Clinical Considerations And Conclusions

In this review we have focused on HMW boron delivery agents and nanovehicles that potentially could be used clinically for targeting intra- and extracranial tumors. Studies carried out in glioma bearing rats have demonstrated that boronated EGF and the mAb, cetuximab, both of which bind to EGFR, selectively targeted receptor ( + ) tumors following direct i.c. delivery. Furthermore, following BNCT, a significant increase in MST was observed, and this was further enhanced if BPA was administered in combination with the HMW agents. These studies provide proof-of-prin-ciple first for the potential utility of HMW agents, and second, the therapeutic gain associated with the combination of HMW and LMW boron delivery agents.

There is a question as to whether or not any of these agents will ever be used clinically. Critical issues must be addressed if BNCT is to ever become a useful modality for the treatment of cancer. Large clinical trials, preferably randomized, must be carried out to convincingly demonstrate the efficacy of BPA and BSH, the two drugs that currently are being used. Once efficacy has been established, studies with HMW EGFR targeting agents could move forward.

Both direct i.t. injection174,175 and CED170,176-179 have been used clinically to deliver mAbs and toxin fusion proteins to patients who have had surgical resection of their brain tumors. These studies provide a strong clinical rationale for the direct intracerabral delivery of HMW agents. Initially, the primary focus should be on determining the safety of administering them to patients prior to surgical resection of their brain tumors. After this has been established, then biodistribution studies could be carried out in patients scheduled to undergo surgical resection of their brain tumors. The patients' tumor and normal tissues would then be analyzed for their boron content, and if there was evidence of preferential tumor localization with boron concentrations in the range 10-20 mg/g and normal brain concentrations of less than 5 mg/g, then therapy studies could be undertaken.

Because there is considerable variability in EGFR expression in gliomas, it is highly unlikely that any single agent will be able to deliver the requisite amount of boron to all tumor cells, and that HMW agents would need to be used in combination with BPA/BSH. This general plan would also be applicable to the other HMW delivery agents and nanovehicles that have been discussed in this review. The joining together of chemistry and nanotechnology180,181 represents a major step forward for the development of effective boron delivery agents for NCT. Nanovehicles offer the possibility of tumor targeting with enhanced boron payloads. Potentially, this could solve the central problem of how to selectively deliver large number of boron atoms to individual cancer cells.

As can be seen from the preceding discussion, the development of HMW boron delivery agents must proceed in step with strategies to optimize their delivery and an appreciation as to how they would be used clinically. Intracerebral delivery has been used in clinically advanced settings, but nuclear reactors, which currently are the only source of neutrons for BNCT, would not be conducive to this. Therefore, the development of accelerator-neutron sources,182 which could be easily sited in hospitals, is especially important. This also would facilitate the initiation of large scale clinical trials at selected centers that treat large numbers of patients with brain tumors and would permit evaluation of new boron delivery agents.

In conclusion, there is a plethora of HMW boron delivery agents that have been designed and synthesized. The challenge is to move from experimental animal studies to clinical biodistribution studies, a step which has yet to be taken.

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