Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries.
1. The blood-brain barrier (BBB) represents the major impediment to successful delivery of therapeutic agents to target tissue within the central nervous system. Intracarotid alkylglycerols have been shown to increase the transfer of chemotherapeutics across the BBB. 2. We investigated the spatial distribution of intracarotid fluorescein sodium and intravenous lissamine-rhodamine B200 (RB 200)-albumin in the brain of normal and C6 glioma-bearing rats after intracarotid co-administration of 1-O-pentylglycerol (200 mm). To elucidate the mechanisms involved in the alkylglycerol-mediated BBB opening, intraluminal accumulation of fluorescein isothiocyanate (FITC)-dextran 40,000 was studied in freshly isolated rat brain capillaries using confocal microscopy during incubation with different alkylglycerols. Furthermore, 1-O-pentylglycerol-induced increase in delivery of methotrexate (MTX) to the brain was evaluated in nude mice. 3. Microscopic evaluation showed a marked 1-O-pentylglycerol-induced extravasation of fluorescein and RB 200-albumin in the ipsilateral normal brain. In glioma-bearing rats, increased tissue fluorescence was found in both tumor tissue and brain surrounding tumor. Confocal microscopy revealed a time- and concentration-dependent accumulation of FITC-dextran 40,000 within the lumina of isolated rat brain capillaries during incubation with 1-O-pentylglycerol and 2-O-hexyldiglycerol, indicating enhanced paracellular transfer via tight junctions. Intracarotid co-administration of MTX and 1-O-pentylglycerol (200 mm) in nude mice resulted in a significant increase in MTX concentrations in the ipsilateral brain as compared to controls without 1-O-pentylglycerol (P<0.005). 4. In conclusion, 1-O-pentylglycerol increases delivery of small and large compounds to normal brain and brain tumors and this effect is mediated at least in part by enhanced permeability of tight junctions.
Kinderklinik der Universität at Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany. erdlenbr@med.uni-goettingen.de
Bernhard
B
Erdlenbruch
Mehrnaz
M
Alipour
Gert
G
Fricker
David S
DS
Miller
Wilfried
W
Kugler
Hansjörg
H
Eibl
Max
M
Lakomek
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002196:Capillaries; D019793:Fluorescein; D005456:Fluorescent Dyes; D005910:Glioma / Q000378:metabolism* / Q000473:pathology; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D007269:Injections, Intra-Arterial; D007276:Injections, Intraventricular; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D009368:Neoplasm Transplantation; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
C468006:1-O-pentylglycerol; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005456:Fluorescent Dyes; D005990:Glycerol; D019793:Fluorescein; D008727:Methotrexate