Research progress and hot fronts of boron-containing drugs for boron neutron capture therapy: Analysis and implications based on the bibliometrics-method

Boron neutron capture therapy (BNCT) is a kind of targeted radionuclide therapy, dealing with selectively concentrating boron compounds in tumour cells and then subjecting the tumour cells to epithermal neutron beam radiation. Compared with common surgical treatment, radiotherapy or chemotherapy, BNCT has shorter treatment cycle. It is considered to be a promising treatment for various cancers. Boron-containing drugs are the key factor to achieve tumor targeting in BNCT. In this paper, based on the bibliometric method, related papers, patents and clinical development progress of boron-containing drugs for BNCT were analyzed. Firstly, the paper output related to boron drug has shown a steady growth, significantly in the past three years. The United States and Japan lead the way with 420 and 357 articles published in the peer-review journals. The publishing institutions are mainly universities and key laboratories in the two countries. Institutions in other countries such as Argentina or Italy also published a large number of papers. Many focused on the structure of boron-containing drugs in recent years, including modification and optimization of boronophenylalanine (BPA) and disodium undecahydro-mercapto-closo-dodecacarborate, the design of drugs for improving drug targeting and increasing of boron carrying capacity of boron-carrying agents. The combination of BNCT with traditional cancer therapy, treatment mechanism and dosimetry of BNCT boron-containing drugs are also important research hotspots. Secondly, from the patent analysis, the United States and Japan are the most important patent priority countries for boron-containing drugs. China began to pay attention to the patent layout in the field of boron-containing drugs from 2016. The United States, Japan and China are the most important patent disclosure countries. Anticancer drugs containing boron and organic active ingredients are the main patent layout directions of boron-containing drugs, which present a high proportion of effective patents. The patent applications of key applicants in the United States mainly focus on the research of drug delivery substances such as liposomes and the research of polymer drugs such as borated metalloporphyrins. The research institutions include universities, companies and achievement transformation institutions in the United States, but patent layout shows weak continuity. There are many joint applications among Japanese key applicants, and the patent layout focuses on the design and preparation of BPA, BSH drugs and their derivatives and precursors. The main applicants in China are mainly universities, and the patent applications are mainly domestic applications. They deploy patent based strategies late in the game, and the technical topics involved are relatively scattered. The layout of key European applicants is carborane, and in recent years, more PCT patents for peptidyl carborane have been deployed; from the analysis of clinical research and development, there are 88 boron-containing drugs used for BNCT, which are mainly small molecule drugs, and some of them involve biological peptides. Most boron-containing drugs are in the biological testing stage or early clinical stage, except one drug available on the market, which has many indications. Significant progress has been made in boron-containing drugs of BNCT. The United States and Japan have conducted research in this field for a long time. especially Japan has certain leading advantages in basic research and patent layout, and has one marketed drug. In recent years, more and more types of boron-containing drugs and their indications have entered the clinic stage. It is recommended that Chinese enterprises collaborate with scientific research institutes and universities to track the latest international developments and focus on strengthening deployment of patents from an international perspective.