Boron delivery agents for boron neutron capture therapy

Abstract

Boron neutron capture therapy (BNCT) is a binary method of radiotherapy, which is based on the nuclear reaction that occurs when boron-10 is irradiated with thermal neutron to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. These particles with high energy and short range can kill cancer cells which absorbed 10B while little damage to normal tissues. BNCT has experienced nearly 90 years of development since it was first proposed in 1936, which is one of the most effective methods for the treatment of malignant glioma. One of the key factors for the success of BNCT is to find boron delivery agents with high targeting and high affinity to tumors. Currently, although there are various of boron delivery agents, the best compound recognized for BNCT is still boronophenylalanine (BPA), for it has little side effect and no chemistry toxicity. BPA can penetrate the BBB and cell membrane, so it owns higher relative biological effectiveness. BPA is the most widely used BNCT drug in the world, which was officially approved in Japan last year, and the therapeutic effect on glioma is without question. In the past few decades, in order to improve the efficacy of BNCT, significant effort has been devoted to developing new boron delivery agents that possess better uptake and favorable pharmacokinetic characteristics for clinical use. This review focuses on differents kinds of boron delivery agents developed over the past years, which can be divided into three generations. At present, the first generation of boron delivery agents has been banned for lacking of targeting. The second generation of boron delivery agents is the most mature of the clinical application, but there are some problems need to be solved, such as limited boron loading and individual uptake varies greatly. The third generation of boron delivery agents contains various agents-The boron-containing amino acids and peptides, the boron-containing compound conjugated with nucleosides, porphyrin derivatives, and different types of nanomaterials, was introduced in detail in this review. The boron loading and targeting of the third generation of boron delivery agents have greatly increased, but most of them are still in the experimental stage, and the safety and effectiveness need to be further verified. The advantages and disadvantages of the three generation boron delivery agents were analyzed and compared. Meanwhile, the limitations of the various boron delivery agents were discussed and summarized. Additionally, the prospect and bottleneck of clinical application of these boron delivery agents was critically analyzed from different view of research institutions, pharmaceutical enterprises and government policy. And the corresponding solutions were proposed: (1) Expand the application scope of BPA and BSH; develop new drugs and expand the application fields of BNCT technology; (2) enhance the cooperation of enterprises, universities and research institutions, and promote the clinical approval and application of BPA and BSH; (3) multi disciplines jointly overcome technical barriers and establish a perfect evaluation system of safety and effectiveness for BNCT. In summary, with the official approval of the Japanese accelerator BNCT treatment system, the application prospects of BNCT technology will be broad all over the world. The comprehensive research of BNCT technology will be promoted by enhancing the intercrossing and coalescence between subjects relative with BNCT, and new ideas will be inspired, all of which will promote the clinical application of BNCT technology, and benefit patients.