Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
PECEM, Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.
Clin Cancer Res. 2020 Jan 15;26(2):477-486. doi: 10.1158/1078-0432.CCR-19-2182. Epub 2019 Dec 12.
Paclitaxel shows little benefit in the treatment of glioma due to poor penetration across the blood-brain barrier (BBB). Low-intensity pulsed ultrasound (LIPU) with microbubble injection transiently disrupts the BBB allowing for improved drug delivery to the brain. We investigated the distribution, toxicity, and efficacy of LIPU delivery of two different formulations of paclitaxel, albumin-bound paclitaxel (ABX) and paclitaxel dissolved in cremophor (CrEL-PTX), in preclinical glioma models.
The efficacy and biodistribution of ABX and CrEL-PTX were compared with and without LIPU delivery. Antiglioma activity was evaluated in nude mice bearing intracranial patient-derived glioma xenografts (PDX). Paclitaxel biodistribution was determined in sonicated and nonsonicated nude mice. Sonications were performed using a 1 MHz LIPU device (SonoCloud), and fluorescein was used to confirm and map BBB disruption. Toxicity of LIPU-delivered paclitaxel was assessed through clinical and histologic examination of treated mice.
Despite similar antiglioma activity , ABX extended survival over CrEL-PTX and untreated control mice with orthotropic PDX. Ultrasound-mediated BBB disruption enhanced paclitaxel brain concentration by 3- to 5-fold for both formulations and further augmented the therapeutic benefit of ABX. Repeated courses of LIPU-delivered CrEL-PTX and CrEL alone were lethal in 42% and 37.5% of mice, respectively, whereas similar delivery of ABX at an equivalent dose was well tolerated.
Ultrasound delivery of paclitaxel across the BBB is a feasible and effective treatment for glioma. ABX is the preferred formulation for further investigation in the clinical setting due to its superior brain penetration and tolerability compared with CrEL-PTX.
紫杉醇由于难以穿透血脑屏障（BBB），因此对治疗脑胶质瘤的效果甚微。低强度脉冲超声（LIPU）联合微泡注射可短暂破坏 BBB，从而改善药物向大脑的递送。我们研究了 LIPU 递送两种不同紫杉醇制剂（白蛋白结合紫杉醇（ABX）和紫杉醇溶解于聚氧乙烯蓖麻油（CrEL-PTX））在临床前脑胶质瘤模型中的分布、毒性和疗效。
比较了 ABX 和 CrEL-PTX 在有和没有 LIPU 递送的情况下的疗效和生物分布。在颅内患者来源的脑胶质瘤异种移植（PDX）荷瘤裸鼠中评估抗脑胶质瘤活性。在经超声处理和未经超声处理的裸鼠中测定紫杉醇的生物分布。使用 1 MHz 的 LIPU 设备（SonoCloud）进行超声处理，并用荧光素证实和绘制 BBB 破坏图。通过对接受治疗的小鼠进行临床和组织学检查，评估 LIPU 递送的紫杉醇的毒性。
尽管具有相似的抗脑胶质瘤活性，但 ABX 延长了 PDX 原位脑胶质瘤荷瘤裸鼠的存活时间，优于 CrEL-PTX 和未治疗的对照组。超声介导的 BBB 破坏使两种制剂的紫杉醇脑浓度增加 3 至 5 倍，并进一步增强了 ABX 的治疗益处。重复 LIPU 递送 CrEL-PTX 和单独的 CrEL 会分别导致 42%和 37.5%的小鼠死亡，而以等效剂量重复给予 ABX 则可耐受。
BBB 内紫杉醇的超声递送至脑是治疗脑胶质瘤的一种可行且有效的方法。与 CrEL-PTX 相比，ABX 具有更好的脑穿透性和耐受性，因此是在临床环境中进一步研究的首选制剂。
