Pharmacokinetics, Brain Delivery, and Efficacy in Brain Tumor-Bearing Mice of Glutathione Pegylated Liposomal Doxorubicin (2B3-101)

PLoS One

Helga E. de Vries¹  Guus A. M. S. van Dongen²  Bert Windhorst²  Danielle J. Vugts²  Olaf van Tellingen³  David Maussang⁴  Francesca Manca⁴  Pieter J. Gaillard⁴  Rick Dorland⁴  Joan van Kregten⁴  Chantal C. M. Appeldoorn⁴ 

[1] Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands;Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands;The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, The Netherlands;to-BBB technologies BV, Leiden, The Netherlands

关键词: Cancer treatment;    Glutathione;    Liposomes;    Blood plasma;    Drug delivery;    Brain metastasis;    Endothelial cells;    Mouse models;   

DOI  :  10.1371/journal.pone.0082331

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Brain cancer is a devastating disease affecting many people worldwide. Effective treatment with chemotherapeutics is limited due to the presence of the blood-brain barrier (BBB) that tightly regulates the diffusion of endogenous molecules but also xenobiotics. Glutathione pegylated liposomal doxorubicin (2B3-101) is being developed as a new treatment option for patients with brain cancer. It is based on already marketed pegylated liposomal doxorubicin (Doxil®/Caelyx®), with an additional glutathione coating that safely enhances drug delivery across the BBB. Uptake of 2B3-101 by human brain capillary endothelial cells in vitro was time-, concentration- and temperature-dependent, while pegylated liposomal doxorubicin mainly remained bound to the cells. In vivo, 2B3-101 and pegylated liposomal doxorubicin had a comparable plasma exposure in mice, yet brain retention 4 days after administration was higher for 2B3-101. 2B3-101 was overall well tolerated by athymic FVB mice with experimental human glioblastoma (luciferase transfected U87MG). In 2 independent experiments a strong inhibition of brain tumor growth was observed for 2B3-101 as measured by bioluminescence intensity. The effect of weekly administration of 5 mg/kg 2B3-101 was more pronounced compared to pegylated liposomal doxorubicin (p<0.05) and saline (p<0.01). Two out of 9 animals receiving 2B3-101 showed a complete tumor regression. Twice-weekly injections of 5 mg/kg 2B3-101 again had a significant effect in inhibiting brain tumor growth (p<0.001) compared to pegylated liposomal doxorubicin and saline, and a complete regression was observed in 1 animal treated with 2B3-101. In addition, twice-weekly dosing of 2B3-101 significantly increased the median survival time by 38.5% (p<0.001) and 16.1% (p<0.05) compared to saline and pegylated liposomal doxorubicin, respectively. Overall, these data demonstrate that glutathione pegylated liposomal doxorubicin enhances the effective delivery of doxorubicin to brain tumors and could become a promising new therapeutic option for the treatment of brain malignancies.

【 授权许可】

CC BY