TY - JOUR
T1 - Ultrasound-mediated delivery of paclitaxel for glioma
T2 - A comparative study of distribution, toxicity, and efficacy of albumin-bound versus cremophor formulations
AU - Zhang, Daniel Y.
AU - Dmello, Crismita
AU - Chen, Li
AU - Arrieta, Victor A.
AU - Gonzalez-Buendia, Edgar
AU - Robert Kane, J.
AU - Magnusson, Lisa P.
AU - Baran, Aneta
AU - David James, C.
AU - Horbinski, Craig
AU - Carpentier, Alexandre
AU - Desseaux, Carole
AU - Canney, Michael
AU - Muzzio, Miguel
AU - Stupp, Roger
AU - Sonabend, Adam M.
N1 - Funding Information:
This work was funded by 5DP5OD021356-05 (AS), P50CA221747 SPORE for Translational Approaches to Brain Cancer (AS & RS), and Developmental funds from The Robert H Lurie NCI Cancer Center Support Grant #P30CA060553 (AS). We are grateful for the generous philanthropic support from Dan and Sharon Moceri. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors would like to thank CarThera for providing the equipment and guidance necessary to perform the US-mediated blood brain barrier opening procedure.
Funding Information:
This work was funded by 5DP5OD021356-05 (AS), P50CA221747 SPORE for Translational Approaches to Brain Cancer (AS & RS), and Developmental funds from The Robert H Lurie NCI Cancer Center Support Grant #P30CA060553 (AS). We are grateful for the generous philanthropic support from Dan and Sharon Moceri. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. The authors would like to thank CarThera for providing the equipment and guidance necessary to perform the US-mediated blood brain barrier opening procedure. P50CA221747 SPORE for Translational Approaches to Brain Cancer, 5DP5OD021356-05, P30CA060553 NCI Cancer Center Support Grant, Philanthropic Support from Dan and Sharon Moceri.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2020/1/15
Y1 - 2020/1/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-19-2182
DO - 10.1158/1078-0432.CCR-19-2182
M3 - Article
C2 - 31831565
AN - SCOPUS:85077921276
SN - 1078-0432
VL - 26
SP - 477
EP - 486
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 2
ER -
