Boron neutron capture therapy (BNCT) is a binary therapeutic modality based on the nuclear capture and fission reactions that occur when the stable isotope boron-10 is irradiated with neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. In this Commentary we will focus on a number of papers that were presented at a Symposium entitled “Current Clinical Status of Boron Neutron Capture Therapy and Paths to the Future”, which was held in September 2017 at the China National Convention Center in Beijing. Results were presented by clinicians from Japan, Finland, the United States, the China mainland and Taiwan, China who have been working in the multiple disciplines that are required for carrying out clinical BNCT. The main focus was on the treatment of patients with malignant brain tumors, recurrent tumors of the head and neck region, and cutaneous melanomas. The results obtained in treating these patients were reported in detail and, although most of the patients with brain tumors and head and neck cancer were not cured, there was evidence of some clinical efficacy. Although there are a number of problems that must be addressed, further clinical studies to evaluate the efficacy of BNCT are warranted. First, despite considerable effort by numerous investigators over the past 40 years, there still are only two boron-containing drugs in clinical use, l-boronophenylalanine (BPA) and sodium borocaptate (BSH). Therefore, until new and more effective boron delivery agents are developed, efforts should be directed to improving the dosing and delivery of BPA and BSH. Second, due to a variety of reasons, nuclear reactor-based BNCT has ended except for its use in the China mainland and Taiwan. Therefore, the future of BNCT depends upon the results of the ongoing Phase II clinical trials that are being carried out in Japan and the soon to be initiated trials that will be carried out in Finland. If the results obtained from these clinical trials are sufficiently promising, then BNCT will have a clear path to the future, especially for patients with the therapeutically challenging malignancies that in the past have been treated with reactor-based BNCT.
Compared with photon-induced binary cancer therapy, such as photothermal therapy (PTT) and photodynamic therapy (PDT), boron neutron capture therapy (BNCT) emerges as an alternative noninvasive treatment strategy that could overcome the shallow penetration of light. One key factor in performing successful BNCT is to accumulate a sufficient amount of B-10 (>20 ppm) within tumor cells, which has been a long-standing challenge for small-molecule-based boron drugs. Boron nitride nanoparticles (BNNPs) are promising boron carriers due to their high boron content and good biocompatibility, as certain types of BNNPs can undergo rapid degradation under physiological conditions. To design an on-demand degradable boron carrier, BNNPs were coated by a phase-transitioned lysozyme (PTL) that protects BNNPs from hydrolysis during blood circulation and can be readily removed by vitamin C after neutron capture therapy. According to PET imaging, the coated BNNPs exhibited high tumor boron accumulation while maintaining a good tumor to nontumor ratio. Tail-vein injections of vitamin C were followed by neutron irradiation, and BNNPs were found to be rapidly cleared from major organs according to ex vivo ICP-OES analysis. Compared with the control group, animals treated with BNCT showed suppression of tumor growth, while almost negligible side effect was observed. This strategy not only utilized the high boron content of BNNPs but also successfully performed an on-demand degradation of BNNPs to avoid the potential toxicity caused by the long-term accumulation of nanoparticles.
Boron neutron capture therapy (BNCT) induces high-energy radiation within cancer cells while avoiding damage to normal cells without uptake of BNCT drugs, which is holding great promise to provide excellent control over locally invasive malignant tumors. However, lack of quantitative imaging technique to determine local boron concentration has been a great challenge for nuclear physicians to apply accurate neutron irradiation during the treatment, which is a key factor that has limited BNCT's application in clinics. To meet this challenge, this study describes coating boronated porphyrins with a biocompatible poly(lactide-co-glycolide)−monomethoxy-poly(polyethylene-glycol) (PLGA−mPEG) micelle for selective tumor accumulation and reduced toxicity comparing with the previously reported boronated porphyrin drugs. Fluorescence imaging and positron emission tomography (PET) imaging were performed, unveiling the potential imaging properties of this boronated porphyrin nanocomplex (BPN) to locate tumor region and to determine tissue-localized boron concentration which facilitates treatment planning. By studying the pharmacokinetics of BPN with Cu-64 PET imaging, the treatment plan was adjusted from single bolus injection to multiple times of injections of smaller doses. As expected, high tumor uptake of boron (125.17 ± 13.54 ppm) was achieved with an extraordinarily high tumor to normal tissue ratio: tumors to liver, muscle, fat, and blood were 3. 24 ± 0.22, 61.46 ± 20.26, 31.55 ± 10.30, and 33.85 ± 5.73, respectively. At last, neutron irradiation with BPN showed almost complete tumor suppression, demonstrating that BPN holds a great potential for being an efficient boron delivery agent for imaging-guided BNCT.
Boronophenylalanine (BPA) is the dominant boron delivery agent for boron neutron capture therapy (BNCT), and [18F]FBPA has been developed to assist the treatment planning for BPA-BNCT. However, the clinical application of BNCT has been limited by its inadequate tumor specificity due to the metabolic instability. In addition, the distinctive molecular structures between [18F]FBPA and BPA can be of concern as [18F]FBPA cannot quantitate boron concentration of BPA in a real-time manner. In this study, a metabolically stable boron-derived tyrosine (denoted as fluoroboronotyrosine, FBY) was developed as a theranostic agent for both boron delivery and cancer diagnosis, leading to PET imaging-guided BNCT of cancer. [18F]FBY was synthesized in high radiochemical yield (50%) and high radiochemical purity (98%). FBY showed high similarity with natural tyrosine. As shown in in vitro assays, the uptake of FBY in murine melanoma B16-F10 cells was L-type amino acid transporter (LAT-1) dependent and reached up to 128 μg/106 cells. FBY displayed high stability in PBS solution. [18F]FBY PET showed up to 6 %ID/g in B16-F10 tumor and notably low normal tissue uptake (tumor/muscle = 3.16 ± 0.48; tumor/blood = 3.13 ± 0.50; tumor/brain = 14.25 ± 1.54). Moreover, administration of [18F]FBY tracer along with a therapeutic dose of FBY showed high accumulation in B16-F10 tumor and low normal tissue uptake. Correlation between PET-image and boron biodistribution was established, indicating the possibility of estimating boron concentration via a noninvasive approach. At last, with thermal neutron irradiation, B16-F10 tumor-bearing mice injected with FBY showed significantly prolonged median survival without exhibiting obvious systemic toxicity. In conclusion, FBY holds great potential as an efficient theranostic agent for imaging-guided BNCT by offering a possible solution of measuring local boron concentration through PET imaging.
Novel boron‐containing carbon dots (BCDs) are designed and prepared for boron neutron capture therapy (BNCT) with superior water solubility and excellent optical property for tracking 10B in vitro and in vivo. Encapsulation of BCDs using exosomes (Exos) from macrophages yields BCD–Exos of ≈100 nm. Fluorescent imaging shows that the BCD–Exos are internalized and distributed around the nuclei of U‐87‐MG glioma cells. BCD–Exos are also verified to cross the blood–brain barrier and significant accumulation in tumor tissue of the orthotopic U‐87‐MG glioma tumor‐bearing mice model 4 h after administration. Using inductively coupled plasma mass spectrometry (ICP‐MS), it is detected that 10B in tumor tissue is 107.07 ± 1.58 ppm, and T/N ratios are enhanced from 2.03 ± 0.08 of boron phenylalanine (BPA) to 5.28 ± 0.29 of the BCD–Exos. In BNCT, the neutron radiation dose is 8.40 ± 0.12 Gy when a 500 mg kg−1 10B dosage is given. Finally, there is a prominent BNCT effect of the BCD–Exos‐treated brain glioma in the mice model, and the survival ratio is 100% at the end of the experiment. The excellent curative effect of BNCT using BCD–Exos to brain glioma is achieved through adjusted biodistribution of boron in the cancer cell, enhanced T/N ratios, and the precise match between boron and neutron exposure in the site of the tumor in vivo with fluorescence imaging of BCD–Exos.
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