Selective targeting of boronophenylalanine to melanoma in BALB/c mice for neutron capture therapy

Abstract

Melanoma cells actively accumulate aromatic amino acids for use as precursors in the synthesis of the pigment melanin. Using the Harding-Passey melanoma carried s.c. in BALB/c mice, we have demonstrated that p-boronophenylalanine (BPA) is taken up by melanoma tissue to a much greater extent than by normal tissues. Following a single i.p. injection, or a series of injections given over 1 h, the accumulation of boron in melanoma was found to be transient, reaching a maximum approximately 6 h postinjection. The concentrations of boron achieved in tumor ranged from 9-33 micrograms/g, and are within the range estimated to be necessary for successful application of the nuclear reaction 10B(n,alpha)7Li for neutron capture therapy. Boron concentrations in tumor and tissues were determined using either a prompt-gamma spectroscopic technique or by quantitative neutron capture radiography using whole-body sections. Distribution studies with the resolved stereoisomers of BPA indicated that the L isomer is preferentially accumulated in the melanoma compared to the D isomer. The L isomer of BPA was shown to be targeted to actively dividing tumor cells by simultaneously comparing the boron and [3H]thymidine distribution in tumor. Under conditions which selectively deliver high concentrations of boron to Harding-Passey melanomas in BALB/c mice, BPA did not deliver useful concentrations of boron to a mammary adenocarcinoma in Hale-Stoner mice. These results, along with the selectivity of the Harding-Passey melanoma for the L isomer of BPA, are consistent with our working hypothesis that BPA is actively transported into the melanomas as an analogue of natural melanin precursors.