University of Arkansas scientists have developed a novel approach to cancer therapy and diagnostics that utilizes nanotubes and other similar nanostructures as both an indirect source of radiation therapy, and as delivery vehicles for other types of radio- and chemo-therapeutic materials, as well as imaging agents for diagnostic purposes. The Board of Trustees of the University of Arkansas (Little Rock, AR) received U.S. Patent 7,608,240 for their discovery.
According to inventors Dan A. Buzatu, Jon G Wilkes, Dwight Miller, Jerry A. Darsey, Tom Heinze, Alex Biris, Richard Berger and Mark Diggs, some embodiments involve the use of boron nitride (BN) nanostructures in boron neutron capture therapy (BNCT). Antibody species are attached to the BN nanostructures to enable them to target tumors when administered to a mammalian subject. These tumor-targeting species are referred to as BN nanostructure-antibody composite species. Once such composite species are in the proximity of a tumor, they can be activated with transdermal neutrons. Once activated, the boron atoms emit alpha particles that are capable of destroying cancerous cells.
Carbon nanostructures (e.g., carbon nanotubes) can be used to deliver radiation to a target region. Radioactive isotopes are attached to a carbon nanostructure to which one or more antibody species are attached. These radioactive-laden carbon nanotube-antibody species can then be employed to selectively target tumors when administered to a mammalian subject.
In other embodiments, tumor cloned IgGs are used to carry nanocontainers (e.g., single-wall carbon nanotubes), bound to the IgGs, to the tumor sites. Ultrasonic waves are then used to explode the carbon nanotubes in the proximity of the tumor. Ultrasound is capable of penetrating deep through tissue without tissue damage because the frequency of the waves can be adjusted to be absorbed only by the target, here carbon or other nanostructures. The technique can also be used to deliver effective chemotherapeutic substances, toxic to a tumor, encapsulated inside the nanostructures.
In all of the above-mentioned embodiments, the BN nanostructures, the carbon nanostructures, and the nanocontainers (nanovessels), can all be encapsulated with a bio-polymer. In some of these embodiments, the antibody species is attached to the nanostructure/nanocontainer through the bio-polymer. Encapsulating materials such as these with bio-polymers can circumvent the need to attach the antibody species (e.g., IgG), and it can reduce potential nanoparticle toxicity and/or enhance the solubility of the IgG-nanostructure complexes in biological fluids.
Tumor cloned IgGs are used to carry nanocontainers, probably single walled nanovessels (e.g., single-wall carbon nanotubes), covalently bound to the IgGs, to the tumor sites. Ultrasound waves with a frequency that is absorbed by the nanotubes (.about.20-40 KHz), are used to explode the carbon nanotubes in the proximity of the tumor. Such use of ultrasound waves to explode carbon nanotubes is analogous to the ultrasound method that is used to destroy kidney stones. Ultrasound is capable of penetrating deep through tissue without tissue damage because the frequency of the waves can be adjusted to be absorbed only by the target, here carbon or other nanostructures. The technique can also be used to deliver effective chemotherapeutic substances, toxic to a tumor, encapsulated inside the nanostructures. Some examples of toxic materials are inorganic substances such as arsenic oxide (AsO), cadmium, cisplatin, etc., as well as organic chemotherapeutic agents such as vinblastine/vincristine, ifosfamide, etoposide, etc.
Unfortunately, while these chemotherapeutic agents are very effective at destroying cells through various mechanisms, they do not discriminate between healthy cells and tumor cells. This can result in the severe side effects that are associated with conventional chemotherapy. However, by using the IgGs to deliver drug-filled nanostructures directly to a tumor, then using ultrasonic waves to break open the nanostructures and release the tumor-toxic substances at the site of the tumor, many of the side effects can be reduced or eliminated. In each case, the IgGs are used to carry nanostructures specifically to a tumor, and ultrasonic waves are used to either explode or break open the nanotubes, destroying the tumor.
Boron Neutron-Capture Therapy
Boron Neutron Capture Therapy (BNCT) is an experimental approach to cancer treatment that is based on a dual-step technique: accumulation of a boron-containing compound within a tumor and treatment with a beam of low-energy neutrons directed at the boron-containing tumor. The nuclei of the boron atoms capture the neutrons and split into two highly charged particles (alpha particle and lithium ion) that have very short path lengths, approximating one cell diameter. These charged particles release sufficient energy locally to kill any tumor cells that contain high concentrations of boron. Over the past nine years, the United States Dept. of Energy (DOE) has supported a nationwide research program to develop BNCT for clinical use.
Catching Neutrons to Combat Cancer
Subjecting boron atoms to low-energy neutron radiation (thermal neutrons) causes the boron nuclei to disintegrate into alpha particles and lithium isotopes with a kinetic energy of 2.5 MeV. When this disintegration occurs in malignant cells, the energy generated is sufficient to destroy them without damaging the neighboring cells, since the range of the particles is only about 10 microns. In such BNCT, it has been estimated that it takes 109 boron atoms per tumor cell for a therapeutic dose. As each tumor cell has about 106 effective antigenic sites that can act as targets, the number of boron atoms required per carrier has been calculated to be 103. Thus, 1,000 boron atoms are needed per antibody molecule for effective treatment. However, this has been heretofore impractical because when this many small carbo-borane molecules are attached to the antibody molecule, it loses its tumor-specific targeting ability.
Other boron-containing compounds (e.g., porphyrins containing boron) currently being used in such therapies, however, generally comprise only a very small amount of boron. It would be useful if a molecular species with a higher percentage of boron (wt. % relative to the overall molecular weight of the molecule) could be used in BNCT.
Boron Nitride Nanotubes
Boron nitride (BN) nanotubes have been synthesized and shown to behave in many ways like their carbon nanotube. For example, they show the same propensity to agglomerate into bundles held together by van der Waals attractive forces. Furthermore, they have been observed to exist as single- or multi-walled varieties. There are notable differences, however, namely that they are insulating and possess a constant bandgap of 5 eV irrespective of tube diameter, number of walls, and chirality.
Use of such BN nanotubes (BNnt) in BNCT would be very advantageous on a percent boron basis--if BN nanotubes could be made therapeutically deliverable. Additionally, other types of nanotubes and nanostructures could be made to serve as delivery vehicles in cancer treatments and in diagnostic imaging. A related advantage is the ability to attach BN nanostructures to an IgG or other targeting biomolecule at only one or a few locations, so that the attached therapeutic atoms do not cover or interfere with the target molecule's receptor and thus compromise specificity.