Evaluation of sodium borocaptate (BSH) and boronophenylalanine (BPA) as boron delivery agents for neutron capture therapy (NCT) of cancer: an update and a guide for the future clinical evaluation of new boron delivery agents for NCT

Abstract

Boron neutron capture therapy (BNCT) is a cancer treatment modality based on the nuclear capture and fission reactions that occur when boron-10, a stable isotope, is irradiated with neutrons of the appropriate energy to produce boron-11 in an unstable form, which undergoes instantaneous nuclear fission to produce high-energy, tumoricidal alpha particles. The primary purpose of this review is to provide an update on the first drug used clinically, sodium borocaptate (BSH), by the Japanese neurosurgeon Hiroshi Hatanaka to treat patients with brain tumors and the second drug, boronophenylalanine (BPA), which first was used clinically by the Japanese dermatologist Yutaka Mishima to treat patients with cutaneous melanomas. Subsequently, BPA has become the primary drug used as a boron delivery agent to treat patients with several types of cancers, specifically brain tumors and recurrent tumors of the head and neck region. The focus of this review will be on the initial studies that were carried out to define the pharmacokinetics and pharmacodynamics of BSH and BPA and their biodistribution in tumor and normal tissues following administration to patients with high-grade gliomas and their subsequent clinical use to treat patients with high-grade gliomas. First, we will summarize the studies that were carried out in Japan with BSH and subsequently at our own institution, The Ohio State University, and those of several other groups. Second, we will describe studies carried out in Japan with BPA and then in the United States that have led to its use as the primary drug that is being used clinically for BNCT. Third, although there have been intense efforts to develop new and better boron delivery agents for BNCT, none of these have yet been evaluated clinically. The present report will provide a guide to the future clinical evaluation of new boron delivery agents prior to their clinical use for BNCT.

Keywords

Boron neutron capture therapy (BNCT) / boronophenylalanine (BPA) / brain tumors / head and neck cancer / sodium borocaptate (BSH)

References

[1] Hatanaka H, Amano K, Kamano S, Sano K. Clinical experience of boron-neutron capture therapy for malignant brain tumors (1968 -1985). In: Hatanaka H, editor. Boron neutron capture therapy for tumors. Japan: Nishimura Niigata; 1986: 447–449.

[2] Hatanaka H, Kamano S, Amano K, Hojo S, Sano K, Egawa S, et al. Clinical experience of boron-neutron capture therapy for gliomas-a comparison with conventional chemo-immuno-radiotherapy. In: Hatanaka H, editor. Boron neutron capture therapy for tumors. Japan: Nishimura Niigata; 1986: 349–378.

[3] Mishima Y, Honda C, Ichihashi M, Obara H, Hiratsuka J, Fukuda H, et al. Treatment of malignant melanoma by single thermal neutron capture therapy with melanoma-seeking 10B-compound. Lancet. 1989; 2(8659): 388–389.

[4] Chanana AD, Capala J, Chadha M, Coderre JA, Diaz AZ, Elowitz EH, et al. Boron neutron capture therapy for glioblastoma multiforme: interim results from the phase I/II dose-escalation studies. Neurosurgery. 1999; 44(6): 1182–1192; discussion 92-3.

[5] Kato I, Fujita Y, Maruhashi A, Kumada H, Ohmae M, Kirihata M, et al. Effectiveness of boron neutron capture therapy for recurrent head and neck malignancies. Applied Radiation and Isotopes. 2009; 67(7, Supplement): S37–S42.

[6] Kankaanranta L, Seppala T, Koivunoro H, Saarilahti K, Atula T, Collan J, et al. Boron neutron capture therapy in the treatment of locally recurred head-and-neck cancer: final analysis of a phase I/II trial. Int J Radiat Oncol Biol Phys. 2012; 82(1): e67–e75.

[7] Hirose K, Konno A, Hiratsuka J, Yoshimoto S, Kato T, Ono K, et al. Boron neutron capture therapy using cyclotron-based epithermal neutron source and borofalan ((10)B) for recurrent or locally advanced head and neck cancer (JHN002): An open-label phase II trial. Radiother Oncol. 2021; 155: 182–187.

[8] Barth RF, Soloway AH, Fairchild RG. Boron neutron capture therapy of cancer. Cancer Res. 1990; 50(4): 1061–1070.

[9] Matsumura A, Asano T, Hirose K, Igaki H, Kawabata S, Kumada H. Initiatives Toward Clinical Boron Neutron Capture Therapy in Japan. Cancer Biother Radiopharm. 2023; 38(3): 201–207.

[10] Asbury AK, Ojemann RG, Nielsen SL, Sweet WH. Neuropathologic study of fourteen cases of malignant brain tumor treated by boron-10 slow neutron capture radiation. J Neuropathol Exp Neurol. 1972; 31(2): 278–303.

[11] Goodwin JT, Farr LE, Sweet WH, Robertson JS. Pathological study of eight patients with glioblastoma multiforme treated by neutron-capture therapy using boron 10. Cancer. 1955; 8(3): 601–615.

[12] Farr LE, Sweet WH, Robertson JS, Foster CG, Locksley HB, Sutherland DL, et al. Neutron capture therapy with boron in the treatment of glioblastoma multiforme. Am J Roentgenol Radium Ther Nucl Med. 1954; 71(2): 279–293.

[13] Soloway AH, Hatanaka H, Davis MA. Penetration of brain and brain tumor. VII. Tumor-binding sulfhydryl boron compounds. J Med Chem. 1967; 10(4): 714–717.

[14] Barth RF, Vicente MG, Harling OK, Kiger WS, 3rd, Riley KJ, Binns PJ, et al. Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer. Radiat Oncol. 2012; 7(1): 146.

[15] Kamano S, Matsuyama M, Minamimura K. A Case of Diffuse Astrocytoma with 32-year Survival after Boron Neutron Capture Therapy. NMC Case Rep J. 2020; 7(4): 211-215.

[16] Mishima Y. Selective Thermal Neutron Capture Therapy of Cancer Cells Using their Specific Metabolic Activities—Melanoma as Prototype. In: Mishima Y, editor. Cancer Neutron Capture Therapy. Boston, MA: Springer US; 1996: 1–26.

[17] Mishima Y, Ichihashi M, Hatta S, Honda C, Yamamura K, Nakagawa T, et al. First human clinical trial of melanoma neutron capture. Diagnosis and therapy. Strahlenther Onkol. 1989; 165(2-3): 251–254.

[18] Coderre JA, Glass JD, Fairchild RG, Micca PL, Fand I, Joel DD. Selective delivery of boron by the melanin precursor analogue p-boronophenylalanine to tumors other than melanoma. Cancer Res. 1990; 50(1): 138–141.

[19] Coderre JA, Joel DD, Micca PL, Nawrocky MM, Slatkin DN. Control of intracerebral gliosarcomas in rats by boron neutron capture therapy with p-boronophenylalanine. Radiat Res. 1992; 129(3): 290–296.

[20] Elowitz EH, Bergland RM, Coderre JA, Joel DD, Chadha M, Chanana AD. Biodistribution of p-boronophenylalanine in patients with glioblastoma multiforme for use in boron neutron capture therapy. Neurosurgery. 1998; 42(3): 463–468; discussion 8-9.

[21] Hatanaka H, Nakagawa Y. Clinical results of long-surviving brain tumor patients who underwent boron neutron capture therapy. Int J Radiat Oncol Biol Phys. 1994; 28(5): 1061–1066.

[22] Nakagawa Y, Kyonghon P, Kitamura K, Kageji T, Minobe T. Long Term Follow up in Patients Who Underwent Boron Neutron Capture Therapy. In: Hawthorne MF, Shelly K, Wiersema RJ, editors. Frontiers in Neutron Capture Therapy: Volume 1. Boston, MA: Springer US; 2001: 141–144.

[23] Takagaki M, Oda Y, Miyatake S, Kikuchi H, Kobayashi T, Sakurai Y, et al. Boron neutron capture therapy: preliminary study of BNCT with sodium borocaptate (Na2B1 2H1 1SH) on glioblastoma. J Neurooncol. 1997; 35(2): 177–185.

[24] Sauerwein W, Moss R, Hideghéty K, Stecher-Rasmussen F. De Vries M, Reulen H-J, et al. Status Report on the European Clinical Trial of BNCT at Petten (EORTC Protocol 11961). In: Hawthorne MF, Shelly K, Wiersema RJ, editors. Frontiers in Neutron Capture Therapy: Volume 1. Boston, MA: Springer US; 2001: 81–86.

[25] Wittig A, Hideghety K, Paquis P, Heimans J, Vos M, Goetz C, et al. Current clinical results of the EORTC-study 11961. Res Develop Neutron Capture Therapy. 2002.

[26] Burian J, Marek M, Rataj J, Flibor S, Rejchrt J, Viererbl L, et al. Report on the first patient group of the phase I BNCT trial at the LVR-15 reactor. In: Sauerwein WM, Raymond M, Wittig A, editor. Research and Development in Neutron Capture Therapy. 12592002. p. 27–32.

[27] Hideghéty K, Sauerwein W, Wittig A, Götz C, Paquis P, Grochulla F, et al. Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial. J Neurooncol. 2003; 62(1-2): 145–156.

[28] Goodman JH, Yang W, Barth RF, Gao Z, Boesel CP, Staubus AE, et al. Boron neutron capture therapy of brain tumors: biodistribution, pharmacokinetics, and radiation dosimetry sodium borocaptate in patients with gliomas. Neurosurgery. 2000; 47(3): 608–621; discussion 21-2.

[29] Detta A, Cruickshank GS. L-amino acid transporter-1 and boronophenylalanine-based boron neutron capture therapy of human brain tumors. Cancer Res. 2009; 69(5): 2126–2132.

[30] Kawabata S, Miyatake S, Nonoguchi N, Hiramatsu R, Iida K, Miyata S, et al. Survival benefit from boron neutron capture therapy for the newly diagnosed glioblastoma patients. Appl Radiat Isot. 2009; 67(7-8 Suppl): S15–S18.

[31] Watanabe T, Sanada Y, Hattori Y, Suzuki M. Correlation between the expression of LAT1 in cancer cells and the potential efficacy of boron neutron capture therapy. J Radiat Res. 2022.

[32] Kawabata S, Miyatake S, Kajimoto Y, Kuroda Y, Kuroiwa T, Imahori Y, et al. The early successful treatment of glioblastoma patients with modified boron neutron capture therapy. Report of two cases. J Neurooncol. 2003; 65(2): 159–165.

[33] Barth RF, Grecula JC, Yang W, Rotaru JH, Nawrocky M, Gupta N, et al. Combination of boron neutron capture therapy and external beam radiotherapy for brain tumors. Int J Radiat Oncol Biol Phys. 2004; 58(1): 267–277.

[34] Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol. 2009; 94(3): 299–312.

[35] Hiratsuka J, Kamitani N, Tanaka R, Yoden E, Tokiya R, Suzuki M, et al. Boron neutron capture therapy for vulvar melanoma and genital extramammary Paget’s disease with curative responses. Cancer Commun (Lond). 2018; 38(1): 38.

[36] Coderre JA, Chanana AD, Joel DD, Elowitz EH, Micca PL, Nawrocky MM, et al. Biodistribution of boronophenylalanine in patients with glioblastoma multiforme: boron concentration correlates with tumor cellularity. Radiat Res. 1998; 149(2): 163–170.

[37] Coderre JA, Morris GM. The radiation biology of boron neutron capture therapy. Radiat Res. 1999; 151(1): 1–18.

[38] Diaz AZ. Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician’s point of view. J Neurooncol. 2003; 62(1-2): 101–109.

[39] Nakagawa Y, Pooh K, Kobayashi T, Kageji T, Uyama S, Matsumura A, et al. Clinical review of the Japanese experience with boron neutron capture therapy and a proposed strategy using epithermal neutron beams. J Neurooncol. 2003; 62(1-2): 87–99.

[40] Miyatake S-I, Kawabata S, Hiramatsu R, Kuroiwa T, Suzuki M, Ono K. Boron Neutron Capture Therapy of Malignant Gliomas. In: Chernov MF, Muragaki Y, McCutcheon IE, Kesari S, editors. Intracranial Gliomas Part III -Innovative Treatment Modalities. S. Karger AG; 2018; 32: 0.

[41] Suzuki M. Boron neutron capture therapy (BNCT): a unique role in radiotherapy with a view to entering the accelerator-based BNCT era. Int J Clin Oncol. 2020; 25(1): 43–50.

[42] Joensuu H, Kankaanranta L, Seppala T, Auterinen I, Kallio M, Kulvik M, et al. Boron neutron capture therapy of brain tumors: clinical trials at the finnish facility using boronophenylalanine. J Neurooncol. 2003; 62(1-2): 123–134.

[43] Pellettieri L, B HS, Rezaei A, Giusti V, Skold K. An investigation of boron neutron capture therapy for recurrent glioblastoma multiforme. Acta Neurol Scand. 2008; 117(3): 191–197.

[44] Busse PM, Harling OK, Palmer MR, Kiger WS, 3rd, Kaplan J, Kaplan I, et al. A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease. J Neurooncol. 2003; 62(1-2): 111–121.

[45] Capala J, Stenstam BH, Skold K, Munck af Rosenschold P, Giusti V, Persson C, et al. Boron neutron capture therapy for glioblastoma multiforme: clinical studies in Sweden. J Neurooncol. 2003; 62(1-2): 135–144.

[46] Skold K, H-Stenstam B. Diaz AZ, Giusti V, Pellettieri L, Hopewell JW. Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f. Acta Neurol Scand. 2010; 122(1): 58–62.

[47] Skold K, Gorlia T, Pellettieri L, Giusti V, H-Stenstam B. Hopewell JW. Boron neutron capture therapy for newly diagnosed glioblastoma multiforme: an assessment of clinical potential. Br J Radiol. 2010; 83(991): 596–603.

[48] Kawabata S, Hiramatsu R, Kuroiwa T, Ono K, Miyatake S. Boron neutron capture therapy for recurrent high-grade meningiomas. J Neurosurg. 2013; 119(4): 837–844.

[49] Kankaanranta L, Seppälä T, Koivunoro H, Välimäki P, Beule A, Collan J, et al. L-boronophenylalanine-mediated boron neutron capture therapy for malignant glioma progressing after external beam radiation therapy: a Phase I study. Int J Radiat Oncol Biol Phys. 2011; 80(2): 369–376.

[50] Koivunoro H, Hippelainen E, Auterinen I, Kankaanranta L, Kulvik M, Laakso J, et al. Biokinetic analysis of tissue boron ((1)(0)B) concentrations of glioma patients treated with BNCT in Finland. Appl Radiat Isot. 2015; 106: 189–194.

[51] Kondo N, Hirano F, Temma T. Evaluation of 3-Borono-l-Phenylalanine as a Water-Soluble Boron Neutron Capture Therapy Agent. Pharmaceutics. 2022; 14(5): 1106.

[52] Dymova MA, Taskaev SY, Richter VA, Kuligina EV. Boron neutron capture therapy: Current status and future perspectives. Cancer Commun (Lond). 2020; 40(9): 406–421.

[53] Malouff TD, Seneviratne DS, Ebner DK, Stross WC, Waddle MR, Trifiletti DM, et al. Boron Neutron Capture Therapy: A Review of Clinical Applications. Front Oncol. 2021; 11: 601820.

[54] Skwierawska D, Lopez-Valverde JA. Balcerzyk M, Leal A. Clinical Viability of Boron Neutron Capture Therapy for Personalized Radiation Treatment. Cancers (Basel). 2022; 14(12): 2865.

[55] Miyatake S, Kawabata S, Yokoyama K, Kuroiwa T, Michiue H, Sakurai Y, et al. Survival benefit of Boron neutron capture therapy for recurrent malignant gliomas. J Neurooncol. 2009; 91(2): 199–206.

[56] Ono K, Masunaga S-i. Kinashi Y, editors. Neutron irradiation under continuous BPA injection for solving the problem of heterogeneous distribution of BPA. Advances in neutron capture therapy 2006 Proceedings of 12th international congress on neutron capture therapy; 2006; Japan.

[57] Lan TL, Lin CF, Lee YY, Lin KH, Chang FC, Lin SC, et al. Advances in Boron Neutron Capture Therapy (BNCT) for Recurrent Intracranial Meningioma. Int J Mol Sci. 2023; 24(5): 4978.

[58] Takai S, Wanibuchi M, Kawabata S, Takeuchi K, Sakurai Y, Suzuki M, et al. Reactor-based boron neutron capture therapy for 44 cases of recurrent and refractory high-grade meningiomas with long-term follow-up. Neuro Oncol. 2022; 24(1): 90–98.

[59] Miyatake SI, Wanibuchi M, Hu N, Ono K. Boron neutron capture therapy for malignant brain tumors. J Neurooncol. 2020; 149(1): 1–11.

[60] Hiratsuka J, Kamitani N, Tanaka R, Tokiya R, Yoden E, Sakurai Y, et al. Long-term outcome of cutaneous melanoma patients treated with boron neutron capture therapy (BNCT). J Radiat Res. 2020; 61(6): 945–951.

[61] Hirose K, Sato M. Clinical Results and Prognostic Factors in Boron Neutron Capture Therapy for Recurrent Squamous Cell Carcinoma of the Head and Neck Under the Japan National Health Insurance System: A Retrospective Study of the Initial 47 Patients. Int J Radiat Oncol Biol Phys. 2024.

[62] Bae Y-s, Kim D-S, Seo HJ, Han J-U, Yoon HJ, Hwang JJ, et al. Advances of LINAC-based boron neutron capture therapy in Korea. AAPPS Bulletin. 2022; 32(1): 34.

[63] www.ClinicalTrials.gov. A Multi-centered, Radiation Dose Escalation, Open, Exploratory, Phase 1/2a Clinical Trial on the Safety, Efficacy and Pharmacokinetic Characteristics of BNCT(Boron Neutron Capture Therapy) in Patients With Recurrent High-grade Gliomas 2023 [cited 2023 2023-02-21]. Available from: https://clinicaltrials.gov/study/NCT05737212#study-overview

[64] Kawabata S, Suzuki M, Hirose K, Tanaka H, Kato T, Goto H, et al. Accelerator-based BNCT for patients with recurrent glioblastoma: a multicenter phase II study. Neurooncol Adv. 2021; 3(1): vdab067.

[65] Nakagawa Y, Hatanaka H. Boron neutron capture therapy. Clinical brain tumor studies. J Neurooncol. 1997; 33(1-2): 105–115.

[66] Horn V, Slansky J, Janku I, Strouf O, Sourek K, Tovarys F. Disposition and tissue distribution of boron after infusion of borocaptate sodium in patients with malignant brain tumors. Int J Radiat Oncol Biol Phys. 1998; 41(3): 631–638.

[67] Cheng X, Li F, Liang L. Boron Neutron Capture Therapy: Clinical Application and Research Progress. Curr Oncol. 2022; 29(10): 7868–7886.

[68] Barth RF, Yang W, Bartus RT, Moeschberger ML, Goodman JH. Enhanced delivery of boronophenylalanine for neutron capture therapy of brain tumors using the bradykinin analog Cereport (Receptor-Mediated Permeabilizer-7). Neurosurgery. 1999; 44(2): 351–359; discussion 9-60.

[69] Barth RF, Yang W, Rotaru JH, Moeschberger ML, Boesel CP, Soloway AH, et al. Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood-brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine. Int J Radiat Oncol Biol Phys. 2000; 47(1): 209–218.

[70] Barth RF, Yang W, Rotaru JH, Moeschberger ML, Joel DD, Nawrocky MM, et al. Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption. Cancer Res. 1997; 57(6): 1129–1136.

[71] Yang W, Barth RF, Bartus RT, Rotaru JH, Moeschberger ML, Ferketich AK, et al. Improved survival after boron neutron capture therapy of brain tumors by Cereport-mediated blood-brain barrier modulation to enhance delivery of boronophenylalanine. Neurosurgery. 2000; 47(1): 189–197; discussion 97-8.

[72] Yang W, Barth RF, Carpenter DE, Moeschberger ML, Goodman JH. Enhanced delivery of boronophenylalanine for neutron capture therapy by means of intracarotid injection and blood-brain barrier disruption. Neurosurgery. 1996; 38(5): 985–992.

[73] Yang W, Barth RF, Rotaru JH, Moeschberger ML, Joel DD, Nawrocky MM, et al. Enhanced survival of glioma bearing rats following boron neutron capture therapy with blood-brain barrier disruption and intracarotid injection of boronophenylalanine. J Neurooncol. 1997; 33(1-2): 59–70.

[74] Yang W, Barth RF, Rotaru JH, Moeschberger ML, Joel DD, Nawrocky MM, et al. Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of sodium borocaptate with or without blood-brain barrier disruption. Int J Radiat Oncol Biol Phys. 1997; 37(3): 663–672.

[75] Cruickshank G, Detta A, Green S, Lockyer N, Ngoga D, Ghani Z, et al. Et-14 * Optimisation of Boronophenylalanine (Bpa) Delivery and Lat1 Expression for the Clinical Application of Boron Neutron Capture Therapy (Bnct) in Glioblastoma. Neuro-Oncology. 2014; 16(suppl 5): v82–v.

[76] Priest R, Ambady P, Neweult E. Actr-23. Safety of Intra-Arterial Chemotherapy with Osmotic Opening of the Blood-Brain Barrier. Neuro-Oncology. 2018; 20(suppl_6): vi16–vi.

[77] Burgess A, Hynynen K. Drug delivery across the blood-brain barrier using focused ultrasound. Expert Opin Drug Deliv. 2014; 11(5): 711–721.

[78] Power EA, Rechberger JS, Gupta S, Schwartz JD, Daniels DJ, Khatua S. Drug delivery across the blood-brain barrier for the treatment of pediatric brain tumors -An update. Adv Drug Deliv Rev. 2022; 185: 114303.

[79] Uluc K, Neuwelt EA, Ambady P. Advances in Intraarterial Chemotherapy Delivery Strategies and Blood-Brain Barrier Disruption. Neurosurg Clin N Am. 2022; 33(2): 219–223.

[80] Hattori Y, Andoh T, Kawabata S, Hu N, Michiue H, Nakamura H, et al. Proposal of recommended experimental protocols for in vitro and in vivo evaluation methods of boron agents for neutron capture therapy. J Radiat Res. 2023; 64(6): 859–869.

[81] Barth RF, Adams DM, Soloway AH, Mechetner EB, Alam F, Anisuzzaman AK. Determination of boron in tissues and cells using direct-current plasma atomic emission spectroscopy. Anal Chem. 1991; 63(9): 890–893.

[82] Dai Q, Yang Q, Bao X, Chen J, Han M, Wei Q. The Development of Boron Analysis and Imaging in Boron Neutron Capture Therapy (BNCT). Mol Pharm. 2022; 19(2): 363–377.

[83] Smith DR, Chandra S, Barth RF, Yang W, Joel DD, Coderre JA. Quantitative imaging and microlocalization of boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy: relevance to neutron capture therapy. Cancer Res. 2001; 61(22): 8179–8187.

[84] Woollard JE, Blue TE, Curran JF, Mengers TF, Barth RF. An alpha autoradiographic technique for determination of 10B concentrations in blood and tissue. Nuclear Instruments and Methods in Physics Research Section A: Accelerators, Spectrometers, Detectors and Associated Equipment. 1990; 299(1-3): 600–605.

[85] Hatanaka H. Boron-neutron Capture Theory For Tumors: Nishimura Co. Ltd.; 1986: 463.

[86] Barth RF. From the laboratory to the clinic: How translational studies in animals have lead to clinical advances in boron neutron capture therapy. Appl Radiat Isot. 2015; 106: 22–228.

[87] Mishima Y, Ichihashi M, Tsuji M, Hatta S, Ueda M, Honda C, et al. Treatment of malignant melanoma by selective thermal neutron capture therapy using melanoma-seeking compound. J Invest Dermatol. 1989; 92(5 Suppl): 321S–325S.

[88] Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS. Phase I clinical trial design in cancer drug development. J Clin Oncol. 2000; 18(3): 684–692.

[89] Laird M, Matsumoto K, Higashi Y, Komatsu A, Raitano A, Morrison K, et al. Organosilica nanoparticles containing sodium borocaptate (BSH) provide new prospects for boron neutron capture therapy (BNCT): efficient cellular uptake and enhanced BNCT efficacy. Nanoscale Adv. 2023; 5(9): 2537–2546.

[90] Ali F, S Hosmane N, Zhu Y. Boron Chemistry for Medical Applications. Molecules. 2020; 25(4): 828.

[91] Beck-Sickinger AG, Becker DP, Chepurna O, Das B, Flieger S, Hey-Hawkins E. et al. New Boron Delivery Agents. Cancer Biother Radiopharm. 2023; 38(3): 160–172.

[92] Calabrese G, Daou A, Barbu E, Tsibouklis J. Towards carborane-functionalised structures for the treatment of brain cancer. Drug Discov Today. 2018; 23(1): 63–75.

[93] Couto M, Alamon C, Nievas S, Perona M, Dagrosa MA, Teixidor F, et al. Bimodal Therapeutic Agents Against Glioblastoma, One of the Most Lethal Forms of Cancer. Chemistry. 2020; 26(63): 14335–14340.

[94] Hawthorne MF. The Role of Chemistry in the Development of Boron Neutron-Capture Therapy of Cancer. Angew Chem, Int Ed Engl. 1993; 32(7): 950–984.

[95] Jalilian AR, Shahi A, Swainson IP, Nakamura H, Venkatesh M, Osso JA. Potential Theranostic Boron Neutron Capture Therapy Agents as Multimodal Radiopharmaceuticals. Cancer Biother Radiopharm. 2022; 37(5): 342–354.

[96] Sauerwein WAG, Sancey L, Hey-Hawkins E. Kellert M, Panza L, Imperio D, et al. Theranostics in Boron Neutron Capture Therapy. Life (Basel). 2021; 11(4): 330.

[97] Seneviratne DS, Saifi O, Mackeyev Y, Malouff T, Krishnan S. Next-Generation Boron Drugs and Rational Translational Studies Driving the Revival of BNCT. Cells. 2023; 12(10): 1398.

[98] Soloway AH, Tjarks W, Barnum BA, Rong FG, Barth RF, Codogni IM, et al. The Chemistry of Neutron Capture Therapy. Chem Rev. 1998; 98(4): 1515–1562.

[99] Yamamoto T, Nakai K, Matsumura A. Boron neutron capture therapy for glioblastoma. Cancer Lett. 2008; 262(2): 143–152.

[100] Yinghuai Z, Lin X, Xie H, Li J, Hosmane NS, Zhang Y. The Current Status and Perspectives of Delivery Strategy for Boronbased Drugs. Curr Med Chem. 2019; 26(26): 5019–5035.

[101] Zhu Y, Hosmane NS. Nanostructured boron compounds for cancer therapy. Pure and Applied Chem. 2018; 90(4): 653–663.

[102] Barth RF, Mi P, Yang W. Boron delivery agents for neutron capture therapy of cancer. Cancer Commun (Lond). 2018; 38(1): 35.

[103] Oloo SO, Smith KM, Vicente M. Multi-Functional Boron-Delivery Agents for Boron Neutron Capture Therapy of Cancers. Cancers (Basel). 2023; 15(13): 3277.

[104] Monti Hughes A, Hu N. Optimizing Boron Neutron Capture Therapy (BNCT) to Treat Cancer: An Updated Review on the Latest Developments on Boron Compounds and Strategies. Cancers (Basel). 2023; 15(16).

[105] Tibbitts J, Fike JR, Lamborn KR, Bollen AW, Kahl SB. Toxicology of a boronated porphyrin in dogs. Photochem Photobiol. 1999; 69(5): 587–594.

[106] Kahl SB, Koo MS. Synthesis of Tetrakis-Carborane-Carboxylate Esters of 2, 4-Bis-(Alpha, Beta-Dihydroxyethyl)-Deuteroporphyrin-Ix. J Chem Soc, Chem Commun. 1990;(24): 1769–1771.

[107] Hill JS, Kahl SB, Kaye AH, Stylli SS, Koo MS, Gonzales MF, et al. Selective tumor uptake of a boronated porphyrin in an animal model of cerebral glioma. Proc Natl Acad Sci U S A. 1992; 89(5): 1785–1789.

[108] Tibbitts J, Sambol NC, Fike JR, Bauer WF, Kahl SB. Plasma pharmacokinetics and tissue biodistribution of boron following administration of a boronated porphyrin in dogs. J Pharm Sci. 2000; 89(4): 469–477.

[109] Ozawa T, Afzal J, Lamborn KR, Bollen AW, Bauer WF, Koo MS, et al. Toxicity, biodistribution, and convection-enhance. delivery of the boronated porphyrin BOPP in the 9L intracerebral rat glioma model. Int J Radiat Oncol Biol Phys. 2005; 63(1): 247–252.

[110] Rosenthal MA, Kavar B, Hill JS, Morgan DJ, Nation RL, Stylli SS, et al. Phase I and pharmacokinetic study of photodynamic therapy for high-grade gliomas using a novel boronated porphyrin. J Clin Oncol. 2001; 19(2): 519–524.

[111] Rosenthal MA, Kavar B, Uren S, Kaye AH. Promising survival in patients with high-grade gliomas following therapy with a novel boronated porphyrin. J Clin Neurosci. 2003; 10(4): 425–427.

[112] Stylli SS, Kaye AH. Photodynamic therapy of cerebral glioma–a review Part I–a biological basis. J Clin Neurosci. 2006; 13(6): 615–625.

[113] Stylli SS, Kaye AH. Photodynamic therapy of cerebral glioma -a review. Part II -clinical studies. J Clin Neurosci. 2006; 13(7): 709–717.

[114] Barth RF, Yang W, Wu G, Swindall M, Byun Y, Narayanasamy S, et al. Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors. Proc Natl Acad Sci U S A. 2008; 105(45): 17493–17497.

[115] García-Montaño LA, Licón-Muñoz Y, Martinez FJ, Keddari YR, Ziemke MK, Chohan MO, et al. Dissecting Intra-tumor Heterogeneity in the Glioblastoma Microenvironment Using Fluorescence-Guided Multiple Sampling. Mol Cancer Res. 2023; 21(8): 755–767.

[116] Baig S, Winkler F. A holistic view of the malignant organism we call glioblastoma. Cell. 2024; 187(2): 271–273.

[117] Miyatake S, Kawabata S, Kajimoto Y, Aoki A, Yokoyama K, Yamada M, et al. Modified boron neutron capture therapy for malignant gliomas performed using epithermal neutron and two boron compounds with different accumulation mechanisms: an efficacy study based on findings on neuroimages. J Neurosurg. 2005; 103(6): 1000–1009.

[118] Kawabata S, Yang W, Barth RF, Wu G, Huo T, Binns PJ, et al. Convection enhanced delivery of carboranylporphyrins for neutron capture therapy of brain tumors. J Neurooncol. 2011; 103(2): 175–185.

[119] Kahl SB, Koo M-S. Synthesis and Properties of Tetrakis-Carborane-Carboxylate Esters of 2, 4-BIS-(α, β-Dihydroxyethyl) Deuteroporphyrin IX. In: Allen BJ, Moore DE, Harrington BV, editors. Progress in Neutron Capture Therapy for Cancer. Boston, MA: Springer US; 1992: 223–226.

[120] Gupta N, Gahbauer RA, Blue TE, Albertson B. Common challenges and problems in clinical trials of boron neutron capture therapy of brain tumors. J Neurooncol. 2003; 62(1-2): 197–210.

RIGHTS & PERMISSIONS

2024 2024 The Author(s). Cancer Communications published by John Wiley & Sons Australia, Ltd on behalf of Sun Yat-sen University Cancer Center.