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
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.
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
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.
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.
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
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
Resonant Theranostics Approach
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.
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
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.
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.
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.
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.
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
The Driving Forces
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.
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.
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.
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
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.)
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
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
- 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.
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.
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.
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.
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
- 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.
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.
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
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
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
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
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 firstname.lastname@example.org.