Differential permeability of a human brain tumor xenograft in the nude rat: impact of tumor size and method of administration on optimizing delivery of biologically diverse agents.
To assess how to maximize drug delivery to intracerebral tumors and surrounding brain, this study examined the effects of route and method of administration and tumor size on the distribution of three agents in a nude rat intracerebral tumor xenograft model. Aminoisobutyric acid (M(r) 103), methotrexate (M(r) 454), and dextran 70 (M(r) 70,000) were administered i.v. or intra-arterially (i.a.) with or without osmotic blood-brain barrier disruption (BBBD) at 8, 12, or 16 days after tumor cell inoculation (n = 72). A 2.2- to 2.5-fold increase in delivery to tumor and surrounding brain was observed when i.a. was compared with i.v., and a 2.5- to 7.6-fold increase was observed when BBBD was compared with the saline control. The combined effect of i.a. administration and BBBD was to increase delivery 6.3-16.7-fold. The greatest benefit of BBBD was seen in animals with 8-day tumors, whereas BBBD had less benefit in improving delivery to intracerebral tumor and brain around tumor as the tumors grew larger. Regional delivery decreased as the molecular weight of the agent increased. Based on these results, we suggest that i.a. administration of antitumor agents may be adequate to obtain initial responses in large, very permeable, intracerebral tumors. However, in smaller, less permeable tumors or after an initial response to treatment, there may be a significant therapeutic advantage to i.a. agent administration and BBBD.
Neuwelt
E A
EA
Department of Neurology, Oregon Health Sciences University, Portland 97201-3098, USA.
Barnett
P A
PA
McCormick
C I
CI
Remsen
L G
LG
Kroll
R A
RA
Sexton
G
G
D000621:Aminoisobutyric Acids / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000556:secondary; D018288:Carcinoma, Small Cell / Q000378:metabolism / Q000473:pathology*; D003911:Dextrans / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007269:Injections, Intra-Arterial; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D008727:Methotrexate / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010539:Permeability; D051381:Rats; D011923:Rats, Nude; D012044:Regression Analysis; D014183:Transplantation, Heterologous; D014316:Tritium; D014407:Tumor Cells, Cultured
D000621:Aminoisobutyric Acids; D003911:Dextrans; D014316:Tritium; D008727:Methotrexate