Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging of L-4-Phenylalanineboronic Acid (BPA) in a Brain Tumor Model Rat for Boron Neutron Capture Therapy (BNCT)

Abstract

Boron neutron capture therapy (BNCT) is a cell-selective particle therapy for cancer using boron containing drugs. Boron compounds are accumulated in high concentration of tens ppm level of boron in target tumors to cause lethal damage to tumor tissue. The examination of boron distribution in target tumor and normal tissue is important to evaluate the efficiency of therapy. The matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) is a powerful tool to visualize the distribution of target analyte in biological samples. In this manuscript, we report a trial to visualize the distribution of a typical BNCT drug, L-4-phenylalanine boronic acid (BPA) in a brain tumor model rat using MALDI-MSI technique. We performed a MALDI-MSI with high mass resolution targeting to [BPA+H] + at m/z 210 in a BPA-treated rat brain section using a spiral orbit-type time of flight (SpiralTOF) mass spectrometer. Several BPA ion species, [BPA+H] + , [BPA-H 2 O+Na] + , [BPA+DHB-2H 2 O+Na] + and [BPA+DHB-2H 2 O+K] + were detected separate from peaks originated from biomolecules or matrix reagent by achieving the mass resolving power of approximately 20,000 (full width at half maximum; FWHM) at m/z 210. The mass images with 60 µm spatial resolution obtained from these BPA ion species in a mass window of 0.02 Da revealed their localization in the tumor region. Additionally, the mass image obtained from [BPA+H] + also likely showed 2 Mass Spectrometry Advance Publication the distribution of BPA inside the tumor. MALDI-MSI with high mass resolution targeting to [BPA+H] + has a great potential to visualize the distribution of BPA in brain tissue with tumor.

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation in BNCT of Brain-Tumor-Model Rats—Ex Vivo Imaging of BPA Using MALDI Mass Spectrometry Imaging

“…Figure 7 show the right-side brain images of the brain-tumor-model rat (Rat C) at 60 min after BPA administration via the CSF method for 160 min. Figure 8 show the right-side brain images of the brain-tumor-model rat (Rat D) at 60 min after BPA administration via the IV method for 120 min, cited from Miyake's paper [27]. Figure 8 show the right-side brain images of the brain-tumor-model rat (Rat D) at 60 min after BPA administration via the IV method for 120 min, cited from Miyake's paper [27].…”

“…Figure 8 show the right-side brain images of the brain-tumor-model rat (Rat D) at 60 min after BPA administration via the IV method for 120 min, cited from Miyake's paper [27]. Figure 8 show the right-side brain images of the brain-tumor-model rat (Rat D) at 60 min after BPA administration via the IV method for 120 min, cited from Miyake's paper [27]. Our study results demonstrate that a considerable amount of BPA is localized in tumor cells after administration via CSF circulation (Figure 6).…”

“…The mass image was obtained from the peak of protonated BPA molecule based on the peak intensity in each pixel of the sample to generate estimations based on the BPA macro images. The details of conditions used in mass spectrometry imaging are as described in our previous report [27].…”

“…Recently, MALDI-MSI has become increasingly popular in both medical and basic research after the discovery of detailed histomolecular signatures in tissues, such as protein, lipid, metabolized, and drug, without the need for tagging or target-specific antibodies [43]. Our team developed an advanced technique for brain BPA macro imaging at a 60 µm spatial resolution with MALDI-MSI and successfully obtained BPA-uptake images in a brain-tumor-model rat [27]. This technique has helped us to evaluate the utility of the CSF administration of BPA, which is the first time such a result has been demonstrated.…”