Auger therapy (AT) is an emerging form of radiation therapy for the treatment of cancer that relies on large numbers of low-energy electrons emitted via the auger effect to damage cancer cells, rather than the high-energy forms of radiation more traditionally used in radiation therapy.   As in other forms of radiation therapy, auger therapy relies on radiation-induced damage to cancer cells - particularly DNA damage - in order to arrest cell division, stop tumor growth and metastasis, and ideally kill existing cancerous cells. It differs from other forms of radiation therapy because the electrons emitted via the auger effect, the auger electrons, are released in large numbers with low kinetic energy. Because of their low energy these electrons exert their damaging effect on cellular structures over a very short range - less than the size of a single cell, and on the order of nanometers.  This very short-range delivery of energy allows for the potential of highly targeted therapies since the radiation emitting nuclide is essentially required to be inside the cell to cause damage to its nucleus, but for the same reason it is a technical challenge since auger therapeutics must get inside their cellular targets to be maximally effective.   In effect, this means that auger therapeutics currently tend to be small molecules that are capable of specifically entering cells of interest and/or binding to specific sub-cellular components, which contain one or more heavy atoms that are capable of emitting auger electrons - either by radioactive decay, or by some form of external excitation. 
- 1 Auger Dose Evaluation
- 2 Candidates of Molecular Modifications with in situ Auger Dose
- 3 Monochromatic X-rays to induce Inner Shell Ionization
- 4 References
Auger Dose Evaluation
The electron energy in a vacuum can be measured accurately by using an electron detector housed in a Faraday cage, for example, where the bias placed on the cage will accurately define the particle energy reaching the detector. The range of low energy electrons in tissue or water, particularly those electrons at the nm scale, however, cannot easily be measured and must be inferred because low energy electrons are easily scattered in very large angles and will travel in a zigzag path whose termination distance must be considered statistically and from differential measurements of higher energy electrons at a much higher range. 20 eV electron, in water, for example, could have a range of 20 nm for 103 gray or 5 nm for 104.7 gray, and for a group of 9-12 Auger electrons with energies at 12-18 eV in water, including the effect of water ionization at approximately 10 eV, an estimate of 106 gray is probably sufficiently accurate. Figure 1 shows the simulated dose calculation in water for a single electron using Monte Carlo random walk  that gives up to 0.1 MGy; therefore for a moderately heavy atom to yield a dozen or more Auger electrons from its inner shell ionization, the Auger dose becomes 106 gray per event.
Figure 1, the Simulated Radiation Dose of a Single Electron in Water, where the Ionization Energy of Water at ~10 eV shows a Resonant Enhancement in Dose. The Upper and Lower Curve stand for the Short and Long Limiting Ranges Respectively. Note that in vacuum, the kinetic energy mev2 =1eV implies an electron velocity of 6x107 cm/s, or 0.2% of the speed of light.
Candidates of Molecular Modifications with in situ Auger Dose
With a very large localized dose in situ for molecular modifications, the most obvious target molecule is the DNA duplex where the two complementary strands are separated by only a few nm. Atoms form the DNA duplex, however, are light elements with only a few electrons each and even if they could be induced by a photon beam to deliver the Auger electrons, the said photons at under 1 keV will be too soft to penetrate any range of tissue thickness to be useful for therapy. Mid-ranged or heavy atoms, from bromine to platinum for example, that could be induced by sufficiently hard X-ray photons to generate enough electrons to provide many low energy charges in an Auger cascade, will be considered in several different therapeutic considerations.
Auger Electrons from Br for the Disruption of a Herpes-Specific Gene Expression
When a normal tissue/cell becomes transformed and replicates non-stop, many unusual genes, including sometimes viral materials such as the Herpes genes that are not expressed normally, becomes expressed with certain viral-specific functions.
The molecules under consideration to disrupt the Herpes gene is BrdC, where the Br replaces a methyl (CH3) where they have almost exactly the same ionic radius and sit normally at the 5th position for BrdU, which has an oxygen at top. BrdC could, therefore, be oxided and be used as BrdU. But prior to become oxide, BrdC could neither be used as dC or dU in mammalian cells except for the Herpes gene that could incorporate the BrdC as given. Next, the bromine atom is made from the element arsenic with the addition of an alpha particle in an ion accelerator to form 77Br with a half-life of 57 hours from its K-electron being captured by a proton from an unstable nucleus and creates a K-hole in Br, leading to bromine's Auger cascade and disrupting the Herpes gene without killing the cell.
This experiment was carried out at Sloan-Kettering by Drs. Lawrance Helson and CG Wang in the 1970s  using 10 different neuroblastoma cell lines, from which two lines were successful in terminating the cell replication with 77Br in vitro and the experiments were followed with a group of nude mice with tumor implants.
The in vivo experiments of mice, however, were complicated by the fact that mice’s liver which would cleave off the sugar component of BrdC that renders both the mammalian and Herpes genes to incorporate the 77Br-containing base with no distinction between them. Nevertheless, the Auger dose with 77BrdC did disrupt the Herpes-specific gene for several transformed cell lines.
Food color Red #95, Rose Bengal, can be ingested with minimal toxicity. The red molecules contain 4 iodine atoms each and when diffused into cells, particular into those leaky transformed cells, they are quickly sent to/absorbed by the lysosomes attached at the goggi complex.
Lysosomes are very small sacks of hydrolytic enzymes in the cytoplasm at pH5. They were discovered by Christian deDuve using centrifugation to separate the cellular components.
In normal cellular functions, lysosomes together with proteosomes would digest a great variety of unwelcomed or discarded cellular components or molecules. With Rose Bengal distributed in the lysosome sac, the Auger dose induced by the inner shell ionization of iodine would disrupt the acidic sacs and alter the pH of the cytoplasm, making it a localized chemotherapy.
The field of metal-based anticancer drugs was initiated by cisplatin, one of the leading agents in clinical use. Cisplatin acts by binding to DNA and forms 1, 2 intrastrand cross-links of the G-G adduct at 70% and the A-G adduct at ~20% of the major groves of the DNA duplexes. The planer cis (on the same side) compound is composed of a square molecule with two chloride ligands on one side and two ammonia ligands on the other side centered with the heavy Pt that could initiate the Auger dose in situ. Upon entering the cell with low NaCl concentration, the aqua/chloride ligands would detach from the compound and allows the sites missing chloride to link up G-G or A-G bases and bend the DNA duplexes 45o to result with a damaging 3-D conformation. Since the discovery in 1978, cisplatin has been extended to carboplatin, nedaplatin and oxaliplatin with minor modifications. They are applied as one of the principle drugs in cancer treatments involving as much as 70% of all chemotherapies at approximately $2 billion in annual sales. Powerful as they are, the platinum drugs are not particularly effective against certain cancers such as breast and prostate tumors. The molecular modifications using in situ megaGy Auger dose could greatly enhance and alter the DNA duplexes in two important aspects:
• Conventional cancer treatment is to kill the transformed cancer cells, and not necessarily aim to alter the transformation process. For cells to replicate, their DNA duplexes must be reproduced precisely in each cell cycle using the “Zipper” during mitosis. Under the MegaGy in situ Auger dose, the nano-scaled damages would likely go well beyond any single DNA strand that can usually be repaired through its complementary strand, but if both the duplex strands are damaged the coding information of DNA becomes lost and the damage becomes beyond repair. We aim to make the zipper getting stuck, so to speak, without necessarily killing the cell, and bring the cell into a state of senescence, and achieve a different mode of therapy, perhaps a more effective method of cancer treatment.
• The second point is that the radiation and chemo dosages are applied to the treatment. Since the DNA genome is a single duplex molecule of 9 billion bases at one meter long without coiling, a single or a few breakages anywhere over the meter long molecule could stop the replication process instead of statistically creating sufficient damages to kill the cell. This senescence rationale would dramatically reduce both the chemo and the radiation doses for reduced side effects as well as deliver the chemo treatment locally as needed.
The aqua/Cl rationale of having the chloride ligands detached from the cisplatin upon entering a cell and become active to bind to G-G or A-G adducts in the major groves of the DNA duplexes, could be applied to other metals such as ruthenium (Ru) having similar chemical properties like Pt. Ru is several times more expensive than Pt, and is used in medical instruments to coat the anode target of mammography X-ray tube in order to avoid any line-emissions so that the mammography tube can be operated with any voltage (22-28kVp) according to the compressed thickness of the breast and deliver an image with a high shadow contrast. While Ru is much lighter than Pt, it can similarly be induced to provide MegaGy Auger dose in situ, and like Pt drugs to function in the DNA adducts, and could also deliver localized chemo treatments. 
Auger Dose for Localized Disruption Using Gadolinium for Oncology and for Deaggregation of Amyloid-β
Gadolinium (Gd) has the highest diamagnetic moment in the periodic table and has been broadly utilized in MRI as a contrast agent. For cancer metastasis, for example, the presence of Gd-compound in MRI from a leaky neovasculature has become the gold-standard for metastasic evaluations.
At a nm scale, the in situ AT could provide molecular modifications. But at a cellular dimension of micrometres, the enhanced Auger dose could increase the irradiating X-ray dose by only a factor of 2 or 3. Having such an enhancement factor, nevertheless, it enables a convenient mode of radiation that the X-ray beam can be used as a complement to surgical procedure to “mop-up” some local area/tissues without undergoing the full high energy gamma beams from various angles.
Photons reaching the K-absorption edge of Gd can be delivered by thulium (Tm) K-emissions using a transmission X-ray tube with a Tm target. That is, the Tm-based X-ray tube would not only enhance the X-ray scattering cross-section with Gd embedded in the target location/region by an enhancement factor of a few on the micrometre-sized scale, but also deliver the 106 Gray in situ to perform molecular modification such as de-aggregation of the Amyloid-β of Alzheimer’s plaques. Figure 2  outlines the formation of mis-folded protein to the plaque material.
Monochromatic X-rays to induce Inner Shell Ionization
X-ray Tube with Transmission Target for Line-Emissions
Monochromatic X-rays can be channeled from synchrotron radiation, obtained from Coolidge X-ray tubes with extensive filtering, or from the preferred transmission X-ray tubes.
To induce an inner shell ionization with resonant scattering from a moderately heavy atom with dozens of electrons, the X-ray photon energy must be 30 kV or higher in order to be effective to penetrate tissues for therapeutic applications. Synchrotron radiation is extremely bright and monochromatic without thermal scattering loss, but its brightness falls off at the 4th power of the photon energy, and at 15-20 kV or higher, a low cost X-ray tube with a Moly target for example, could deliver as much X-ray fluence as that of a typical moderately-sized synchrotron instrument. In fact, the Coolidge X-ray tube becomes bright by (kVp)1.7 while the synchrotron brightness goes like (kV)-4, implying that it is generally not useful for desired Auger therapy.
Coolidge X-ray tubes become brighter at higher energies, but by using external filters to haverst the useful photons without having the tissue to be exposed to unnecessary skin dose, the X-ray tube fluence must typically reduce by two orders or more in brightness, which is not an ideal case for therapy applications. This leaves the unique X-ray tube with end-window transmission targets.
In a transmission X-ray target, the X-rays are harvested along the direction of the e-beam path, in contrast to the conventional Coolidge tube where the X-rays from a solid target are collected mostly at 90° from the e-beam path. The said X-ray beam has a sharp cut-off blocked by the target material at angles much beyond 90°, and becomes much softer at angles below 90°. As a result, the useful X-ray beam from a typical Coolidge tube is only 12-14o, although such a narrow cone could be extended along the surface of the solid target to result with a fan-beam that is commonly employed for body-slicing in computed tomographic (CT) imaging.
To harvest the X-ray fluence at 90° from the e-beam path is indeed an optimal position in brightness without relativistic transform. Being six years older than Einstein, Coolidge at the turn of the 20th century did not engage the proper electron dynamics with his design, the hundred years old patented X-ray tube including the rotational anode design for heat spread for higher thermal load. With relativistic transform, the bremsstrahlung trajectories become forward leaning, moving along the e-beam direction, and if the X-ray fluence is collected from the transmission target in the forward direction and integrated over the azimuth angles, the X-ray fluence could typically be several hundredfold enhanced as compared to the Coolidge tube. More importantly, the e-beam range in an X-ray target material is only a few micrometres, so that for a 30 μm thick transmission X-ray target, most of the target thickness would function as a filter that not only absorbs the very low energy photons, but also transfers high energy photons into the fluorescent K or L-lines characteristic to the target element. In addition, the monochromatic line-emissions are emitted from the same refined X-ray focal point. Figure 4.1 demonstrates the K-line emissions of Moly and Silver targets, showing that the transmission target would deliver mostly bright, monochromatic X-rays from the small X-ray focal point defined by the e-beam focus.
Figure 4.1 Transmission X-ray Tube Spectrums with Moly and Ag Targets
Transmission Tube Structure
By mixing the function of e-beam target with X-ray filtering, the transmission tube is different from the conventional Coolidge X-ray tube in several structured designs.
For a Coolidge tube, the filament for e-beam is at ground potential so that it can readily use a tungsten hair-pin to heat with several amperes of current. For a transmission target, the target must be grounded and the e-beam filament becomes negatively biased for the kVp, from which the filament current of several amperes cannot readily be supplied from a high voltage cable. As a result, the X-ray transmission tube and its high voltage power supply are integrated in a single unit in order to avoid the use of a massive high voltage cable as shown in Figure 4.2.
The transmission X-ray tube could deliver the X-ray beam far more efficiently than one using a solid e-beam target. Nevertheless, the thin target sheet has limited thermal capacity so that the target sheet must be attached to a thicker, thermally conductive material that is highly transparent to X-rays. Be of a few mm thick is therefore used for the end-window material that conducts the heat, seals the vacuum and positions the target layer.
The e-beam target layer could also be formed with a stack of different materials with each having a different set of line-emissions and allow the e-beam to be electronically switched to reach the desired layer for the preferred line-emissions. This line-emission with an electronically tunable feature could be very useful for image manipulation.
While this is a lower power unit than the proposed X-ray generator for AT, they are all small and portable.
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