Insights into the Use of Gadolinium and Gadolinium/Boron-Based Agents in Imaging-Guided Neutron Capture Therapy Applications

Abstract

Gadolinium neutron capture therapy (Gd-NCT) is currently under development as an alternative approach for cancer therapy. All of the clinical experience to date with NCT is done with 10 B, known as BNCT, a binary treatment combining neutron irradiation with the delivery of boron-containing compounds to tumors. Currently, the use of gadolinium for NCT has been getting more attention because of its highest neutron cross-section. Although Gd-NCT was first proposed many years ago, its development has suffered due to lack of appropriate tumor-selective Gd-agents. This review aims to highlight the recent advances for the design, synthesis and biological testing of new Gd-and B-Gd-containing compounds with the task of finding the best systems able to improve the NCT clinical outcome. Keywords:Gadolinium Neutron Capture Therapy, Boron Neutron Capture Therapy, MRI, Gd contrast agents, Tumor Treatment, Nanosized Gd agents. 3 General introduction on NCT: rationale and applicationNeutron Capture Therapy (NCT) is a non-conventional radiotherapy that combines low energy neutron irradiation with the presence of a neutron-absorbing substance at the targeted cells [1][2].Two isotopes are of major interest because of their large capture cross section: head and neck recurrent cancer [6][7], melanoma [8] and adenocarcinoma liver metastases [9]; ii) sodium mercaptoundecahydro-closo-dodecaborate (BSH) that has been investigated for the treatment of malignant glioma [10]. Despite their clinical use and the safe and effective BNCT, trials performed with these two drugs until now, both BPA and BSH show low selectivity and great efforts have been made by several research groups to develop new and more selective boron delivery agents [11][12].The use of BNCT to destroy malignant cells was proposed long time ago [13]. In spite of huge promises, it has not attained an established position in the mainstream medicine.However, the methodology has never been discarded and it remains in an intermediate state with a small group of enthusiast supporters and many critical spectators. The reasons why BNCT has not maintained the original promises rely mainly in the lack of properly designed agents. The conditions for an effective therapeutic output are well established: the BNCT agent must reach selectively a given concentration inside cells and the not-attainment of this task makes the therapy less effective. Only a proper NCT agent design (based on an improved knowledge on how molecules enter healthy and diseased cells) allows to reach selectively the needed threshold of intracellular concentration required to drive the breakthrough of BNCT in the field of conventional and diffused treatments for cancer. Moreover, the in vivo assessment of the amount of NCT agent can now be tackled by its conjugation to a suitable imaging-reporter. [14][15] To date there is no non-invasive means to evaluate boron concentration in tumor and healthy tissues of the subject undergoing the irradiation. Thus, dose calculations are based on boron content values in...

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“…In this particular case, the location of the isotope is not critical with regard to the target cell, given the longer ranges of γ‐rays. With the different mechanisms of action between BNCT and Gd‐NCT, their combined use could be advantageous . One straightforward route involves the simultaneous administration of two NCT agents, one carrying 10 B, the other 157 Gd, but this approach has the disadvantage that the uptake and distribution of the to atom types within the tumor may be quite different.…”

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