Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101)

PLoS One. 2014 Jan 8;9(1):e82331. doi: 10.1371/journal.pone.0082331. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Brain / blood supply
  • Brain / drug effects
  • Brain / pathology*
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / pathology
  • Brain Neoplasms / ultrastructure
  • Capillaries / pathology
  • Cell Proliferation / drug effects
  • Doxorubicin / analogs & derivatives*
  • Doxorubicin / blood
  • Doxorubicin / pharmacokinetics
  • Doxorubicin / pharmacology
  • Doxorubicin / therapeutic use
  • Drug Delivery Systems*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Female
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology
  • Glutathione / analogs & derivatives*
  • Glutathione / blood
  • Glutathione / pharmacokinetics
  • Glutathione / pharmacology
  • Glutathione / therapeutic use
  • Humans
  • Mice
  • Mice, Nude
  • Polyethylene Glycols / pharmacokinetics
  • Polyethylene Glycols / pharmacology
  • Polyethylene Glycols / therapeutic use
  • Survival Analysis
  • Time Factors
  • Tissue Distribution / drug effects
  • Treatment Outcome

Substances

  • glutathione pegylated liposomal doxorubicin
  • liposomal doxorubicin
  • Polyethylene Glycols
  • Doxorubicin
  • Glutathione

Grant support

All of the work presented in this manuscript was supported by to-BBB technologies BV (http://www.tobbb.com/). DJ Vugts, B Windhorst, GAMS van Dongen, HE de Vries, and O van Tellingen have received research funding from to-BBB technologies for their part of the work. Other than through the scientific input of their participating employees, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.