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In Vitro Determination of Uptake, Retention, Distribution, Biological Efficacy, and Toxicity of Boronated Compounds for Neutron Capture Therapy: A Comparison of Porphyrins with Sulfhydryl Boron Hydrides¹

Brookhaven National Laboratory, Upton, New York 11973 [R. G. F., B. H. L., J. K-E., E. A. P.]; University of California, San Francisco, California 94143 [S. B. K.]; and University of Ioannina, Ioannina, 451.10 Greece [J. K-E.]

A major problem remaining in the evaluation of boronated compounds for neutron capture therapy (NCT) is the need to know the intra- or extracellular microdistribution of boron. This is a consequence of the short range of the ¹⁰B(n,)⁷Li reaction products (10 µm), such that biological efficacy is dependent upon intracellular distribution. In particular, if boron location is predominantly extracellular, a significant reduction in efficacy would be expected.

The in vitro procedure described here was developed mainly to provide information regarding the intra- and extracellular location and concentration of boron. However, use of the technique also allows the measurement of compound uptake and retention (binding) and the determination of biological efficacy by the evaluation of survival curves obtained following irradiation with thermal neutrons. Comparison is made to results obtained with boric acid (H₃¹⁰BO₃) and to results calculated for various boron distributions. Concomitantly, an indication of compound toxicity can be obtained from the plating efficiency of unirradiated control cells.

Currently, most investigators utilize in vivo systems for testing and evaluating boron uptake from various carrier molecules. Given the large number of boron compounds being synthesized and needing evaluation as to their usefulness for NCT, the in vitro technique described here is simple and advantageous for initial compound screening. In addition to sparing animal lives, it is both time and cost effective and utilizes much smaller quantities of test compound than are required for an in vivo assay.

A boronated porphyrin (BOPP) evaluated by the above procedure shows an uptake and retention 20 times that of sulfhydryl boron hydride monomer (BSH); the latter compound is currently being used clinically for NCT in Japan and is anticipated for use in clinical trials in the United States. If the advantages demonstrated by BOPP in these in vitro studies are validated in animal experiments, BOPP should be considered for clinical application.

¹ Research carried out under the auspices of the United States Department of Energy under contract DE-AC02-76CH00016 and contract CA 37961 with NIH.

² To whom requests for reprints should be addressed, at Medical Department, Brookhaven National Laboratory, Associated Universities, Upton, Long Island, NY 11973.

Received 1/ 3/90. Revised 4/11/90.

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