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

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-(alpha,beta-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 approximately 3.8 and tumor/distal skin approximately 1.8. Other important ratios were tumor/thyroid approximately 6.6 and tumor/lung approximately 2.9. These results open the possibility of improving the efficacy of BNCT for the treatment of this so far "orphan" tumor.

Boron neutron capture therapy in cancer: past, present and future

“…from 1-7 days before BPA and the boron uptake was measured 60 min after BPA administration. We observed that the combination of 5 days after BOPP and 60 min after BPA the boron uptake was 45 ppm, doubling the results obtained with BPA alone (10).…”

Design, Synthesis, Selective Recognition Properties and Targeted Drug Delivery Application

“…Intensive research has led to the design and study of many porphyrin conjugates with carborane units, such as porphyrins substituted in their meso-positions 292,343-359 and on the porphyrin core itself, 360 or protoporphyrin IX derivatives such as BOPP (the tetrakis-carborane carboxylate ester of 2,4-bis-(1,2-dihydroxyethyl)deuteroporphyrin IX) (Figures 36-38). [361][362][363][364][365][366][367][368] An interesting result was obtained by Perona et al using BOPP as a radiosensitizer. 369 They found that cancer cells (WRO, follicular cancer cell line) displayed approximately three times higher sensitivity for BNCT than normal control cells.…”

First Evaluation of the Biologic Effectiveness Factors of Boron Neutron Capture Therapy (BNCT) in a Human Colon Carcinoma Cell Line

“…Although these drugs are safe, they can deliver to the tumor only a limited amount of boron, and therefore other new boron compounds, such as boronated porphyrins, are being analyzed. Tetrakiscarborane carboxylate ester of 2,4-bis-(a,b-dihydroxyethyl)-deutero-porphyrin IX (BOPP) has been shown to be a good boron carrier in different animal models (4,5). Recently BNCT has also been applied to the treatment of liver metastases of colon cancer.…”