Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7.
Previous studies have shown that the bradykinin agonist, RMP-7, can safely permeabilize the blood brain barrier (BBB) by activation of constitutive B2 receptors on endothelial cells. The paper describes a series of studies using quantitative autoradiography and intracarotid infusions of RMP-7 to further elucidate the effect on BBB permeability. Because earlier studies also demonstrated that even greater effects of RMP-7 were observed in the BBB associated with brain tumors, animal models were employed so that comparisons could be made between the effects of RMP-7 within tumor, brain tissue proximal to tumor, and brain tissue distal from tumor. In the first study, the effect of RMP-7 on enhancing the BBB permeation of three compounds of different physical characteristics was directly compared ([14C]carboplatin, small, hydrophilic; [14C]dextran, large, hydrophilic; [14C]BCNU, small, lipophilic). RMP-7 increased permeability of the vascular barriers to both hydrophilic compounds, carboplatin and dextran. While the effects of RMP-7 were observed on nontumor BBB, the greatest and most consistent effects were observed on the blood brain tumor barrier. This was true for both carboplatin and dextran, with progressively less effect seen as the distance from tumor boundary increased. This topographic effect was more pronounced with the larger molecular weight compound, dextran. No effect of RMP-7 was seen in permeabilizing the BBB or the blood brain tumor barrier for the lipophilic drug, BCNU. In a second study, the generality of RMP-7's effects was established by demonstrating similar increases in permeability to carboplatin in both inbred (Fischer 344) and outbred (Wistar) rat strains, implanted with varying tumor cell lines. Finally, several additional studies were performed to gain greater insight into the dynamics involved with eventual restoration of the BBB following RMP-7 administration. In one series, it was demonstrated that the BBB begins to close nearly immediately upon withdrawal of RMP-7, with complete restoration occurring within minutes. In another series, tachyphylaxis or desensitization resulting from continuous RMP-7 infusion was studied. These studies demonstrated that 60 min of continuous RMP-7 infusion resulted in complete, spontaneous restoration of the barrier to both carboplatin and dextran. Moreover, the desensitization appears to be linked to the initial activation of the receptors in a way which suggests that obligatory desensitization may exist as part of a more complete response. These data are discussed as they relate to practical issues to enhance delivery of drugs across the BBB, as well as more fundamental issues involving the function of the BBB and its interaction with the brain.
Bartus
R T
RT
Alkermes Inc., Cambridge, Massachusetts 02139, USA.
Elliott
P J
PJ
Dean
R L
RL
Hayward
N J
NJ
Nagle
T L
TL
Huff
M R
MR
Snodgrass
P A
PA
Blunt
D G
DG
D000818:Animals; D001345:Autoradiography; D015415:Biomarkers; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001920:Bradykinin / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D001932:Brain Neoplasms; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D016190:Carboplatin / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics*; D002330:Carmustine / Q000493:pharmacokinetics*; D003911:Dextrans / Q000493:pharmacokinetics*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D009368:Neoplasm Transplantation; D010952:Plasma Substitutes / Q000493:pharmacokinetics*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D015415:Biomarkers; D002250:Carbon Radioisotopes; D002273:Carcinogens; D003911:Dextrans; D010952:Plasma Substitutes; C089876:RMP 7; D016190:Carboplatin; D001920:Bradykinin; D002330:Carmustine