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The X-ray: Reloaded
Rearming radiography with resonant theranostics

By Eric H. Silver, PhD, Anil K. Pradhan, PhD, and Yan Yu, PhD

Article available online at: http://www.rt-image.com/1201Reloaded

Resonant theranostics (RT) is a new, integrated approach to cancer diagnosis and therapy born from an interdisciplinary collaboration between scientists working in atomic and molecular spectroscopy, astrophysics, nanotechnology/nanomedicine, X-ray instrumentation, radiation therapy, and biomedical robotics.

RT promises to be extremely efficient in diagnostic radiology, reducing radiation exposure by factors from 10 to 100. For therapeutic applications, the radiation dose to neighboring healthy tissue will be significantly lower than in conventional methods.

The Underplayed X-ray

Since Wilhelm Roentgen obtained the first X-ray image of the human hand on film in 1895, the generation and detection of ionizing radiation for biomedical use has not changed fundamentally.

Externally energized X-ray sources are all based on the production of Bremsstrahlung radiation, in which a beam of energetic electrons is decelerated by striking a target made from an element with a high atomic number, Z. Photons are emitted with energies spreading over a continuous spectrum up to the maximum kinetic energy of the electrons being accelerated.

However, the prevailing use of broadband continuum radiation is problematic from the biophysical perspective. Low-energy X-rays are too readily absorbed by otherwise healthy tissue, and malignant tissue is transparent to high-energy X-rays, resulting in unnecessary radiation exposure across the entire spectral band.

The ideal approach is to target precisely tuned radiation with maximal absorptive capacity at the tumor site. Until now, healthcare professionals have not utilized this kind of line radiation for clinical applications. However, incremental improvements have been made since Roentgen’s time.

X-ray filters are used to reduce the amount of unwanted low-energy photons that contribute to shallow doses, and specialized targets are used in mammography to limit the amount of high-energy photons that often reduce soft-tissue contrast.

Similarly, megavoltage linear electron accelerators are used to achieve skin-sparing and penetrative quality in therapeutic radiology. In radiography, multiple rotating solid-state detectors, flat-panel and cone-beam tomographic reconstruction geometries have largely replaced screen-film. However, the detector elements do not discriminate and sort photons based on their energies.

Using radiation in these ways profoundly limits our approaches to disease detection/screening, diagnosis, treatment, monitoring of early response and follow-up. To date, the detailed elemental composition and concentrations that can be extracted from full spectroscopic analysis of tissue absorption and fluorescent emission are completely lost.

For megavoltage (MV) therapy, control over energy specificity is indirect and minimal. In addition, it’s impossible to target a specific type or depth of tissue using a single radiation beam – after an initial buildup approximately equal to the range of energetic Compton electrons, absorbed dose continually decreases with depth due to tissue attenuation, causing collateral damage throughout.

In order to deliver a tumoricidal dose to the target site while sparing adjacent, overlying, and underlying normal tissues, 3-D conformal treatment planning and intensity-modulated radiation therapy (IMRT) have been developed. However, these solutions clearly do not directly address the problem: Therapeutic MV radiation is indiscriminant of tissue types, whether malignant or benign.

It is well known that IMRT may increase the probability of second malignancies in long-term cancer survivors due to lower concentrations of radiation to larger volumes of the body – this, in turn, has spurred interest in proton therapy. Proton (and heavy ion) beams preferentially deliver the dose at the Bragg peak – a measure of the energy loss of ionizing radiation during its travel through matter.

By modulating the beam energy, the Bragg peak can be placed at the tumor depth and scanned over the target volume. However, the cost, infrastructure, and personnel requirements of a proton therapy facility are so exorbitant that it is unlikely to meet even a fraction of society’s healthcare needs.

In light of this, there is clearly a need to reexamine the present-day use of diagnostic and therapeutic X-ray regimens and to develop more targeted, disease-specific methodologies based on advances in X-ray physics and biomedical nanotechnology.

Resonant Theranostics Approach

Every element or compound has a unique spectral fingerprint in the X-ray band of the electromagnetic spectrum. One can observe these signatures whenever the atoms in a substance emit or absorb X-rays.  Using advanced spectroscopic instruments, these telltale features manifest as extremely narrow peaks or valleys at specific energy locations along the smooth continuum of background Bremsstrahlung radiation.

The depth of the valleys can be very large, especially in the heavier elements, and there are specific atomic energy levels that are more prone to X-ray absorption than others. The overall vision of RT is a paradigm change from traditional X-ray imaging and therapy to resonance spectroscopic disease identification, localization, and ablative therapy.

For diagnostics, tracer quantities of any known high-Z elemental contribution can be identified through resonant excitation by a monochromatic X-ray light source matched to the spectroscopic signatures of the high-Z atomic species, while depositing a minimal dose to nonresonant normal tissues.

Any endogenous tracer elements or exogenous nano-engineered targeting agents can be specifically targeted by creating a plasma of matching atomic species in a novel X-ray light source, called an electron beam ion trap (EBIT).

For therapeutic applications, the same resonantly matched EBIT X-ray source would be operated at high output flux, and the plasma ionization would be tuned to produce the appropriate emission for resonant absorption by the high-Z tagged species in the tissue. The dose in the vicinity of the target would be greatly enhanced, while the dose elsewhere along the beam path would be minimal.

Since K-shell ionization energies of high-Z elements, such as gold, are approximately 80 keV, attenuation lengths for photons at these resonant energies are approximately 20 cm; therefore K-shell resonant absorption by nanoparticles attached to tumors will serve as diagnostics. Resultant L-shell fluorescent emission due to Auger decay would be localized, owing to its short attenuation of less than 1 cm, and will serve as therapy components.

A micro-plasma, or a plasmoid on nanoscales, will be created by multiple stages of ionization in vivo within the target volume, mirroring the ionization/ recombination rates of the X-ray source plasma. However, the ablative effects of this type of in vivo plasmoids have not been studied to date, because such conditions do not yet exist in biomedical media.

Imaging in the Quantum Age

The implications of this transition from using traditional X-rays to in vivo absorption and fluorescence are far-reaching. Firstly, diagnostic imaging studies can achieve very high sensitivity (below 100 fluorescent photons), high specificity (limited only by specific uptake of high-Z species), at low body dose (no resonant absorption by low Z species that make up tissue composition).

In the long run, tissue diagnosis may be avoided because fluorescent spectroscopy is an excellent tool to differentiate atomic and molecular level signatures nondestructively (virtual biopsy). For early detection, significantly lower body doses may lead to population screening for more disease sites or even whole-body screening – provided that safety issues relating to nanoparticles are understood.

Secondly, therapeutic ionizing radiation will be truly target-seeking, similar to treatments using monoclonal antibodies to seek out specific tumors that over-express certain proteins. Dose sparing of normal tissues is only limited by the uptake specificity of high-Z species.

For example, if high-Z vehicles become available to target a systemic disease, it would be plausible to administer total-body irradiation at very low organ doses. Also, the need to artificially define a tumor margin for treatment planning could be eliminated, as micro-metastases are labeled for fluorescent absorption of tumoricidal dose while in-field normal tissue absorbs minimal dosage.

There may be no need for shielded treatment rooms, thus the entire paradigm of radiotherapy will be shifted away from current environments and into truly versatile, interactive settings that are conducive to patient encounters.

The Driving Forces

The proposed framework of rationally designed atomic level theranostics will be built upon three key components: EBIT, cryogenic X-ray spectroscopic calorimeter, and resonant spectral modeling.

  • EBIT
For the last 20 years, the EBIT has been used by astrophysicists to simulate plasma conditions found in stars. A beam of electrons is injected by an electron gun into an accelerating structure (electrostatic drift tubes) and focused by magnetic coils. Acceleration is by means of the voltage bias applied to the drift tubes, similar to traditional X-ray tubes.

Additionally, the electron beam is compressed down to approximately 75 Ìm in diameter by a strong axial magnetic field. An operating voltage of 40 keV is enough to theoretically strip any element to the helium-like state, and even to fully strip elements up to an atomic number of 50.

The energy of the electron beam can be varied up to just beyond 200 keV in a Super EBIT to produce hydrogen-like uranium, which has the highest atomic number (Z=92) among the naturally occurring elements. The EBIT plasma is created by electron impact ionization of the elemental species by the electron beam.

Fluorescent X-rays are emitted and can be harvested through ports surrounding the plasma. The X-ray photons are characteristic of the trapped element and its stage of ionization in the plasma. In addition, there is no Bremsstrahlung background.

For RT, the objective is to convert the EBIT into a unique and inexpensive biomedical X-ray source. By adding a set of magnetic and electrostatic lenses to the EBIT, the highly charged ions can be extracted from the trap. (See Figure 1.) 

A simple X-ray microscope results through subsequent slow collisions of the extracted ions with an electron source, thin foil. The interaction with the foil will prompt X-ray emission as the ions recombine and the X-rays will be characteristic of the atomic structure of the recombining ions.

By making the target material from a very thin film of plastic or beryllium, the X-rays produced by the ions will pass through to a detector or eventually to a target of live tissue for study. It is a highly novel concept for producing ionizing radiation tuned to match the resonant absorption energies of the embedded nanoparticle tracers.

  • Cryogenic X-ray Spectroscopic Calorimeter
Broadband nondispersive devices, such as proportional counters, solid state detectors, and several kinds of scintillating materials, obtain X-ray spectra over an energy range of many keV. Although they have poor-to-modest energy resolution, their quantum efficiency can approach 100 percent.

For certain applications, such as charged coupled devices, arrays of these detectors are used for imaging as well. Narrow-band dispersive instruments, such as diffraction gratings or Bragg crystals, are used to study discrete spectral features. These possess high resolving power but only modest efficiencies.

Position-sensitive broadband detectors are used to record the dispersed spectrum. All of these instruments have been the traditional tools for X-ray spectroscopy in atomic and nuclear physics, astrophysics, materials science, solid-state physics, and biological and medical physics.

Although they have yielded many excellent results, their limitations have made it difficult to address scientific problems that require high spectral resolution, broad energy coverage, and high efficiency simultaneously.

This motivated the X-ray astronomy community to embark on the development of cryogenic X-ray microcalorimeters 20 years ago. In a microcalorimeter, X-ray photons are absorbed by a metal foil and converted into heat. (See Figure 2.)

The resulting temperature rise is proportional to the X-ray energy. Microcalorimeters combine the broadband response and high efficiency of the conventional nondispersive detector with a resolving power approaching that of a crystal or grating spectrometer. (See Figure 3.)

Initially, RT professionals will use the microcalorimeter to verify the resonant absorption signatures predicted by their atomic physics calculations in a variety of elements – with atomic numbers ranging from Z=33 to Z=79. The microcalorimeter will allow them to tune the EBIT plasma to the band of resonant absorption edges in the tagged nanoparticles.

For RT, the microcalorimeter will be used as an imaging spectrometer. Its unprecedented signal-to-noise ratio means that it can identify line emission with less than 20 counts per energy resolution element. This means that the eventual dose for diagnostic imaging will be extremely low.

  • Nano-Plasma Spectral Modeling
RT entails targeting K-resonance complexes while trapping resultant fluorescent radiative decays from L- and M-shells, and electron cascades from multiple ionization stages. The basic scientific principles are well-established and have recently been investigated theoretically.

The largest resonances arise simply from strong dipole transition arrays associated with 1s-2p (K), 2p-3d (L), 3d-4f (M) complexes, which can contain many thousands of lines concentrated in specific energy ranges. Note that the in situ production of secondary low-energy electrons by Auger ionization would also induce DNA strand breakup via electron attachment resonances.

Therefore, resonant fluorescence yields two exactly complementary branches of photon emission and electron ejection for in vivo theranostics. Furthermore, the near-resonance enhancement, relative to off-resonance, should be a factor of 11.6 for K-shell resonances, and a factor of 1,200 for the huge L-shell resonance arrays.

Also of importance, these resonances are not at the K- and L-shell ionization edges, as previous investigations assumed. In fact, they are generally spread over a narrow energy range (approximately 0.5 keV) located significantly below the edge energies. This spread refers to multiple ionization stages of the element undergoing Auger ionization.

Our on-resonance computational estimates indicate that Au K-emission energies at a tumor located 10cm deep in tissue and behind 2 cm of bone is to be up to 656 percent that of the maximum dose anywhere in the tissue (assuming zero uptake in tissue).

It has already been shown that in vivo X-ray irradiation of gold nanoparticles embedded in cancerous tumors in mice leads to significant reduction in the tumor. However, these studies have not exploited the new concept of targeted resonant spectroscopy, which should result in a large increase in the dose at the high-Z uptake site, while significantly reducing the overall dose to the tissue.

In order to achieve resonance specificity, we will compute and model the entire spectrum of targeted nanoparticles and nano- and microplasmoids created by X-ray irradiation, including all subsequent pathways and processes, for a wide variety of physical conditions and 3-D geometries.

Since the resultant products of resonant complexes in nano-plasmoids would be trapped inside the tumor, it’s essential to model a priori, and calibrate against EBIT experiments.

Initially, such experiments and calibration would be carried out in vitro for relatively lighter-Z compounds of bromine and iodine, Bromodeoxyuridine, and Iodeoxyuridine injected intratumorally. Later experiments would calibrate the high-Z compounds, such as platinum, using cis-Pt or gold nanoparticles.

The Long-Term Goals

We envision theranostic techniques in which any heavy-element-tagged nanoparticles or contrast agents developed for disease-specific targeting can be activated using resonant absorption by matching ion plasmas generated by an EBIT.

As an imaging method (see Figure 1), its versatility should far exceed PET, dynamic contrast-enhanced MRI, and magnetic resonance spectroscopic  imaging because the resonance absorption magnifies the presence of nanoparticles without introducing systemic radioactivity. Indeed, certain diagnostic procedures may be turned into screening procedures that minimize normal tissue exposure.

For example, if chest imaging can be performed at one-hundredth of a standard chest CT dose, yearly lung cancer screening would be equivalent to 10 days of exposure to natural background radiation.

As a therapeutic oncology procedure, the highly concentrated – but relatively safe – transfer of energy at the heavy-element site should compare favorably to treatments using proton or ion beams, while the cost and shielding of an EBIT facility should be a fraction of an MRI or linear accelerator installation.

— Eric H. Silver, PhD, is a senior astrophysicist at the Cambridge, Mass.-based Harvard-Smithsonian Center for Astrophysics; Anil K. Pradhan, PhD, is professor of astronomy at the Columbus-based Ohio State University; and Yan Yu, PhD, is professor and director of medical physics at the Philadelphia-based Thomas Jefferson University Medical School. Questions and comments can be directed to editorial@rt-image.com.






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©iStockphoto.com/Christopher Pattberg
©iStockphoto.com/Christopher Pattberg

Figure 1: In X-ray theranostics, the ions from the EBIT are extracted through a vacuum pipe and focused onto a thin window located near the sample. The sample is rotated in order to obtain a 3-D image, and can also be translated vertically if it is larger than the acceptance angle of the detector array. To minimize the X-ray dose to the sample from the X-rays that are not subtended by the detector at the source, a collimating aperture is placed along the source-detector line-of-sight. (Harvard-Smithsonian Center for Astrophysics)
Figure 1: In X-ray theranostics, the ions from the EBIT are extracted through a vacuum pipe and focused onto a thin window located near the sample. The sample is rotated in order to obtain a 3-D image, and can also be translated vertically if it is larger than the acceptance angle of the detector array. To minimize the X-ray dose to the sample from the X-rays that are not subtended by the detector at the source, a collimating aperture is placed along the source-detector line-of-sight. (Harvard-Smithsonian Center for Astrophysics)

Figure 2: SEM micrograph of a single detector pixel microcalorimeter
Figure 2: SEM micrograph of a single detector pixel microcalorimeter

Figure 3: Microcalorimeter spectrum of Kr XXVII in the EBIT. The strongest Ne-like lines are labeled by 3s and 3d. Lines from higher lying levels are also observed. These are fluorescent lines and there is no bremsstrahlung background.
Figure 3: Microcalorimeter spectrum of Kr XXVII in the EBIT. The strongest Ne-like lines are labeled by 3s and 3d. Lines from higher lying levels are also observed. These are fluorescent lines and there is no bremsstrahlung background.








©iStockphoto.com/Christopher Pattberg
©iStockphoto.com/Christopher Pattberg

Figure 1: In X-ray theranostics, the ions from the EBIT are extracted through a vacuum pipe and focused onto a thin window located near the sample. The sample is rotated in order to obtain a 3-D image, and can also be translated vertically if it is larger than the acceptance angle of the detector array. To minimize the X-ray dose to the sample from the X-rays that are not subtended by the detector at the source, a collimating aperture is placed along the source-detector line-of-sight. (Harvard-Smithsonian Center for Astrophysics)
Figure 1: In X-ray theranostics, the ions from the EBIT are extracted through a vacuum pipe and focused onto a thin window located near the sample. The sample is rotated in order to obtain a 3-D image, and can also be translated vertically if it is larger than the acceptance angle of the detector array. To minimize the X-ray dose to the sample from the X-rays that are not subtended by the detector at the source, a collimating aperture is placed along the source-detector line-of-sight. (Harvard-Smithsonian Center for Astrophysics)

Figure 2: SEM micrograph of a single detector pixel microcalorimeter
Figure 2: SEM micrograph of a single detector pixel microcalorimeter

Figure 3: Microcalorimeter spectrum of Kr XXVII in the EBIT. The strongest Ne-like lines are labeled by 3s and 3d. Lines from higher lying levels are also observed. These are fluorescent lines and there is no bremsstrahlung background.
Figure 3: Microcalorimeter spectrum of Kr XXVII in the EBIT. The strongest Ne-like lines are labeled by 3s and 3d. Lines from higher lying levels are also observed. These are fluorescent lines and there is no bremsstrahlung background.









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