Biology contribution
Intra-arterial administration of sodium borocaptate (BSH)/lipiodol emulsion delivers B-10 to liver tumors highly selectively for boron neutron capture therapy: experimental studies in the rat liver model

https://doi.org/10.1016/j.ijrobp.2003.12.018Get rights and content

Abstract

Purpose

Boron neutron capture therapy (BNCT) is particle radiotherapy with alpha (4He) particle and recoiled lithium nucleus (7Li) derived from a reaction of boron (10B) and thermal neutron. We investigated applying BNCT to malignant liver tumors. The purpose of the present study was to reveal the efficacy for administration of emulsion of a boron compound (sodium borocaptate; BSH) and lipiodol via a hepatic artery using a rat liver tumor model.

Methods and materials

Rat liver tumors were developed by direct injection of Walker 256 cells into the liver parenchyma. BSH (75 mg/kg)/lipiodol (0.3 mL/kg) emulsion was administered via the hepatic artery. Boron concentrations in the tumors, liver, and blood were measured at 1, 6, and 12 h after administration. Neutron capture radiography (NCR) was taken to confirm the selective accumulation of 10B in the liver tumors.

Results

Boron concentrations in the liver tumors and the tumor/liver (T/L) boron concentration ratio at 1, 6, and 12 h after administration of BSH/lipiodol emulsion (concentration: T/L ratio) were 479.2 ppm: 4.0, 197.3 ppm: 14.9, and 96.5 ppm: 6.6, respectively. Highly selective irradiation was clearly demonstrated by the NCR images.

Conclusions

Intra-arterial administration of BSH/lipiodol emulsion is effective method for delivering high concentration of 10B selectively to the liver tumors.

Introduction

Boron neutron capture therapy (BNCT) is based on the nuclear reaction as follows; nonradioactive isotope 10B atoms that absorbed low-energy (<0.5 eV) neutrons disintegrate into an alpha (4He) particle and a recoiled lithium nucleus (7Li). These particles deposit high energy along their very short path (less than 10 μm) (1). For BNCT to be successful, a sufficient number of 10B atoms must be accumulated in the tumors and the gradient of the amount of 10B atoms between the tumors and surrounding normal tissues must be large.

In a clinical trial of BNCT for brain tumors, sodium borocaptate (BSH) as a boron carrier has been used in Europe and Japan 2, 3, 4, 5, 6. Goodman et al. published detailed pharmacokinetics and biodistribution findings on BSH used for treating 23 patients with malignant gliomas by intravenous infusion (7). In Goodman's study, the boron concentration in blood, skin, and muscle were 62.6, 43.1, and 39.2 ppm during 3 to 7 h after administration of BSH at a dose of 50 mg boron/kg (88.2 mg BSH/kg), respectively. These values were higher than that for glioblastoma multiform (17.1 ppm). The boron concentration ratio for tumor/blood, skin, and muscle were 0.27, 0.40, and 0.44, respectively. Kageji et al. reported that BSH moves easily from the circulation into peripheral organs and is retained there and eliminated very slowly (6). The high accumulation of BSH in normal tissues is one of the difficult problems for BNCT application to other extracranial sites.

We investigated the possibility of application of BNCT to malignant liver tumors. Our previous study using mice liver tumor models demonstrated that p-boronophenylalanine, another boron delivery compound used clinically, is more suitable than BSH from the viewpoint of therapeutic gain factor (8). In our previous findings, a high boron concentration in normal liver after administration of BSH was a serious problem.

To overcome the problem of high accumulation of BSH in the normal liver tissues, we attempted to deliver BSH via a hepatic artery. The reason for intra-arterial administration was as follows. The liver receives a double blood flow via both the portal vein and hepatic artery. The former constitutes two thirds of the total blood flow in the liver. Liver tumors, especially hepatic cellular carcinoma, receive mainly hepatic arterial flow, whereas normal liver receives portal vein flow (9). Thus intra-arterial administration of BSH may accumulate more in the tumor than in normal liver.

Another attempt to increase the boron concentration in the liver tumor was to use lipiodol, which is an iodinated and esterified lipid of poppy seed oil. Lipiodol administered with chemotherapeutic agents via the hepatic artery is selectively accumulated in liver tumors 10, 11, 12. Joeng et al.(13) explained the reason for selective accumulation of lipiodol in live tumors by different features between normal and tumor vessels. The low flow rate of the tumor vessels resulting from their increased curvature, lower elasticity, and decreased regulation leads to the congestion of lipiodol inside the tumor vessels. Because of selective embolization of the tumor vessels with lipiodol, chemotherapeutic agents can remain in liver tumors and come in contact with tumor cells for long periods. Therefore, intra-arterial administration of boron compounds/lipiodol emulsion may augment the accumulation of the boron compound in the liver tumor and lead to a high boron concentration in the tumor. The purpose of the present study was to reveal the pharmacokinetics of BSH administered intra-arterially with or without lipiodol and to clarify the possibility for application of BNCT to liver tumors.

Section snippets

Animals and tumor cell line

All procedures for animal experiments were carried out in accordance with the regulations of Kyoto University animal facility regarding animal care and handling. Female Wistar rats weighing 180–220 g were used. Walker 256 cells, a rat breast cancer cell line, were maintained in vitro in RPM-1640 containing 10% fetal bovine serum. Walker 256 cells were provided by Cell Resource Center for Biomedical Research, Tohoku University.

Inoculation

Walker 256 cells were collected from monolayer cultures, and

BSH distribution in the BSH/lipiodol emulsion

Separation of physiologic saline and lipiodol was observed within 5 min of the mixture of BSH solution (1000 ppm) and lipiodol. Figure 1 shows that the almost all of BSH remained in the physiologic saline and little BSH moved into lipiodol. This result was compatible with the extreme high hydrophilic character of BSH.

Intra-arterial vs. intravenous

The alteration of 10B concentrations in the tumor, liver and blood in the intra-arterial group and intravenous group are shown in Fig. 2. In the intra-arterial group, the 10B

Discussion

We have shown that the 10B concentrations in the liver tumor were 100–500 ppm within 12 h of intra-arterial administration of BSH/lipiodol emulsion and the T/L 10B concentration ratio was approximately 15 at 6 h after administration. The values of the 10B concentrations in the liver tumor and the T/L 10B concentration ratio in the present study are higher than those reported previously, which were obtained by systemic administration of BSH. The previous published findings on 10B concentrations

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    Supported in part by Grant-in-Aid No. 13770525 for scientific research from the Ministry of Education, Science, Sports, and Culture, Japan, and by grants from the Association for Nuclear Technology in Medicine.

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