title: Enhanced doxorubicin delivery to the brain administered through glutathione PEGylated liposomal doxorubicin (2B3-101) as compared with generic Caelyx,(®)/Doxil(®)--a cerebral open flow microperfusion pilot study.
abstract: The neuroprotective blood-brain barrier (BBB) keeps many drug candidates below therapeutic levels in the central nervous system. Glutathione PEGylated liposomal doxorubicin (2B3-101) has been developed to safely enhance the delivery of doxorubicin to brain tumors. However, doxorubicin concentration in extracellular brain fluid cannot yet be reliably measured using conventional techniques. Cerebral open flow microperfusion (cOFM), a recently developed sampling technique, allows monitoring of drug concentrations in the brain independent of molecular weight and lipophilicity. In combination with cOFM sampling, sodium fluorescein (NaF) is used as a marker for BBB integrity. Rats received one intravenous dose of 7 mg/kg of either 2B3-101 or PEGylated liposomal doxorubicin (generic Caelyx(®)). Blood and cOFM sampling was performed for 5 h after dose injection. NaF concentration in the brain was monitored and remained low indicating an intact BBB. The brain-to-blood ratio of doxorubicin was 4.8-fold higher after administration of 2B3-101 as compared with generic Caelyx(®) (p = 0.0016). In conclusion, by using cOFM it was possible to show that 2B3-101 leads to enhanced doxorubicin concentration in the brain without affecting the BBB integrity.
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria. Electronic address: ca.health@joanneum.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Birngruber
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria.
authors.forename: Reingard
authors.initials: R
authors.lastname: Raml
authors.affiliation: to-BBB Technologies BV, Leiden, The Netherlands.
authors.forename: Werner
authors.initials: W
authors.lastname: Gladdines
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria.
authors.forename: Christina
authors.initials: C
authors.lastname: Gatschelhofer
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria.
authors.forename: Edgar
authors.initials: E
authors.lastname: Gander
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Arijit
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kroath
authors.affiliation: to-BBB Technologies BV, Leiden, The Netherlands.
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Gaillard
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria; Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.affiliation: HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research, Graz, Austria; Division of Endocrinology and Metabolism, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Frank
authors.initials: F
authors.lastname: Sinner
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D016903:Drug Monitoring / Q000379:methods; D019793:Fluorescein / Q000493:pharmacokinetics; D005978:Glutathione / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D007275:Injections, Intravenous; D008297:Male; D017551:Microdialysis / Q000379:methods*; D010477:Perfusion; D010539:Permeability; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: C000591311:glutathione pegylated liposomal doxorubicin; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005978:Glutathione; D019793:Fluorescein
keywords: 2B3-101; CNS; Caelyx®; Doxil®; blood brain barrier; cancer; cerebral open flow microperfusion; doxorubicin; drug targeting; liposomes