title: Pharmacokinetics, brain delivery, and efficacy in brain tumor-bearing mice of glutathione pegylated liposomal doxorubicin (2B3-101).
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.
authors.affiliation: to-BBB technologies BV, Leiden, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Gaillard
authors.affiliation: to-BBB technologies BV, Leiden, The Netherlands.
authors.forename: Chantal C M
authors.initials: CC
authors.lastname: Appeldoorn
authors.affiliation: to-BBB technologies BV, Leiden, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Dorland
authors.affiliation: to-BBB technologies BV, Leiden, The Netherlands.
authors.forename: Joan
authors.initials: J
authors.lastname: van Kregten
authors.affiliation: to-BBB technologies BV, Leiden, The Netherlands.
authors.forename: Francesca
authors.initials: F
authors.lastname: Manca
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Danielle J
authors.initials: DJ
authors.lastname: Vugts
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Windhorst
authors.affiliation: Department of Radiology and Nuclear Medicine, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Guus A M S
authors.initials: GA
authors.lastname: van Dongen
authors.affiliation: Blood-Brain Barrier Research Group, Molecular Cell Biology and Immunology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Helga E
authors.initials: HE
authors.lastname: de Vries
authors.affiliation: to-BBB technologies BV, Leiden, The Netherlands.
authors.forename: David
authors.initials: D
authors.lastname: Maussang
authors.affiliation: The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AvL), Amsterdam, The Netherlands.
authors.forename: Olaf
authors.initials: O
authors.lastname: van Tellingen
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000648:ultrastructure; D002196:Capillaries / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution / Q000187:drug effects; D016896:Treatment Outcome
chemical_list: C000591311:glutathione pegylated liposomal doxorubicin; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005978:Glutathione