Gadolinium delivery agents for neutron capture therapy

Abstract

<p indent=0mm>Neutron capture therapy (NCT) is a binary form of radiation therapy that combines neutron irradiation with a tumor targeting agent labeled with a stable isotope having a high thermal neutron capture cross section and yielding charged particle reaction products after neutron capture. At present, NCT has largely, but not exclusively, focused on the use of boron-10 as the target nuclide. Gadolinium neutron capture therapy (Gd-NCT) is an alternative and supplementary method of boron neutron capture therapy (BNCT). Gd-157, which has the largest cross-section (254000 barn) of thermal neutrons of all stable isotopes, is the most effective isotope in terms of neutron capture. The Gd neutron capture reaction, ¹⁵⁷Gd(n, γ)¹⁵⁸Gd, provokes complicated nuclear decay transitions that generate low linear energy transfer (LET) gamma photons and the emission of high LET conversion electrons and Auger electrons. Therefore, Gd is considered to be highly suitable for the absorption of thermal neutrons in the NCT reaction. Another advantage of Gd-NCT is Gd³⁺ has a longer retention time and can thus be tracked by means of magnetic resonance imaging (MRI) methods. Currently, Gd(III) based MRI contrast agents are most commonly used in clinical practice. However, due to lack of appropriate tumor-selective Gd agents, the Gd-NCT concept has not yet been clinically tested. For a successful neutron capture therapy, a target nuclide delivery system with high therapeutic efficiency and low adverse effects is crucial. Three major classes Gd delivery agents have been developed so far, small molecule chelates of Gd, nano- delivery agents, and Gd-B dual delivery agents. In the first trial of Gd-NCT, commercially available MRI contrast agents composed of Gd-chelating compounds were used as Gd delivery agents. However, due to the insufficient number of tumor cell nuclei incorporating Gd, efficacy of small molecule chelates of Gd as Gd-NCT delivery agents is generally low. In recent years, with the rapid development of nanotechnology, nanomaterials have been widely employed as carriers for cancer theranostics. A variety of Gd-based nanomaterials have been developed for pre-clinical trials of NCT. Majority of them are constructed by incorporating commercially available MRI contrast agents in biocompatible nanomaterials (liposomes, albumin, and micelles), or employing Gd based nanoparticles with their unique physiochemical properties. While nano-Gd delivery agents have proved to be a promising strategy in Gd-NCT, it is also possible to integrate of both Gd and B in one delivery agent. The design of many Gd-NCT agents to date has focused on combined BNCT and Gd-NCT agents in order to maximise cytotoxicity from the combined effects or to use the B component for NCT and the Gd component as a MRI imaging agent. This paper highlights the recent advances in Gd selective and efficient delivery methods and the preclinical outcome of Gd-NCT, both advantages and disadvantages of various Gd delivery agents were addressed. Finally, we offered our perspectives on the challenges and future development of Gd delivery agents for Gd-NCT.