在治疗中枢神经系统（CNS）肿瘤过程中，有效穿越血脑屏障（BBB）传递治疗药物是开发安全和有效疗法的主要挑战。局部区域药物传递平台通过在目标组织中实现高药物浓度并减少系统曝光，提供了改善疗效的方法。脑脊液（脑室内）[IT]和强流体传送[CED]是目前应用于各种CNS恶性肿瘤的两种临床相关方法。这两种独立的平台都受到被动的给药后分布力的限制，有时限制了对肿瘤治疗的期望分布。以局部聚焦超声和微泡介导的血脑屏障开放（FUS-BBBO）是一种用于增强药物传递的新型技术。有人假设将FUS与这些替代传递途径相结合可能会带来好处。多模式FUS可以在IT给药后提供增加神经实质传递深度的能力，并为CED提供定向途径。此外，已经确立了FUS-BBBO所实现的短暂增强渗透能力，但尚未确定药物滞留和中转时间，而这对于临床剂量安排至关重要。本研究由两个不同的研究组成：1. 进行全面的定量评估，以阐明FUS-BBBO与不同给药途径（IT和IV）相结合在促进药物穿透纹状丘脑区内的效果。2. 调查将FUS-BBBO与CED相结合对药物分布的影响，重点关注目标区域内药物滞留的时间动态。首先，我们定量评估了FUS-BBBO与IT和IV相结合对荧光染料（Dextran 2000kD和70kDa）在预定纹状丘脑区内的分布和浓度的影响，使用了正常小鼠。其次，我们通过测量染料的分布体积和时间依赖浓度来分析使用FUS介导的BBB破坏与CED相结合的药代动力学效应。我们的结果表明，将IV给药与FUS-BBBO相结合可以成功增强染料进入预定声华靶区。相反，在IT给药后，声华靶区的染料浓度较低。FUS可以增强CED后染料的分布体积。此外，与单独应用CED相比，CED与FUS-BBBO相结合时观察到更短的滞留时间。1. 根据我们的研究结果，与IT给药相比，IV给药与FUS-BBBO相结合是传递至深部靶区（即纹状丘脑区）在预定空间结构内更有效的方法。2. FUS-BBBO增加了CED给药后染料的分布体积（Vd），但导致了较短的滞留时间。是否可以对其他类别的药物（如细胞毒性药物、抗体、病毒颗粒和细胞疗法）进行可重复的研究，需要进一步探讨。版权所有©2023．Elsevier B.V.

Efficient delivery of therapeutics across the blood-brain barrier (BBB) for the treatment of central nervous system (CNS) tumors is a major challenge to the development of safe and efficacious therapies. Locoregional drug delivery platforms offer an improved therapeutic index by achieving high drug concentrations in the target tissue with negligible systemic exposure. Intrathecal (intraventricular) [IT] and convection-enhanced delivery [CED] are two clinically relevant methods being employed for various CNS malignancies. Both of these standalone platforms suffer from passive post-administration distribution forces, sometimes limiting the desired distribution for tumor therapy. Focused ultrasound and microbubble-mediated blood-brain barrier opening (FUS-BBBO) is a recent modality used for enhanced drug delivery. It is postulated that coupling of FUS with these alternative delivery routes may provide benefits. Multimodality FUS may provide the desired ability to increase the depth of parenchymal delivery following IT administration and provide a means for contour directionality with CED. Further, the transient enhanced permeability achieved with FUS-BBBO is well established, but drug residence and transit times, important to clinical dose scheduling, have not yet been defined. The present investigation comprises two discrete studies: 1. Conduct a comprehensive quantitative evaluation to elucidate the effect of FUS-BBBO as it relates to varying routes of administration (IT and IV) in its capacity to facilitate drug penetration within the striatal-thalamic region. 2. Investigate the impact of combining FUS-BBBO with CED on drug distribution, with a specific focus on the temporal dynamics of drug retention within the target region.Firstly, we quantitatively assessed how FUS-BBBO coupled with IT and IV altered fluorescent dye (Dextran 2000kD and 70 kDa) distribution and concentration in a predetermined striatal-thalamic region in naïve mice. Secondly, we analyzed the pharmacokinetic effects of using FUS mediated BBB disruption coupled with CED by measuring the volume of distribution and time-dependent concentration of the dye.Our results indicate that IV administration coupled with FUS-BBBO successfully enhances delivery of dye into the pre-defined sonication targets. Conversely, measurable dye in the sonication target was consistently less after IT administration. FUS enhances the distribution volume of dye after CED. Furthermore, a shorter time of residence was observed when CED was coupled with FUS-BBBO application when compared to CED alone.1. Based on our findings, IV delivery coupled with FUS-BBBO is a more efficient means for delivery to deep targets (i.e. striatal-thalamic region) within a predefined spatial conformation compared to IT administration. 2. FUS-BBBO increases the volume of distribution (Vd) of dye after CED administration, but results in a shorter time of residence. Whether this finding is reproducible with other classes of agents (e.g., cytotoxic agents, antibodies, viral particles, cellular therapies) needs to be studied.Copyright © 2023. Published by Elsevier B.V.