INTRACAROTID INFUSION OF RMP-7, A BRADYKININ ANALOG - A METHOD FOR SELECTIVE DRUG-DELIVERY TO BRAIN-TUMORS

The bradykinin analog, RMP-7, was investigated for its ability to sele ctively increase uptake of molecular tracers in RG2 glial tumors. When infused in low doses (0.1 mu g/kg/min) through the intracarotid arter y ipsilateral to RG2 gliomas in rats, RMP-7 significantly increased th e permeability of tumor capillaries to methotrexate and to four other tracers of varying molecular weights, compared to intracarotid infusio n of vehicle alone. Tracers used to examine permeability included radi olabeled alpha-aminoisobutyric acid (M(r) 103 D), sucrose (M(r) 342 D) , methotrexate (M(r) 454.5 D), inulin (M(r) 5000 D), and dextran (M 70 ,000 D). Permeability was expressed as the unidirectional transfer; co nstant, K-i (mu l/gm/min). The permeability (K-i) of tumors in the RMP -7 group compared to the vehicle control group was as follows: alpha-a minoisobutyric acid, 35.3 +/- 9.11 versus 12.7 +/- 4.56 (p < 0.001); s ucrose, 16.5 +/- 3.83 versus 9.28 +/- 3.12 (p < 0.05); methotrexate, 2 6.3 +/- 10.3 versus 8.98 +/- 6.78 (p < 0.005); inulin, 13.5 +/- 3.23 v ersus 6.55 +/- 4.32 (p < 0.005); dextran, 15.2 +/- 3.42 versus 1.47 +/ - 1.24 (p < 0.001). The permeability of RG2 gliomas to high-molecular- weight dextran (70,000 D) was 10.3-fold higher in the RMP-7 group than in the vehicle control group. Intracarotid infusion of RMP-7 did not significantly increase the blood volume in tumor or brain tissue. The permeability of normal brain capillaries was unaffected by intracaroti d infusion of 0.1 mu g/kg/min RMP-7 relative to that achieved in tumor . These data support the idea that intracarotid infusion of RMP-7 will be a useful technique for selective delivery of antitumor compounds t o brain tumors.