Boron delivery agents for neutron capture therapy of cancer

Abstract

Boron neutron capture therapy (BNCT) is a binary radiotherapeutic 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. This review will focus on tumor-targeting boron delivery agents that are an essential component of this binary system. Two low molecular weight boron-containing drugs currently are being used clinically, boronophenylalanine (BPA) and sodium borocaptate (BSH). Although they are far from being ideal, their therapeutic efficacy has been demonstrated in patients with high grade gliomas, recurrent tumors of the head and neck region, and a much smaller number with cutaneous and extra-cutaneous melanomas. Because of their limitations, great effort has been expended over the past 40 years to develop new boron delivery agents that have more favorable biodistribution and uptake for clinical use. These include boron-containing porphyrins, amino acids, polyamines, nucleosides, peptides, monoclonal antibodies, liposomes, nanoparticles of various types, boron cluster compounds and co-polymers. Currently, however, none of these have reached the stage where there is enough convincing data to warrant clinical biodistribution studies. Therefore, at present the best way to further improve the clinical efficacy of BNCT would be to optimize the dosing paradigms and delivery of BPA and BSH, either alone or in combination, with the hope that future research will identify new and better boron delivery agents for clinical use.

Keywords: Boron delivery agents; Brain tumors; Head and neck cancer; Melanoma; Neutron capture therapy.

Fig. 1

Boron neutron capture therapy is based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, a constituent of natural elemental boron, 80% of which is in the isotopic form of ¹¹B and 20% as ¹⁰B, is irradiated with low-energy (0.025 eV) thermal neutrons or, alternatively, higher-energy (10,000 eV) epithermal neutrons. The latter become thermalized as they penetrate tissues. The resulting ¹⁰B(n,α)⁷Li capture reaction yiels high linear energy transfer (LET) α paricles (stripped down helium nuclei [⁴He]) and recoiling lithium-7 (⁷Li) atoms (a). A sufficient amount of ¹⁰B must be delivered selectively to the tumor (~ 20–50 μg/g or ~ 10⁹ atoms/cell) in order for BNCT to be successful (b). A collimated beam of either thermal or epithermal neutrons must be absorbed by the tumor cells to sustain a lethal ¹⁰B(n,α)⁷Li capture reaction. Since the α paricles have very short pathlengths in tissues (5–9 μm), their destructive effects are limite to boron-containing cells. In theory, BNCT provides a way to selectively destroy malignant cells and spare surrounding normal tissue if the required amounts of ¹⁰B and neutrons are delivered to the tumor cells.

Fig. 2

Some low- and high-molecular weight boron delivery agents (with the exception of #3) that have been investigated by Barth et al. (1) BPA (boronophenylalanine, Na₂¹⁰B₁₀H₁₀) and (2) BSH (sodium borocaptate, Na₂¹⁰B₁₂H₁₁SH, undecahydro-mercapto-closo-dodecaborate) are the only two drugs in clinical use. (3) GB–10 (sodium decaborate, Na₂B₁₂H) has been used in only a few animal studies; although at one time it had an approved U.S. Food and Drug Administration (FDA) Investigational New Drug designation (IND), it never has been used clinically. (4) N5-2OH (3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl] thymidine) is a carboranyl thymidine analogue (CAT) that yielded promising results in the RG2, but not the F98, rat glioma models following intracerebral convection-enhanced delivery (i.c. CED). (5) cis-ABCHC and trans-ABCHC (1-amino-3-borono-cycloheptanecarboxylic acid) as a racemic mixture is an unnatural amino acid that has in vivo uptake comparable to BPA in the B16 melanoma model, but far superior tumor:blood boron concentration ratios compared with BPA. (6) VEGF-BD-Cy5 is a heavily boronated vascular endothelial growth factor (VEGF) linked to Cy5 for near infrared imaging of the construct. (7) H₂-DCP (di [3,5-(nido-carboranylphenyl) tetra-benzoporphyrin]) is one of a group of carboranyl porphyrins containing multiple carborane clusters, which show high in vitro cellular uptake. In vivo BNCT following i.c. CED yielded survival data comparable to that of intravenously administered BPA (8) C225-G5-B₁₀₀₀ is a heavily boronated form of the monoclonal antibody cetuximab that specifically targets the human epidermal growth factor receptor (EGFR), which has been used for BNCT of the F98_EGFR rat glioma. (9) EGFR-targeting, boron-containing immunoliposomes with cetuximab as the targeting moiety

Fig. 3

BSH-dendrimer conjugates for BNCT. a Conjugation scheme for the linkage of a boron-containing dendrimer to cetuximab; b Cellular binding of cetuximab. Varying amounts (5 − 100 ng) of ¹²⁵I-cetuximab were incubated at 4 °C for 90 min with cells expressing wild-type EGF receptors (F98_EGFR) (black up-pointing triangle), mutant EGFRvIII receptors (F98_EGFRvIII) (black circle), and receptor-negative parental cells (F98_WT) (white square). c Boron neutron capture therapy effect of BSH-polymer conjugation on colon 26 subcutaneous tumor-bearing BALB/c mice. Reproduced with permission. Copyright 2004, ACS [150]

Fig. 4

BSH-polymer conjugates for tumor BNCT. a Synthetic scheme of BSH-polymer conjugates [PEG-b-P(Glu-SS-BSH) and P(Glu-SS-BSH)]; b Time-lapsed cellular uptake of PEG-b-P(Glu-SS-BSH) by C26 cancer cells was investigated by confocal laser scanning microscopy (CLSM). Both PEG-b-P(Glu-SS-BSH) and P(Glu-SS-BSH) were labeled with Alexa488 (green color), and their dose was 20 µg/mL on a BSH basis, while the nuclei were stained with Hoechst (blue color). c Relative cellular uptake of BSH, PEG-b-P(Glu-SS-BSH) and P(Glu-SS-BSH) was measured by inductively coupled plasma mass spectrometry (ICP-MS). The C26 cancer cells were exposed to BSH, PEG-b-P(Glu-SS-BSH) and P(Glu-SS-BSH) for 1, 6 and 24 h (n = 3), at a dose of 100 µg/mL on a BSH basis, while the results were measured by ICP-MS and normalized by comparing with the cellular uptake of BSH at 1 h. The data are expressed as the mean ± SD, ***P < 0.001. d Tumor growth ratio of C26 subcutaneous tumors in BALB/c mice that were irradiated with thermal neutrons (1.6–2.2 × 10¹² neutron/cm²) at Kyoto University Reactor (KUR) for 1 h after intravenous injection of phosphate buffered saline (PBS), BSH, and BSH-polymer conjugates for 24 h at a dose of 100 mg/kg on a BSH basis. Reproduced with permission. Copyright 2017, Elsevier [86]

Fig. 5

Boron cluster-loaded liposomes for tumor BNCT. a Schematic illustration of liposomes incorporating Na₃ [1-(2′-B₁₀H₉)-2-NH₃B₁₀H₈] for BNCT. b The biodistribution of boron in EMT6 tumor-bearing mice after a single intravenous injection (340–345 µg of boron; red diamond = blood, green triangle = tumor, blue square = liver). c Tumor growth curves normalized with respect to mean volume on day 0 after BNCT treatment consisted of a 30-min irradiation following double injection of liposomal suspension (set as the time of irradiation): black circle control group; white square, BNCT group. d Kaplan–Meier time-to-event curves indicating time required to reach a 500-mm³ tumor volume (solid black line, control group; solid gray line, neutron irradiation-only group; dashed line, BNCT group). Reproduced with permission. Copyright 2013, National Academy of Science [99]

Fig. 6

Boron cluster containing redox nanoparticles (BNP) for tumor BNCT. a Scheme for preparing boron cluster containing redox nanoparticles. b Biodistribution of BNP in tumor-bearing mice. c Tumor growth curves of tumor-bearing mice after 40-min thermal neutron irradiation (1.3–1.7 × 10¹² neutron/cm²). Mice with a mean original tumor volume of 140 mm³ received BNP at doses of 15 and 5 mg ¹⁰B/kg. Mice administered BPA–fructose complex at a dose of 40 mg ¹⁰B/kg were used as the positive control. Mice administered boron cluster containing redox nanoparticles with the same amount of nitroxide radical as in the BNP-treated group at a dose of 15 mg ¹⁰B/kg and PBS with and without (PBS-C) irradiation were used as negative controls (n = 3, mean ± SD, *P < 0.01, **P < 0.005, Student’s t test). Reproduced with permission. Copyright 2016, Elsevier [117]