Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation for BNCT in a Rat Melanoma Model

SIMPLE SUMMARY: The blood–brain barrier (BBB) is formed by the brain capillary endothelium and prevents almost all therapeutic agents from reaching the brain. The importance of the BBB in brain tumor treatments has not been recognized until recently, including in the case of boron neutron capture therapy (BNCT), although it affects therapeutic efficacy when treating brain tumors. Recently, some drug delivery systems to bypass the BBB have been developed for brain tumor therapy, and our laboratory has been developing a system for boron delivery to brain cells using cerebrospinal fluid (CSF) circulation, which we call the “boron CSF administration method”. In this study, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. As a result, we found that boron injected using the CSF administration method accumulates to high levels in tumor cells, with a high T/N ratio. In addition, the dose required for the boron drug was much lower than that used in the intravenous (IV) administration method for equivalent effects. This approach makes it possible for clinicians to inject a lower drug dose into patient, thus reducing the potential side effects of excessive amounts of the drug and decreasing its cost. We hope our findings will inspire additional studies on boron delivery to brain tumors for BNCT. ABSTRACT: Recently, exploitation of cerebrospinal fluid (CSF) circulation has become increasingly recognized as a feasible strategy to solve the challenges involved in drug delivery for treating brain tumors. Boron neutron capture therapy (BNCT) also faces challenges associated with the development of an efficient delivery system for boron, especially to brain tumors. Our laboratory has been developing a system for boron delivery to brain cells using CSF, which we call the “boron CSF administration method”. In our previous study, we found that boron was efficiently delivered to the brain cells of normal rats in the form of small amounts of L-p-boronophenylalanine (BPA) using the CSF administration method. In the study described here, we carried out experiments with brain tumor model rats to demonstrate the usefulness of the CSF administration method for BNCT. We first investigated the boron concentration of the brain cells every 60 min after BPA administration into the lateral ventricle of normal rats. Second, we measured and compared the boron concentration in the melanoma model rats after administering boron via either the CSF administration method or the intravenous (IV) administration method, with estimation of the T/N ratio. Our results revealed that boron injected by the CSF administration method was excreted quickly from normal cells, resulting in a high T/N ratio compared to that of IV administration. In addition, the CSF administration method resulted in high boron accumulation in tumor cells. In conclusion, we found that using our developed CSF administration method results in more selective delivery of boron to the brain tumor compared with the IV administration method.