while the larger bolus volume resulted in a + 2.3%ID (p = 0.1910) increase. The bolus and flush rates analyzed had minimal, statistically non-significant effects.
CONCLUSIONS: These results predict the effects of lumbar injection parameters on solute distribution in the intrathecal space in NHPs. Specifically, the choice of injection location, flush, and bolus volume significantly improved solute delivery to eaCSF. The in vitro NHP CSF model and results offer a system to help predict and optimize IT delivery protocols for pre-clinical NHP studies.