In vivo imaging of the neutron capture therapy agent BSH in mice using ¹⁰B MRI

Abstract

Boron neutron capture therapy (BNCT) is an experimental cancer treatment modality requiring the targeting of 10 B-enriched compounds to the tumor, which is then irradiated by low-energy neutrons. One of the boron-containing compounds used for this purpose is the mercaptoborane Na 2 B 12 H 11 SH (BSH). The first in vivo MR images of 10 B-enriched BSH are presented here. BSH, injected into the tail vein of mice with implanted M2R melanoma xenografts, was imaged using 3D gradient echo 10 B MRI. 10 B NMR spectroscopy, localized mainly to the tumor by virtue of the use of a small surface coil, was applied to measure the T 1 (2.9 ؎ 0. Boron neutron capture therapy (BNCT) is based on the high cross section of 10 B for capturing thermal neutrons (1,2). This nuclear reaction yields alpha particles and recoiling lithium nuclei, both with high linear energy transfer (LET) and relatively short spatial range (ϳ10 m). Therefore, the combined targeting of neutron irradiation and boron accumulation can lead to selective damaging of tumor cells. Borocaptate sodium, Na 2 B 12 H 11 SH (BSH) was used as BNCT agent in Japanese patients since 1968 (3) and is now under evaluation in a European Phase I clinical trial (4).The ability for noninvasive imaging of the administered drug is a highly desirable goal for both the research of BNCT and for its clinical implementation. So far, the in vivo MR imaging of BSH was demonstrated only for the natural abundance compound (5), using 11 B detection ( 11 B has 80% natural abundance). This approach is obviously not suitable for clinical applications, where the boronated molecules are enriched in 10 B to over 95%. It was always assumed that direct 10 B detection would not be sensitive enough for MRI of BNCT agents, due to the low gyromagnetic ratio of 10 B, and therefore considerable efforts were devoted to the development and implementation of indirect detection methods. In BSH, 11 out of the 12 boron nuclei are coupled to protons (J ϭ 43 Hz) and several reports exploiting this fact for 10 B-edited, proton detection of BSH were published (6 -9). We decided, nevertheless, to explore the possibility for direct 10 B MRI of BSH, following measurements indicating that indirect 1 H detection may not be as advantageous as previously assumed (10). MATERIALS AND METHODSMouse M2R melanoma cells, routinely maintained as monolayers, were scraped, suspended in saline at 1 ϫ 10 6 cells / 0.25 ml, and injected subcutaneously into the rear thigh of CD1 nude mice. Mice (n ϭ 3) with tumors grown to about 1-2 cm in size were used for MRI experiments and 10 B relaxation time measurements (7). A solution (180 l) containing 0.11 M of 10 B-enriched (Ͼ95%) BSH (Boron Biologicals, Raleigh, NC) in PBS was injected into the mice tail veins. During the injection and the subsequent NMR experiments, the mice were anesthetized with Isoflurane (Medeva, Bethlehem, PA) in 70% N 2 O/30% O 2 . NMR experiments were conducted on a spectrometer with a 4.7T horizontal 30 cm bore magnet (Biospec, Bruker, Ettlingen, Germany). For MRI, ...

Boron analysis and boron imaging in biological materials for Boron Neutron Capture Therapy (BNCT)

“…Fig. 13 shows the results of imaging 10 Benriched BSH in a mouse with an implanted tumor [104], using 10 B MRI. Fig.…”

Biomedical applications of10B and11B NMR

“…injection of the compound. 39 The experiments were performed at 4.7 T, with the animals placed on a 2.5 cm circular surface coil, tuned for 10 B (21.5 MHz), contained within a 1 H resonator (200.2 MHz) for the provision of anatomic reference images. An example of a 10 B MR image is shown in the bottom part of Fig.…”

Novel Pharmacological and Magnetic Resonance Strategies to Enhance Boron Neutron Capture Therapy (BNCT) Efficacy in the Clinical Treatment of Malignant Glioma

“…Among these, MRI and MRS provide useful methods for non-invasive and non-destructive real-time monitoring of 10 B compounds during BNCT treatment in vivo. Given the low sensitivity of the 10 B NMR method (Bendel et al, 2001;Bendel 2005) and the intense proton background signal that makes 1 H-MRS (Zuo et al, 1999) and Magnetic Resonance Spectroscopy Imaging (MRSI) techniques problematic in vivo, new strategies to detect BPA by NMR are in progress.…”