Dr. B. S. Sekhon
The 10B isotope is used in pharmaceuticals as an emerging binary therapy called boron neutron capture therapy (BNCT).
BNCT is an investigational form of a two-part radiation therapy which has the potential ability to selectively kill tumor cells embedded within normal tissue. In BNCT, a 10Boron -containing compound that preferentially concentrates in tumor sites is administered intravenously to the patient. It is based on the ability of the non-radioactive isotope 10B to capture thermal neutrons to yield two highly energetic 4He and 7Li nuclei. Both 10B and 4He nuclei have a very short range (about one cellular diameter) and cause significant damage to the tumor cell, while largely sparing healthy tissue cell. A variety of low molecular weight and high molecular weight compounds as boron delivery agents have been developed and are being tested in vitro and in vivo in BNCT.
Scientists are of the opinion that an ideal therapy for cancer is to selectively destroy all tumor cells without damaging normal tissues. In this approach, most of the cancer cells should be destroyed, either by the treatment itself or with the help from the body's immune system; otherwise the danger exists that the tumor may reestablish itself. In spite of today's available standard treatments (surgery, radiation therapy and chemotherapy) for many kinds of cancers, there are still many treatment failures. The promise of a new experimental cancer therapy with some indication of its potential efficacy has led many scientists from around the world to work on an approach called boron nuclear capture therapy (BNCT). BNCT is an experimental combination of chemo- and radiotherapy to treat a malignancy, highgrade gliomas.
Boron is nonmetal in group 13. It has two stable naturally isotopes: 11B and 10B. The very large, effective nuclear cross-section of the 10B nucleus (3837 barns, 1 barn = 10-24 cm2, natural abundance = 19.8 %) makes it highly amenable to the neutron capture process.
What is BNCT?
BNCT is a binary form of cancer radiation therapy which uses a 10Boron -containing compound that preferentially concentrates in tumor sites. The tumor site is then irradiated by a neutron beam. The neutrons in the beam interact with the 10B in the tumor to yield highly energetic 2He4 and recoiling 3Li7 nuclei along with γ-radiation and 2.4 MeV of kinetic energy 1, 2.
Both 3Li7 and 2He4 particles have a very short range (about one cellular diameter) and cause significant damage to the cell in which it is contained. In this way, damage is done to the tumor cell, while largely sparing healthy tissue. It should be noted that boron atoms and neutrons are not cytotoxic on their own, but by combining the components they have the potential to be highly cytotoxic.
In order to be therapeutically useful, an ideal boronated candidate should have the following characteristics (i) high tumor targeting selectivity (ii) low toxicity (iii) appropriate water solubility and (iv) high uptake by cancer cells.
BNCT was proposed in 1936 by Locher3 and the first clinical trials took place at Brookhaven National Laboratory (BNL) in the 1950s and early 1960s using boric acid and some of its derivatives as delivery agents. These simple chemical compounds had poor tumor retention and were nonselective 4, 5.
Among the hundreds of synthesized low-molecular weight boron-containing compounds, there are only two boron compounds that have been used in BNCT clinical trials. These two low molecular weight (LMW) boron delivery agents (administered intravenously) are, sodium mercaptoundecahydrocloso- dodecaborate , called sodium borocaptate (Na2B12H11SH) or BSH (Fig.1a) and second (L)-4-dihydroxy-borylphenylalanine, referred to as boronophenylalanine or BPA (Fig.1b) and these are currently in Phase I and Phase II clinical trials 6-10.
10B enriched BPA, complexed with fructose to improve its water solubility, and BSH have been used clinically for BNCT of brain, as well as extracranial tumors. Scientists observed that the selective accumulation of both compounds in tumors is not ideal but the safety of these two drugs administered has been well established 11-12. Researchers in Europe and Japan are also working on BNCT and the boron compound being used is BSH. Brookhaven’s research with animals has shown BSH to be less effective than BPA in enhancing radiation dose to tumor tissue.
There have been many reports on the use of BSH and BPA in clinical trails for treatment of malignant melanoma and brain tumor 13-15. Further, studies have been reported regarding the effects of boron neutron capture therapy on liver tumors and normal hepatocytes in mice 16. Researchers have published an article in 1987 related to the structure and thermal motion of triphenylboroxin 17.
Recently, several improvements have been made in boron delivery agents and epithermal neutron beam design. Clinical trials were resumed at BNL in 1994 for glioblastoma multiforme (a particularly insidious form of cerebral cancer), at MIT in 1996 for cutaneous and intracerebral melanoma and at the high flux reactor in Petten, Netherlands in 1998 for glioblastoma. The pharmaceutical composition containing a therapeutically effective amount of triphenylboroxin (phenylboronic anhydride) Fig.1c as a boron source and a pharmaceutically acceptable carrier, such as lipiodol has been reported for boron neutron capture therapy 18
A critical and realistic assessment of various aspects of basic and clinical BNCT research which include neutron sources, tumor-targeted boron delivery agents, brain tumor models to assess therapeutic efficacy, computational dosimetry and treatment planning, results of clinical trails in the United States, Japan and Europe, pharmacokinetic studies of BSH and BPA, positron emission tomography imaging of BPA for treatment planning has been reported 19. More recently, it also has been used to treat patients with head and neck 20-21 and metastatic liver cancer 22-23.
High molecular weight boron delivery agents
A variety of high molecular weight (HMW) agents consisting of boron containing macromolecules and nanovehicles as boron delivery agents have been developed and recently reviewed24. HMW boron delivery agents and nanovehicles that potentially could be used clinically for targeting intra and extra-cranial tumors include monoclonal antibodies, dendrimers, liposomes, dextrans, polylysine, avidin, folic acid, epidermal and vascular endothelial growth factors (EGF) and vascular endothelial growth factor (VEGF). HMW delivery agents usually contain a stable boron group or cluster linked via a hydrolytically stable bond to a tumor-targeting moiety, such as monoclonal antibodies (mAbs) or low molecular weight receptor targeting ligands. Examples of these include epidermal growth factor (EGF) or the mAb cetuximab (IMC-C225) to target the EGF receptor or its mutant isoform EGFRvIII, which are over-expressed in a variety of malignant tumors including gliomas, and squamous cell carcinomas of the head and neck. In case of HMW, yet the important challenge is to move from experimental animal studies to clinical biodistribution studies, a step which has yet to be taken or has initiated.
Other classes of boron-containing compounds25-29 have been designed and synthesized that include carborane substituted porphyrin compounds complexed with a metal or transition metal, for example, the dipotassium salt of 2,4-bis-['alpha','beta'-(1,2-dicarbaclosododecaborane carboxy)ethyl]deuteroporphyrin, which is complexed with a metal or a transition metal. These compounds are well solubilized in water, and are suitable for oral administration. Copper tetracarboranyltetraphenylporphyrin 30 (CuTCPH, Fig.2) and its analogues are minimally toxic carborane-containing porphyrins that has safely delivered high concentrations of boron for experimental BNCT
Boron Neutron Capture Using Boron Nanoparticles
The development of boron neutron capture using boron nanoparticles called boron carbide nanoparticles by Thomas Bjørnholm, Ph.D., and colleagues at the University of Copenhagen, in Denmark provided a much needed method for increasing the amount of boron that gets into tumor cells rather than remaining in circulation. Researchers prepared 73-nanometer-diameter boron carbide nanoparticles for uptake by T cells that are targeted to tumors 31. These T cells can be isolated from a patient, loaded with the nanoparticles, and then reintroduced into the patient, where in theory; they travel to tumors and deliver the nanoparticles.
Boronated dipeptide, borotrimethylglycylphenylalanine (BGPA) as a possible boron carrier for BNCT for malignant brain tumours, had the same effect as p-boronophenylalanine (BPA) when used at equal concentrations of 10B in the extracellular medium in vitro32. The amide bond of BGPA is free from enzymatic attack, since it is protected from hydrolysis by the presence of a boron atom at the α-carbon position of glycine and thus appears to have advantages over both BPA and BSH.
Coated nanoparticles can be translocated into murine EL4 thymoma cells and B16 F10 malignant melanoma cells in amounts as high as 0.3 wt. % and 1 wt. %, respectively 33. Neutron irradiation of a test system consisting of untreated B16 cells mixed with B16 cells loaded with boron carbide nanoparticles inhibited the proliferative capacity of untreated cells. These results indicated that cells loaded with boron-containing nanoparticles can hinder the growth of neighboring cells upon neutron irradiation, and could provide the first step toward a T cell-guided boron neutron capture therapy.
Receptor-targeted liposomal delivery of boron-containing cholesterol mimics for BNCT has been developed recently and the results demonstrated that the novel carboranyl cholesterol mimics are excellent lipid bilayer components for the construction of nontargeted and receptor-targeted boronated liposomes for BNCT of cancer 34.
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Dr. B. S. Sekhon, Ex. Professor of Chemistry, Department of Biochemistry and Chemistry, Punjab Agricultural University, Ludhiana -141 004 , India. Main areas of interest include Coordination Chemistry, Bioinorganic Chemistry and Bioorganometallic Chemistry.