Boron Neutron Capture Therapy: A Promising Front on the War on Cancer

Stephanie Baima
CHEM 310: Department of Chemistry, The Pennsylvania State University, University Park, PA 16802

Overview
Neutron capture therapy is a form of radiation therapy that causes damage to cancer cells through nuclear fission. The procedure begins with the injection of a stable, non-radioactive isotope with a high neutron-capture cross section, σ, (high affinity for neutrons) into the tumor. The isotope-containing drug is preferentially taken up by cancer cells and the tissue is exposed to a neutron beam, inducing fission reactions. These reactions produce an alpha particle and a lithium ion, both of which contribute to the destruction of the cancer cells due to their energetic ionizations.

Boronated Drugs
4-dihydroxyborylphenylalanine (BPA) 4-dihydroxyborylphenylalanine, or BPA, (not to be confused with bisphenol A, a chemical used in plastics) is the first low molecular weight boronated drug that has made it through to clinical trials. BPA is a phenyl ring with carboxylic acid, amine, and alcohol functionalities, as seen in Figure 2:

Delivery Methods
Not all boronated drugs are inherently or readily biologically compatible like BPA, thus, functionalization that imparts metabolic uptake is vital. The following four delivery methods have been developed: An emulsion, or mixture of immiscible liquids, has proven to be an effective delivery method for BSH, as evidenced by tumor:healthy tissue ratios of >4. Lipiodol, a poppy seed-based oil originally used as a contrast agent in radiology, as well as iodised poppy seed oil, have been used to form water-inoil-in-water emulsions with BSH. A bilayer version of a micelle called a liposome has shown promise as a boronated drug delivery method in two different ways. Liposomes, with their hydrophobic centers may be used to encapsulate a hydrophobic (lipophilic) drug such as BSH. Alternatively, if the “heads” of the phospholipid components of the bilayer contain the boronated drug, it may be delivered via incorporation.

Figure 2. 4-dihydroxyborylphenylalanine (BPA).

Sodium mercaptoundecahydrocloso-dodecaborate (Na2B12H11SH)
Figure 1. Reaction scheme of Boron Neutron Capture Therapy (BNCT).

Why Boron?
Suitable anti-cancer agents must possess the following characteristics:  Low toxicity. Boron has a negligible toxicity.  Availability. The non-radioactive boron-10 isotope has a natural abundance of 19.9% .  Effective in fission reaction. Boron has a comparatively large effective nuclear cross-section σ, (~1000 times greater than hydrogen’s σ), which correlates to a high neutron-uptake.  Selectivity.  Steady concentration.  Ability to penetrate the blood-brain-barrier. Boron alone does not meet these requirements, however it may be functionalized by attachment to a carrier/delivery molecule designed to meet these needs.

Sodium borocaptate, or BSH, is the second low molecular weight boronated compound that has persisted in clinical trials. BSH is an icosahedra-type carborane compound, as seen in Figure 3. Carboranes are neutral, lipophilic, cluster/cage-like structures composed primarily of carbon, boron, and hydrogen. Carborane-containing compounds have shown promise in BNCT research due to their low toxicity, metabolic persistence (stability), and ease of functionalization.

Figure 4: Left: encapsulation method, right: incorporation method.

Dendrimers, or repetitively, symmetrically branched molecules, may also be used to deliver boronated drugs. Scientists have a high degree of control over the structure of dendrimers, and are thus able to produce heavily boronated compounds that are also highly amenable to functionalization.

Internal voids
Figure 3. Sodium borocaptate (BSH).

Core

References
1. 2. Calabrese, G.; Nesnas, J.; Barbu, E.; Fatouros, D.; Tsibouklis, J. The formulation of polyhedral boranes for the boron neutron capture therapy of cancer. Drug Discovery Today. 2012, 17, 153-159. Molinari, A.; Emiliano, C.; Hughes, A.; Heber, E.; Garabalino, M. “Sequential” Boron Neutron Capture Therapy (BNCT): A Novel Approact to BNCT for the Treatment of Oral Cancer in the Hamster Cheek Pouch Model. Radiation Research. 2011, 175, 463-472. Petersen, M.; Petersen, C.; Agger, R.; Sutmuller, M.; Jensen, M. Boron Nanoparticles Inhibit Tumor Growth by Boron Neutron Capture Therapy in the Murine B16-OVA Model. Anticancer Research. 2008, 28, 571-576. Lin, Y.; Wang, S.; Chung, H.; Liu, H.; Chou, F. Low dose of gamma irradiation enhanced boronophenylalanine uptake in head and neck carcinoma cells for boron neutron capture therapy. Applied Radiation and Isotopes. 2011, 69, 1728-1731. Molinari, A.; Emiliano, C.; Hughes, A.; Heber, E.; Garabalino, M. Tumor Blood Vessel “Normalization” Improves the Therapeutic Efficacy of Boron Neutron Captrue Therapy (BNCT) in Experimental Oral Cancer. Radiation Research. 2012, 177, 59-68.

Use of BNCT
BNCT and other targeted cancer treatments are on the frontier of current cancer research since they spare healthy tissue. Furthermore, because neutron capture therapy is non-invasive, this method has a lot of potential applications for inoperable cancers, particularly brain tumors, where surgery presents the most risk. Although hundreds of boron-containing compounds have been tested to date, all but the two discussed here have failed to make it through to clinical trials. Researchers have seen some success in both animal-based and human trials, however BNCT hasn’t yet produced better results than old standbys like cis-platin. Hopefully, with continued research and development this more targeted alternative will prove to be a useful weapon against cancer.

Branching units

Densely packed surface groups

3.

Figure 5: Dendrimer structure.

4.

5.

Finally, carbon nanotubes have recently been introduced as a drug delivery method. Little is known about their toxicity, however nanotubes are easily and densely functionalizable,. They are also able to pass the blood-brain-barrier, making the attached boronated drugs accessible to brain tumors.

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