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Article

Biodistribution of Boron Compounds in an Animal Model of Human Undifferentiated Thyroid Cancer for Boron Neutron Capture Therapy

M. Alejandra Dagrosa,^† Mabel Viaggi,^† Raul Jimenez Rebagliati,^‡ Daniel Batistoni,^‡ Stephen B. Kahl,*^§ Guillermo J. Juvenal,^† and Mario A. Pisarev^†

Departments of Radiobiology and Chemistry, National Atomic Energy Commission, Buenos Aires, Argentina, Department of Biochemistry, University of Buenos Aires, School of Medicine, Buenos Aires, Argentina, and Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143

Mol. Pharm. , 2005, 2 (2), pp 151–156

DOI: 10.1021/mp049894a

Publication Date (Web): February 19, 2005

†

Department of Radiobiology, National Atomic Energy Commission.

‡

Department of Chemistry, National Atomic Energy Commission.

Corresponding author. Mailing address: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94143-0446. Tel: 415-476-4684. Fax: 415-476-4684. E-mail: sbkahl@itsa.ucsf.edu.

University of California.

University of Buenos Aires, School of Medicine.

Address reprint requests to M.A.P. Mailing address: Department of Radiobiology, CNEA, Av del Libertador 8250, Buenos Aires 1429, Argentina. Fax: 5411-6772-7121. E-mail: pisarev@cnea.gov.ar.

Abstract

Undifferentiated thyroid carcinoma (UTC) is a rapidly growing, highly invasive malignant tumor that currently lacks any effective treatment. Boron neutron capture therapy (BNCT) has been investigated recently for some types of tumors including glioblastoma multiforme and malignant melanoma. In previous studies we have shown the selective uptake of p-boronophenylalanine (BPA) by undifferentiated thyroid cancer cells in vitro and in vivo, as well as the histologic cure of 50% of the nude mice transplanted with human UTC cells when treated with BPA and an appropriate neutron beam. The present studies were performed to further optimize this treatment through the investigation of a boronated porphyrin, both alone and in combination with BPA. In vitro studies with cells in culture showed that BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(α,β-dihydroxyethyl)-deutero-porphyrin IX) is localized intracellularly, with a highest concentration in the 11500g (mitochondrial-enriched pellet) fraction. When BOPP was administered alone to NIH nude mice transplanted with UTC human cells, no significant tumor uptake or selectivity in our in vivo model was observed. In contrast, when BOPP was injected 5−7 days before BPA and the animals were sacrificed 60 min after administration of BPA, a significant increase in boron uptake by the tumor was found (38−45 ppm with both compounds vs 20 ppm with BPA alone). On day 5 the tissue boron selectivity ratios were tumor/blood 3.8 and tumor/distal skin 1.8. Other important ratios were tumor/thyroid 6.6 and tumor/lung 2.9. These results open the possibility of improving the efficacy of BNCT for the treatment of this so far “orphan” tumor.