Direct Intracerebral Delivery

Studies carried out by us have clearly demonstrated that the systemic route of administration is not suitable for delivery of boronated EGF or mAbs to glioma-bearing rats.75,165 Intravenous injection of technetium-99m labeled EGF to rats bearing intracerebral implants of the C6 rat glioma, which had been genetically engineered to express the human EGFR gene, resulted in 0.14% I.D. localizing in the tumor. Intracarotid (i.c.) injection with or without BBB disruption increased the tumor uptake from 0.34 to 0.45% I.D./g, but based even on the most optimistic assumptions the amount of boron that could be delivered to the tumor by i.v. injection, this would have been inadequate for BNCT.165 Direct i.t. injection of boronated EGF (BSD_EGF), on the other hand, resulted in tumor boron concentrations of 22 mg/g compared to 0.01 mg/g following i.v. injection and almost identical boron uptake values were obtained using the F98egfr glioma model.77 This was produced by transfecting F98 glioma cells with the gene encoding human EGFR. Based on our biodistribution results, therapy studies were initiated with the F98EGFR glioma in syngeneic Fischer rats. F98EGFR glioma bearing rats that received BSD_EGF i.t. had a MST of 45+ d compared to 33+2 d in animals that had EGFR( —) wildtype F98 gliomas. Because it is unlikely that any single boron delivery agent will be able to target all tumor cells, the combination of i.t. administration of BSD_EGF with i.v. injection of BPA was evaluated. This resulted in further increase in MST to 57 + 8 d compared to 39 + 2 d for i.v. BPA alone.73 These data provide proof-of-principle for the idea of using a combination of LMW and HMW boron delivery agents.

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