Convection-enhanced delivery of boronated epidermal growth factor for molecular targeting of EGF receptor-positive...

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 micro l/min for 15, 30, and 60 min [infusion volumes (V(I)) of 5, 10, and 20 micro l, 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 (125)I-boronated EGF in tumor or brain was studied by quantitative autoradiography and gamma-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 micro l with corresponding V(i) ranging from 5 to 20 micro l. The V(d) of BD-EGF in the brain was 64.8 +/- 13.4 micro l with CED (V(i) 10 micro ), and the V(d):V(i) ratio was 6.5 compared with a V(d) of 9.4 +/- 1.6 micro l and a V(d):V(i) ratio of 0.9 after direct intracerebral injection. As determined by quantitative autoradiography and gamma-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.