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

• Published in: PloS one Vol. 9; no. 1; p. e82331
• Main Authors: Gaillard, Pieter J, Appeldoorn, Chantal C M, Dorland, Rick, van Kregten, Joan, Manca, Francesca, Vugts, Danielle J, Windhorst, Bert, van Dongen, Guus A M S, de Vries, Helga E, Maussang, David, van Tellingen, Olaf
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08-01-2014; Public Library of Science (PLoS)
• Subjects: Animals; Anthracyclines; Antioxidants; Bioluminescence; Blood-brain barrier; Body Weight - drug effects; Brain - blood supply; Brain - drug effects; Brain - pathology; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Brain Neoplasms - ultrastructure; Brain research; Brain tumors; Breast cancer; Cancer; Cancer therapies; Capillaries - pathology; Cell Proliferation - drug effects; Chemotherapy; Diffusion barriers; Disease control; Doxorubicin; Doxorubicin - analogs & derivatives; Doxorubicin - blood; Doxorubicin - pharmacokinetics; Doxorubicin - pharmacology; Doxorubicin - therapeutic use; Drug delivery; Drug Delivery Systems; Drug therapy; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Glioblastoma; Glioblastoma - drug therapy; Glioblastoma - pathology; Gliomas; Glutathione; Glutathione - analogs & derivatives; Glutathione - blood; Glutathione - pharmacokinetics; Glutathione - pharmacology; Glutathione - therapeutic use; Humans; Inhibition; Medical prognosis; Medical treatment; Metastasis; Mice; Mice, Nude; Neurosciences; Nuclear medicine; Pharmacokinetics; Pharmacology; Plasma physics; Polyethylene Glycols - pharmacokinetics; Polyethylene Glycols - pharmacology; Polyethylene Glycols - therapeutic use; Studies; Survival Analysis; Thiols; Time Factors; Tissue Distribution - drug effects; Treatment Outcome; Tumors; Xenobiotics; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0082331

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.