Ultrasound-mediated Delivery of Paclitaxel for Glioma: A Comparative Study of Distribution, Toxicity, and Efficacy of Albumin-bound Versus Cremophor Formulations.

ABSTRACT

PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: Despite similar antiglioma activity in vitro, 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. CONCLUSIONS: 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.