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Convection-enhanced Delivery of Boronated Epidermal Growth Factor for Molecular Targeting of EGF Receptor-positive Gliomas¹

Department of Pathology [W. Y., R. F. B., D. M. A.], College of Pharmacy [S. S., W. T.], and Department of Internal Medicine [M. A. C.], The James Cancer Hospital and Comprehensive Cancer Center [R. F. B., M. A. C.], The Ohio State University, Columbus, Ohio 43210, and Department of Neurosurgery, Roswell Park Cancer Institute, Buffalo, New York 14263 [M. J. C., R. A. F.]

Convection enhanced delivery (CED) is potentially a powerful method to improvethe targeting of macromolecules to the central nervous system by applying a pressure gradient to establish bulk flow through the brain interstitium during infusion. The purpose of the present study was to evaluate CED as a means to improve the intracerebral and intratumoral (i.t.) uptake of a heavily boronated macromolecule (dendrimer; BD) linked to epidermal growth factor (EGF) for neutron capture therapy in rats bearing a syngeneic epidermal growth factor receptor (EGFR) + glioma. Boronated EGF was radiolabeled with ¹²⁵I and administered by CED at a rate of 0.33 µl/min for 15, 30, and 60 min [infusion volumes (V_I) of 5, 10, and 20 µl, respectively], using a syringe pump connected to an indwelling cannula implanted into the right caudate nucleus of normal rats or i.t. in rats bearing either F98_EGFR or F98 wild-type (F98_WT) gliomas. After infusion, rats were euthanized, and their brains were removed and serially sectioned. The uptake and biodistribution of ¹²⁵I-boronated EGF in tumor or brain was studied by quantitative autoradiography and -scintillation counting. The volume of distribution (V_d) in brain was assessed using a computer interfaced image analysis system. After CED, the V_d increased from 34.4 to 123.5 µl with corresponding V_i ranging from 5 to 20 µl. The V_d of BD-EGF in the brain was 64.8 ± 13.4 µl with CED (V_i 10 µ), and the V_d:V_i ratio was 6.5 compared with a V_d of 9.4 ± 1.6 µl and a V_d:V_i ratio of 0.9 after direct intracerebral injection. As determined by quantitative autoradiography and -scintillation counting at 24 h after CED, 47.4% of the injected dose per gram tissue (%ID/g) was localized in F98_EGFR gliomas compared with 33.2%ID/g after direct i.t. injection and 12.3%ID/g in F98_WT gliomas. On the basis of these observations, we have concluded that CED is more effective than i.t. injection as a way to deliver boronated EGF to EGFR (+) gliomas for boron neutron capture therapy.

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