Exploring the Biological and Physical Basis of Boron Neutron Capture Therapy (BNCT) as a Promising Treatment Frontier in Breast Cancer

Abstract

BNCT is a high LET radiation therapy modality that allows for biologically targeted radiation delivery to tumors while reducing normal tissue impacts. Although the clinical use of BNCT has largely been limited to phase I/II trials and has primarily focused on difficult-to-treat malignancies such as recurrent head and neck cancer and recurrent gliomas, recently there has been a renewed interest in expanding the use of BNCT to other disease sites, including breast cancer. Given its high LET characteristics, its biologically targeted and tumor specific nature, as well as its potential for use in complex treatment settings including reirradiation and widespread metastatic disease, BNCT offers several unique advantages over traditional external beam radiation therapy. The two main boron compounds investigated to date in BNCT clinical trials are BSH and BPA. Of these, BPA in particular shows promise in breast cancer given that is taken up by the LAT-1 amino acid transporter that is highly overexpressed in breast cancer cells. As the efficacy of BNCT is directly dependent on the extent of boron accumulation in tumors, extensive preclinical efforts to develop novel boron delivery agents have been undertaken in recent years. Preclinical studies have shown promise in antibody linked boron compounds targeting ER/HER2 receptors, boron encapsulating liposomes, and nanoparticle-based boron delivery systems. This review aims to summarize the physical and biological basis of BNCT, the preclinical and limited clinical data available to date, and discuss its potential to be utilized for the successful treatment of various breast cancer disease states.

A Compact Neutron Generator for the Niort® Treatment of Severe Solid Cancers

“…The basic idea in the nIORT® is to irradiate tumour beds "directly" with the monoenergetic 2.45 MeV neutrons emitted by the DD source, e.g., without moderating to epithermal or thermal energies as in the BNCT. 5,6,7 This high energy neutrons are very effective in cancer cells killing because of their high LET and RBE: @16 for 2.45 MeV neutrons. 9,30 This RBE value is significantly higher than of the proton in the Spread Out Bragg Peak (SOBP, estimated to be 1.1 to 1.2) and of the currently used 50 kV Xrays medical devices for IORT, which are 1.26 to 1.42 as measured in a phantom model.…”

“…Indeed, the almost spherically symmetric IR on the tumour bed has the advantages to be less sensitive to the margins of the surgery cavity and to the possible intra-tumour heterogeneity of the solid tumour cells since the neutron irradiator behaves like an IR "foam" within the cavity. Differently from the Boron Neutron Capture Therapy (BNCT) exploiting thermal and epithermal neutrons to induce (n, a) reactions in boron carriers injected into patients 5,6,7 , the fast neutrons interact directly and efficiently with the hydrogen nuclei, producing recoil protons that ionize the tissues. Monte Carlo simulations have shown that the nIORT® delivers on the tumour bed a fast-neutron IR with a high linear energy transfer (LET) 8 and a relative biological effectiveness (RBE) 9 significantly higher than all other IRs such as X-rays, electrons and protons, thus resulting very efficient in producing DNA double strand breaks (DSBs) of the cancer cells.…”

Recent Development of Radiofluorination of Boron Agents for Boron Neutron Capture Therapy of Tumor: Creation of 18F-Labeled C-F and B-F Linkages

“…Of the boron-containing agents reported so far, boronophenylalanine (BPA) and borocaptate sodium (BSH) are the two most commonly used boron agents for clinical treatment ( Figure 1 ). In addition, various boron agents have been developed in the past decades, including peptides [ 27 , 28 ], antibody-based delivery systems [ 29 , 30 ], boron compound conjugates [ 31 , 32 ], boron-containing nanoparticles [ 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ], boric acid [ 41 , 42 , 43 ], and decahydrodecaborate (GB-10) [ 44 , 45 ].…”

Enhancement in the Therapeutic Efficacy of In Vivo BNCT Mediated by GB-10 with Electroporation in a Model of Oral Cancer

“…It is a binary treatment that combines the administration of boron-10 carriers that are taken up preferentially by tumor cells and the subsequent irradiation with a thermal/epithermal neutron beam. The nuclear reaction between a 10 B atom (a stable isotope) and a thermal neutron generates high linear energy transfer (LET) particles (alpha particles and 7 Li recoil nuclei) and low LET gamma radiation [1][2][3]. High LET particles travel a short distance in tissue, approximately the diameter of a single tumor cell (10 µm); thus, they only destroy 10 B-containing tumor cells [4], preserving the surrounding normal tissue.…”

“…BNCT clinical trials on recurrent glioblastoma, primary and recurrent head and neck cancer, sarcoma, meningioma, melanoma, hepatocellular carcinoma, and malignant mesothelioma were and/or are currently performed around the world [6,7]. Particularly, for the treatment of recurrent head and neck tumors, the BNCT overall tumor response rate was up to 90% [2].…”