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

被引：200

作者：

Gaillard, Pieter J. ^{[1
]}

Appeldoorn, Chantal C. M. ^{[1
]}

Dorland, Rick ^{[1
]}

van Kregten, Joan ^{[1
]}

Manca, Francesca ^{[1
]}

Vugts, Danielle J. ^{[2
]}

Windhorst, Bert ^{[2
]}

van Dongen, Guus A. M. S. ^{[2
]}

de Vries, Helga E. ^{[3
]}

Maussang, David ^{[1
]}

van Tellingen, Olaf ^{[4
]}

机构：

[1] To BBB Technol BV, Leiden, Netherlands

[2] Vrije Univ Amsterdam Med Ctr, Dept Radiol & Nucl Med, Amsterdam, Netherlands

[3] Vrije Univ Amsterdam Med Ctr, Blood Brain Barrier Res Grp, Amsterdam, Netherlands

[4] Antoni van Leeuwenhoek Hosp NKI AvL, Netherlands Canc Inst, Amsterdam, Netherlands

来源：

PLOS ONE | 2014年 / 9卷 / 01期

关键词：

MALIGNANT GLIOMA; CHEMOTHERAPY; TRANSPORT; BARRIER; CELLS; MODEL; BIODISTRIBUTION; ADRIAMYCIN; PACLITAXEL; METASTASES;

D O I：

10.1371/journal.pone.0082331

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

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 (R)/Caelyx (R)), 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.

引用

页数：10

共 49 条

[1]

Function of the Blood-Brain Barrier and Restriction of Drug Delivery to Invasive Glioma Cells: Findings in an Orthotopic Rat Xenograft Model of Glioma [J].