Boron Chemistry And Applications To Cancer Treatment.pdf

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Neutron capture therapy (NCT) is a type of radiotherapy for treating locally invasive malignant tumors such as primary brain tumors, recurrent cancers of the head and neck region, and cutaneous and extracutaneous melanomas. It is a two-step process: first, the patient is injected with a tumor-localizing drug containing the stable isotope boron-10 (10B), which has a high propensity to capture low energy "thermal" neutrons. The neutron cross section of 10B (3,837 barns) is 1,000 times more than that of other elements, such as nitrogen, hydrogen, or oxygen, that occur in tissue. In the second step, the patient is radiated with epithermal neutrons, the sources of which in the past have been nuclear reactors and now are accelerators that produce higher energy epithermal neutrons. After losing energy as they penetrate tissue, the resultant low energy "thermal" neutrons are captured by the 10B atoms. The resulting decay reaction yields high-energy alpha particles that kill the cancer cells that have taken up enough 10B.

All clinical experience with NCT to date is with boron-10; hence this method is known as boron neutron capture therapy (BNCT).[1] Use of another non-radioactive isotope, such as gadolinium, has been limited to experimental animal studies and has not been done clinically. BNCT has been evaluated as an alternative to conventional radiation therapy for malignant brain tumors such as glioblastomas, which presently are incurable, and more recently, locally advanced recurrent cancers of the head and neck region and, much less often, superficial melanomas mainly involving the skin and genital region.[1][2][3]

James Chadwick discovered the neutron in 1932. Shortly thereafter, H. J. Taylor reported that boron-10 nuclei had a high propensity to capture low energy "thermal" neutrons. This reaction causes nuclear decay of the boron-10 nuclei into helium-4 nuclei (alpha particles) and lithium-7 ions.[4] In 1936, G.L. Locher, a scientist at the Franklin Institute in Philadelphia, Pennsylvania, recognized the therapeutic potential of this discovery and suggested that this specific type of neutron capture reaction could be used to treat cancer.[5][1] William Sweet, a neurosurgeon at the Massachusetts General Hospital, first suggested the possibility of using BNCT to treat malignant brain tumors to evaluate BNCT for treatment of the most malignant of all brain tumors, glioblastoma multiforme (GBMs), using borax as the boron delivery agent in 1951.[6] A clinical trial subsequently was initiated by Lee Farr using a specially constructed nuclear reactor at the Brookhaven National Laboratory[7] in Long Island, New York, U.S.A. Another clinical trial was initiated in 1954 by Sweet at the Massachusetts General Hospital using the Research Reactor at the Massachusetts Institute of Technology (MIT) in Boston.[6]

aThe delivery agents are not listed in any order that indicates their potential usefulness for BNCT. None of these agents have been evaluated in any animals larger than mice and rats, except for boronated porphyrin (BOPP) that also has been evaluated in dogs. However, due to the severe toxicity of BOPP in canines, no further studies were carried out.bSee Barth, R.F., Mi, P., and Yang, W., Boron delivery agents for neutron capture therapy of cancer, Cancer Communications, 38:35 (doi: 10.1186/s40880-018-0299-7), 2018 for an updated review.cThe abbreviations used in this table are defined as follows: BNCT, boron neutron capture therapy; DNA, deoxyribonucleic acid; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; MoAbs, monoclonal antibodies; VEGF, vascular endothelial growth factor.

The technological and physical aspects of the Finnish BNCT program have been described in considerable detail by Savolainen et al.[43] A team of clinicians led by Heikki Joensuu and Leena Kankaanranta and nuclear engineers led by Iro Auterinen and Hanna Koivunoro at the Helsinki University Central Hospital and VTT Technical Research Center of Finland have treated approximately 200+ patients with recurrent malignant gliomas (glioblastomas) and head and neck cancer who had undergone standard therapy, recurred, and subsequently received BNCT at the time of their recurrence using BPA as the boron delivery agent.[13][14] The median time to progression in patients with gliomas was 3 months, and the overall MeST was 7 months. It is difficult to compare these results with other reported results in patients with recurrent malignant gliomas, but they are a starting point for future studies using BNCT as salvage therapy in patients with recurrent tumors. Due to a variety of reasons, including financial,[44] no further studies have been carried out at this facility, which has been decommissioned. However, a new facility for BNCT treatment has been installed using an accelerator designed and fabricated by Neutron Therapeutics.[45] This accelerator was specifically designed to be used in a hospital, and the BNCT treatment and clinical studies will be carried out there after dosimetric studies have been completed in 2021. Both Finnish and foreign patients are expected to be treated at the facility.[46][47][48]

The single most important clinical advance over the past 15 years[51] has been the application of BNCT to treat patients with recurrent tumors of the head and neck region who had failed all other therapy. These studies were first initiated by Kato et al. in Japan.[51][52] and subsequently followed by several other Japanese groups and by Kankaanranta, Joensuu, Auterinen, Koivunoro and their co-workers in Finland.[14] All of these studies employed BPA as the boron delivery agent, usually alone but occasionally in combination with BSH. A very heterogeneous group of patients with a variety of histopathologic types of tumors have been treated, the largest number of which had recurrent squamous cell carcinomas. Kato et al. have reported on a series of 26 patients with far-advanced cancer for whom there were no further treatment options.[51] Either BPA + BSH or BPA alone were administered by a 1 or 2 h i.v. infusion, and this was followed by BNCT using an epithermal beam. In this series, there were complete regressions in 12 cases, 10 partial regressions, and progression in 3 cases. The MST was 13.6 months, and the 6-year survival was 24%. Significant treatment related complications ("adverse" events) included transient mucositis, alopecia and, rarely, brain necrosis and osteomyelitis.

Katsumi Hirose and his co-workers at the Southern Tohoku BNCT Research Center in Koriyama, Japan, recently have reported on their results after treating 21 patients with recurrent tumors of the head and neck region.[71] All of these patients had received surgery, chemotherapy, and conventional radiation therapy. Eight of them had recurrent squamous cell carcinomas (R-SCC), and 13 had either recurrent (R) or locally advanced (LA) non-squamous cell carcinomas (nSCC). The overall response rate was 71%, and the complete response and partial response rates were 50% and 25%, respectively, for patients with R-SCC and 80% and 62%, respectively, for those with R or LA SCC. The overall 2-year survival rates for patients with R-SCC or R/LA nSCC were 58% and 100%, respectively. The treatment was well tolerated, and adverse events were those usually associated with conventional radiation treatment of these tumors. These patients had received a proprietary formulation of 10B-enriched boronophenylalanine (Borofalan), which was administered intravenously. Although the manufacturer of the accelerator was not identified, it presumably was the one manufactured by Sumitomo Heavy Industries, Ltd., which was indicated in the Acknowledgements of their report.[71] Based on this Phase II clinical trial, the authors suggested that BNCT using Borofalan and c-BENS was a promising treatment for recurrent head and neck cancers, although further studies would be required to firmly establish this.

Patients undergoing BNCT are given a boron-based reagent, often injected intravenously, which accumulates in cancer cells. When a stable boron isotope (boron-10) of the reagent is hit by a beam of neutrons in the cancer cells, it captures neutrons, which causes a nuclear reaction and creation of energetic helium (alpha particle) and lithium nuclei. The nuclei deposit their energy within the tumour cell, causing damage and cell death. The tumour is targeted by selectively introducing the boron reagent into tumour cells, and not by aiming the beam at the cells, as in other radiation therapies, in which healthy tissue still may get damaged as a result. The high biological effectiveness of this procedure and the precisely targeted cell damage are major advantages of BNCT in clinical therapy.

Background: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer α particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT.

Third-generation boron delivery agents. So-called third-generation compounds mainly consist of a stable boron group or cluster attached via a hydrolytically stable linkage to a tumor-targeting moiety, such as low molecular weight biomolecules or monoclonal antibodies (mAb). For example, the targeting of the epidermal growth factor (EGF) receptor (EGFR) and its mutant isoform EGFRvIII, which are overexpressed in gliomas as well as in squamous cell carcinomas of the head and neck, also has been one such approach (42). Usually, the low molecular weight biomolecules have been shown to have selective targeting properties and many are at various stages of development for cancer chemotherapy, photodynamic therapy, or antiviral therapy. The tumor cell nucleus and DNA are especially attractive targets because the amount of boron required to produce a lethal effect may be substantially reduced if it is localized within or near the nucleus (43). Other potential subcellular targets are mitochondria, lysosomes, endoplasmic reticulum, and Golgi apparatus. Water solubility is an important factor for a boron agent that is to be administered systemically, whereas lipophilicity is necessary for it to cross the blood-brain barrier (BBB) and diffuse within the brain and the tumor. Therefore, amphiphilic compounds possessing a suitable balance between hydrophilicity and lipophilicity have been of primary interest because they should provide the most favorable differential boron concentrations between tumor and normal brain, thereby enhancing tumor specificity. However, for low molecular weight molecules that target specific biological transport systems and/or are incorporated into a delivery vehicle, such as liposomes, the amphiphilic character is not as crucial. The molecular weight of the boron-containing delivery agent also is an important factor, because it determines the rate of diffusion within both the brain and the tumor. 2b1af7f3a8