Bradykinin Selectively Opens Blood-Tumor Barrier in Experimental Brain Tumors

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Abstract
Bradykinin, infused in low doses (10 μg/kg/min) through the carotid artery ipsilateral to RG2 glioma in rats, significantly increased the permeability in tumor capillaries to six different tracers of varying molecular weights compared with intracarotid infusion of saline alone. Permeability in normal brain capillaries was not significantly increased by intracarotid bradykinin infusion. Tracers used to examined permeability included radiolabeled α-aminoisobutyric acid (AIB; MW 103), sucrose (MW 342.3), inulin (MW 5000), and dextran (MW 70,000), horseradish peroxidase (HRP) and Evans blue (EB). Permeability was expressed as the unidirectional transfer constant Ki (μl/g/min). The permeabilities ( Ki) of tumors in the bradykinin group versus the control saline group for AIB, sucrose, inulin, and dextran were 25.91 ± 6.78 vs. 13.95 ± 4.29 (p < 0.01), 17.90 ± 2.65 vs. 10.75 ± 4.55 (p < 0.01), 23.92 ± 6.99 vs. 6.20 ± 4.37 (p < 0.01), and 17.84 ± 1.00 vs. 1.47 ± 1.24 (p < 0.001), respectively (mean ± SD). Permeability of RG2 gliomas to high molecular weight dextran (70,000) was 12-fold higher in the bradykinin group than in the saline infusion group. Intracarotid infusion of bradykinin did not significantly increase the blood volume in tumor or brain tissue despite its known vasodilative effect. The permeability of normal brain capillaries was unaffected by intracarotid bradykinin infusion. The increased permeability was reversed 20 min after stopping the intracarotid infusion. Electron microscopic and gross qualitative analysis was performed using HRP and EB. Intracarotid bradykinin infusion increased HRP and EB within tumor tissue but not normal tissue. We believe that intracarotid infusion of bradykinin will be a useful technique for selective delivery of antitumor compounds to brain tumors.