Patent Application
20140326900
The present disclosure relates generally to devices and methods for synthesizing radionuclides, and more particularly, to the use of a quasi-neutral plasma jet for the synthesis of radionuclides.
Positron emission tomography (PET) is a method of imaging that uses radiolabeled probe molecules to target, detect, and quantify biological processes in vivo. PET techniques are used to study disease mechanisms, to develop new diagnostic and therapeutic methods, to detect early stage disease, and to monitor responses to therapies. The equipment, infrastructure, and personnel currently required to produce PET probes severely constrain the availability and diversity of probes, hindering advances in disease diagnosis, therapy, and medical research that requires this imaging method.
The approach to synthesis of biochemical compounds with radioactive nuclei generally starts with a charged particle accelerator. Particle accelerators have the following attributes: an ion source, electrostatic extraction optics that select a single polarity of ion for acceleration, electromagnetic fields to accelerate and focus the ions, a vacuum chamber to prevent elastic and inelastic scattering of the ion beam, collimation apertures, and external shielding to protect operators and electronics from neutron and ionizing radiation produced in the accelerator. Referring to
Effective formation and acceleration of ions by electromagnetic fields requires operation in vacuum chamber (105), so the next step impinges the energetic ion flux through a window material (105) and onto a solid, liquid, or gas precursor material (106). The energetic ions convert some of the precursor (106) to radionuclides (107) by nuclear reactions. The mixture of precursor and radionuclides (106, 107) are transferred (108) to a separately shielded (109) hot cell or microfluidic reactor where chemical reactions (110) and purifications (111) convert the radionuclide into an injectable radiochemical reagent.
The collision of the accelerated ions with the precursor material occasionally results in a nuclear reaction whose probability is quantified as the integral of the product of a cross-section Q(E), the energy distribution of the ion flux (f(E)), and the relative velocity of the ion and precursor nuclei (v(E)). The rate of radionuclide (RN) production from a concentration of precursor is given by
These nuclear reactions yield an unstable material that decays by releasing a positron, which in turn collides with an ambient electron to produce two counter-propagating gamma rays. The gamma rays are then recorded by coincidence detection in a toroidal sensor. Following tomographic inversion the location of the decaying radionuclide can be determined to within fractions of a millimeter. PET imaging has been applied to the diagnosis of vascular function (Laking et al., The British Journal of Radiology, 76 (2003), S50-S59 E), arthritis (Bruijnen et al., Arthritis Care & Research Vol. 66, No. 1, January 2014, pp 120-130), and tumerogenesis (Aluaddin, Am J Nucl Med Mol Imaging 2012; 2(1):55-76), among many others.
The specific activity (SA) of a radioactive tracer is an important figure of merit for a PET reagent. It is defined as the intensity of radiation divided by the mass or number of moles of material, and it decreases with time (t) according to the expression exp(−t/τ) where the decay rate (1/τ) is a fundamental property of the specific radionuclide. This decay begins the moment a radionuclide is formed, and extensive research has been devoted to methods of swiftly and efficiently inserting the radionuclide into a biological probe through chemical reactions and purifications to produce a PET reagent in the shortest possible times.
Representative values of τ are listed in table I. Small values of τ imply rapid decay, which is advantageous because it produces more decay events per second and therefore greater signal to noise ratios when collecting image data. However, for these same values of τ any factor that increases t leads to a faster loss of potency of the reagent.
11C
11B
11C
14N
13N
13C
13N
16O
15O
15N
15O
16O
18F
18O
One problem with the current methods is their requirement for an accelerator or cyclotron to produce the ion beam from which radionuclides are formed. Cyclotrons require heavy and expensive magnets, high voltages, substantial electric power, and extensive radiation shielding. For example, Bhaskar Mukherjee has summarized the shielding requirements in Optimisation of the Radiation Shielding of Medical Cyclotrons using a Genetic Algorithm, which is incorporated herein by reference in its entirety. According to Mukherjee, “[t]he important radioisotopes produced by Medical Cyclotrons for present day diagnostic nuclear medicine include 201Tl (T1/2=73.06 h) and 67Ga (T1/2=78.26 h). These radioisotopes are generated by bombarding the thick copper substrates electroplated with enriched parent target materials with 30 MeV protons at ˜400 μA beam current. The target bombardments result in the production of intense fields of high-energy neutrons and gamma rays.” A summary of medical cyclotron characteristics abstracted from a presentation by Jean-Marie Le Goff, [A very low energy cyclotron for PET isotope Production, European Physical Society Technology and Innovation Workshop Erice, 22-24 Oct. 2012] is reproduced in Table II. As can be seen with reference to Table II, the average weight of a medical cyclotron is 36 tons, the average weight required for shielding is 47 tons, and the average power requirement is 101 kilowatts. The smallest device in Table II has a total weight of ten tons and requires 10 kW of power. In other words, the size, weight, and power of a cyclotron require that it be placed in a fixed installation.
A second problem with PET isotope synthesis stems from the fact that materials prepared at the fixed cyclotron site lose specific activity during transport to the site where patients are scanned. This problem is particularly acute when the transport time t_transport is long compared to the decay time τ, because the specific activity drops by exp(−ttransport/τ).
A third problem results from the economics of producing the reagents at a central site. In order to spread the capital and operating costs of the facility many doses must be made at once, and these must be distributed in a timely manner to patients at dispersed locations. This complicates the logistics of patient care because scanning facilities must be choreographed with the production schedule of the cyclotron while accounting for material degradation in transit.
Yet another problem is that isotopes with very short lifetimes (small values of τ) cannot be used except in very close proximity to the accelerator because their specific activity degrades too rapidly to permit detection with useful signal to noise ratios in a PET scanner. For example, the half-life of H215O, a PET tracer used to measure perfusion in cardiac imaging, is only 2 minutes.
Another problem is that production of multiple doses at once requires higher beam currents, which in turn demand windows between the vacuum and precursor regions that can manage thermo-mechanical stresses without significantly degrading the energy or current of the ion beam. A second problem with higher beam currents is collateral radiation damage to the chemical composition of the precursor. The irradiation of a large protein molecule containing nitrogen with large currents of 2H+ ions from a cyclotron to synthesize 15O radiolabels, for example, may degrade or denature the protein. This collateral damage limits the range of precursor materials to those that resist radiation damage, such as H218O, one precursor for production of 18F by proton beams.
Once a radionuclide is formed it can be chemically bound into a molecule that serves to mark specific molecular or biological activity. For example, 18F is produced from H218O as aqueous 18F− anions that are converted through one or more chemical reactions to 18F-fluoro-deoxyglucose. This injectable reagent is taken up in vivo by cells and accumulates in their mitochondria, providing an indication of cellular metabolism rates. These chemical reactions and purifications are performed in heavily shielded enclosures or ‘hot cells’, named so due to the large amount of shielding required to prevent radiation exposure to the operators. The typical reaction volume of “hot cells” is of the order of 1 milliliter (mL) though the amount of radioactive atoms or molecules present is extremely small, typically 6×1011 atoms or molecules. A typical processing time processing (tprocess) is 40-50 minutes, that with the exception of 18F, exceeding by far the decay time of most interesting RN. The time and care required for this manual conversion contributes significantly to loss of specific activity in the final product.
Van Dam et al. disclosed a significant improvement in U.S. Pat. No. 7,829,032, entitled Fully Automated Microfluidic System for the Synthesis of Radiolabeled Biomarkers for Positron Emission Tomography, which is incorporated herein by reference in its entirety. Incorporating small-volume, automated processing substantially reduced the time required to convert radioactive precursors to injectable reagents, enabling higher specific activity and safer production than prior methods. However, a limitation of this approach is that it separates production of the radioisotope from chemical conversion, so the time to transfer radionuclides between a cyclotron and the microfluidic system (ttransfer), indicated schematically by (108) in
U.S. Pat. No. 8,080,815 discloses use of microfluidic systems to synthesize radioactive tracers, which is incorporated herein by reference in its entirety. This reference discloses use of commercial micro-fluidic technology to process radionuclides created by a small cyclotron accelerator that separately produces radionuclide for one dose for human image needs, for example approximately 10 milliCurie (mCi) for 18F-fluoro-deoxyglucose. This method suffers from all of the shielding and auxiliary deficiencies of electromagnetic accelerators, and also from the need to convey radionuclides from the cyclotron to the microfluidic reactor as indicated by (108) in
Referring to
Efficient generation of radionuclides requires maximizing the integrated product of the velocity-weighted energy distribution f(E)*v(E) with the cross section Q(E) in equation 1 above. Another problem with accelerator-based radionuclide synthesis is that the resulting ion beams generally have energies well above that for which the radionuclide precursor has its maximum cross section. This in turn requires larger currents to increase the production rate, concurrently increasing collateral radiation damage to the precursor materials.
Accordingly, there exists a need for additional devices and methods for production of radioactive reagents, and in particular, devices and methods that avoid the aforementioned limitations. Such devices and methods would be particularly useful in nuclear medicine, including positron emission tomography.
Disclosed herein are methods and apparatus for portable production of radiolabeled chemical compounds for use in nuclear medicine, radiology, and medical imaging. The methods use a directed jet of quasi-neutral plasma to activate precursor materials that undergo nuclear reactions and produce radionuclides. The radionuclides can be subsequently converted to radiolabeled compounds (e.g., radionuclides can be converted by microfluidic reactions and purifications to an injectable radioactive reagent).
The plasma jet can be produced by firing a sub-picosecond laser pulse with peak power greater than about one terawatt and less than about thirty terawatts at a solid, liquid, or gaseous target in vacuum. The jet can be directed by target normal sheath acceleration through a window onto a solid, liquid, or gaseous precursor that undergoes nuclear reactions to produce radionuclides. The irradiated precursor can be contained in a disposable reusable cartridge that converts the radiolabeled precursor into injectable reagent using standard microfluidic chemical reactions and purifications. The wavelength, pulse duration, focus, and energy of the laser, as well as the density gradients, composition, and orientation of the target can be selected to produce a plasma jet whose ion energy distribution substantially overlaps the cross-section for nuclear transformation of the precursor to a desired radionuclide.
The apparatus can have dramatically smaller size, weight, power, shielding requirements, and operating costs than prior systems, thereby allowing portable devices that can be located proximate to the patient and imaging scanner. The disclosed methods and apparatus moreover can relieve the logistical burden of transporting radioactive materials and scheduling patients, and provide radioactive probes with higher specific activity and shorter half-lives to be used in nuclear medicine and medical imaging. These and other advantages of the method and apparatus will be apparent from the detailed description below.
The present disclosure relates to methods and devices for synthesizing radiochemical compounds. The methods include generating a quasi-neutral plasma jet, and directing the plasma jet onto a radionuclide precursor to provide one or more radionuclides. The radionuclides can be used to prepare radiolabeled compounds, such as radiolabeled biomarkers.
The methods and devices can use a quasi-neutral plasma jet impinging through a window onto a precursor in a microfluidic reactor for subsequent chemical reactions and purifications. The plasma jet can be produced by target normal sheath acceleration created by a light pulse interacting with a dense solid, liquid, or gaseous target. This can eliminate the need for conventional accelerators, reducing the size, weight, power, and shielding requirements, and enabling portable production of and access to short-lived radioisotopes for biomedical imaging and radiology.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.
The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.
The conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term. For example, the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B are present. The phrases “at least one of A, B, . . . and N” or “at least one of A, B, . . . N, or combinations thereof” are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.
The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.
The term “pre-pulse light,” as used herein, may refer to light that arises from amplified spontaneous emission whose intensity is less than about 10−4 times that of the main pulse. The energy in the pre-pulse can be spread out over much longer times and may cause ionization of target material that interferes with TNSA. There are two types of pre-pulses: (1) pedestal—duration of a few to tens of picoseconds—since this is long compared to the light pulse its intensity is comparatively small; and (2) leakage from a regenerative amplifier whose duration is slightly longer than the light pulse so its relative intensity is 10−6 to 10−8.
Radionuclides can be created by bombardment of a precursor with a quasi-neutral plasma jet, and in particular, a quasi-neutral plasma jet that contains a significant flux of positive ions with an energy distribution f(E) that spans the cross section Q(E) of the relevant nuclear reaction. Referring to
The disclosed methods do not require isolation of charged particles with one polarity. The absence of an electromagnetic accelerator can reduce the size, weight, power, and shielding requirements for the system to the point that it can be portable. Since the synthesis of the PET reagent can occur proximate to the patient, the contribution of ttransport to the decay of specific activity is reduced or eliminated.
Referring to
One example of optimizing production according to equation 1 refers to
A first step may include converting the energy of short, high power pulses of light to energetic plasma jets by bombarding thin material targets. Coherent light sources that generate ultra-short (0.03-2 picoseconds), high power (>1018 Watts/cm2) pulses in the wavelength range of 0.5-10 nm and experiments using them to bombard targets revealed that judicious choice of the laser and target parameters converts photon energy to quasi-neutral energetic jets of plasmas with controlled ionic content. The fundamental physical process, known as Target Normal Sheath Acceleration (TNSA), converts pulses of light to energetic, quasi-neutral plasma jets with hot electrons (temperature of several Mega-Electron Volts (MeV)) and protons with energy up to 30 MeV. These plasma jets have high brightness (>5×1010 protons per pulse), small virtual source size (<1 μm), low emittance (0.005π mm·mrad) and conversion efficiency of light energy to multi-MeV protons between 1-10%. Machi, in Superintense Laser-Plasma Interaction Theory Primer, Springer Briefs in Physics, (New York:Springer Verlag, 2013), summarizes the experimental and theoretical developments of converting light to quasi-neutral plasma jets, the disclosure of which is incorporated herein by reference in its entirety.
TNSA can include two steps. A first step comprises the almost instantaneous ionization and formation of quasi-neutral plasma with electrons whose temperature substantially exceeds that of the heavier positive ions. An important parameter for TNSA is the ratio of the maximum plasma density n to the critical density of the plasma nc, defined on the basis of the laser parameters as nc=1.1×1021λ−2 cm−3, where λ is the laser wavelength in microns (μm). The critical density is the plasma density at which the laser frequency equals the electron plasma frequency. Experiments and theory have established that, for subcritical interactions, when n<nc, the target is transparent to radiation and very little laser energy is transferred to the plasma. Optimal coupling occurs for values equal to or slightly above nc. Another important parameter that controls the conversion of light energy to energetic plasma jets is the value of the dimensionless vector potential, α0, =0.6λ √I, where I is the laser intensity in units of 1018 W/cm2 and λ is the laser wavelength in μm. The parameter α0 represents the ratio of the oscillatory momentum of the plasma electrons in the presence of the laser field to moc. The electron temperature Te is of the order of the cycled averaged oscillation energy in the electric field of the laser light in vacuum and is given by
Values of αo larger than unity imply that the temperature of the electrons Te exceeds one MeV. Computer simulations and experiments indicate that the distribution function of the hot electrons fe has the form:
The second step involves expansion of the hot electrons into the vacuum surrounding the thin target, producing a transient electrostatic sheath. Quasi-neutrality is quickly restored by transferring energy from the hot electrons to the ions. Self-similar solutions confirmed by experiments indicate formation of a quasi-neutral energetic plasma jet containing ions with energy up to 10 Te follows charge neutralization.
In certain embodiments, a short laser pulse can be impinged onto solid targets to produce a quasi-neutral plasma jet with an ion energy distribution falling between about 1 and about 15 MeV. Examples of a solid target include polymeric or metallic foils with adsorbed moisture, hydrogen, deuterium, or molecules containing hydrogen, thin metallic targets upon which one or more, less dense “foam” layers are deposited [Sgattoni et al., Physical Review E85,036405, 2012] and “limited mass targets” [Buffechoux et al, Physical Review Letters 105, 015005, 2010] with surface area smaller than 104 μm2 and thickness less than 10 μm.
In certain embodiments, a short laser pulse can be focused onto a liquid film or liquid droplet to produce a quasi-neutral plasma jet. The liquid composition and optical thickness are chosen so as to maximize the plasma density gradient following irradiation, which in turn produces optimal target normal sheath interactions.
In certain embodiments, a short laser pulse can be impinged onto a pulsed gas jet. This composition of the gas jet is chosen to produce specific ions of, for example, H+, D+, or He+. A second requirement for the gas jet is that it have sufficient optical and mass density to produce plasmas with n>nc and sharp gradients in the plasma density following the first few femtoseconds of the irradiation. In order to achieve these conditions, the backing pressure behind the pulsed valve from which the jet is formed preferably exceeds 100 kPa, and more preferably is greater than 10 MPa. A sub millimeter diameter pulsed gas jet device described by Sylla et al. [Review of Scientific Instruments, 83, 033507,2012] produces pressures of 30-40 MPa, enabling TNSA under overcritical or critical conditions and facilitating control of the plasma density gradients.
Many pulsed light sources produce optical radiation that precedes the light pulse. This ‘pre-pulse’ radiation can interact with the target and interfere with TNSA. In certain embodiments, one or more plasma mirrors [Monot et al., Optics Letters, 29, 8093,2004; Buffechoux et al. Physical Review Letters 105, 015005, 2010] can be utilized to preferentially absorb this radiation and to thereby increase the ratio of energy in the light pulse to that preceding the light pulse, also known as pre-pulse contrast, above 1010.
In certain embodiments, plasma microlenses [Kazir et al., Applied Physics Letters, 95,031101, 2009; Nakatsutsumi et al., Optics Letters 35, 2314, 2010] can be used to increase the light intensity on the target by about a factor of 10 and to achieve extremely low focal f-numbers. This can increase the conversion efficiency of light to plasma jets and can reduce the diameter of the plasma target chamber to less than about 15 cm, enabling the system size and weight to be substantially less than prior art cyclotrons and linear accelerators.
Recognizing that ions produced by TNSA are emitted in the direction normal to the target surface, whether the target is flat or has curvature, the quasi-neutral plasma jet can be focused by appropriately shaping the target surface, for example by the use of a concave or spherical target. Ion beams produced by traditional accelerators are strongly defocused by the Coulomb force between ions, requiring strong electrostatic and magnetic fields to collimate and direct the ions. The disclosed plasma jets are quasi-neutral and can be focused with relative ease. Focusing from a curved target was demonstrated experimentally, where the plasma jet intensity increased by an order of magnitude when spherical, rather than flat, thin foil targets were used. [Kaluza et al., Phys. Rev. Lett., 93, 045003-1-4 (2004)]. The same logic applies to liquid and gas jet targets, where the geometric shape of the target density profile can be chosen to focus the quasi-neutral plasma jet.
The light pulse may be generated by commercial Ti:sapphire laser systems with appropriate optics, such as the Amplitude Technologies TT-Mobile system. [http://www.amplitude-technologies.com]. Alternative methods for producing sub-picosecond optical pulses with minimal pre-pulse energy including fiber amplifiers, Nd:YAG amplifiers, optical parametric chirped-pulse amplifiers, and the like are familiar to those practiced in the art of laser physics and may be used so long as the value of α0 is greater or equal to 1.
The laser pulse energy, duration, and wavelength are chosen to produce a quasi-neutral plasma whose energy distribution f(E) maximizes the production rate of radionuclide from the specific solid, liquid, or gaseous target based on their cross-sections Q(E) in accordance with equation 1. Examples of controlling f(E) and the efficiency of TNSA by combinations of laser energy, pulse shape, transient plasma lenses and mirrors, and various target compositions with pulsed light sources are shown in
The proton flux induced by the hydrocarbon target was five times larger than for the gold target. Analysis and simulations indicate that the ionic component of the energetic plasma jets has three different origination channels: from the rear side to the forward direction, from the front side to the forward direction, and from the front side to the backward direction. The efficiency and energy of the plasma jet depend strongly on the sharpness of the density gradient [Mackinnon et al. Physical Review Letters 86,1769, 2001]. In most of the early experiments the sharpest density gradient occurred on the illuminated side of the target thereby generating a dominant plasma jet in the backward direction.
The influence of target thickness on TNSA has been elucidated. Referring to
The understanding of the role of the laser pulse shape led to the development of additional scaling laws. First, experiments [Ceccotti et al., Physical Review Letters, 99, 185002, 2007] discovered that the maximum energy and the conversion efficiency continue to increase for target thickness smaller than 10 μm, as long as the contrast between laser pulse and its pre-pulse is very large. These results are shown in
These and other considerations provide control of f(E) and light to plasma jet conversion efficiency through changes in the geometry, phase (solid, liquid, or gas), and dimensions of the target as well as the focus, energy, pulse shape, and wavelength of the light source.
The precursor material, a non-limiting example being H218O, can be exposed to the plasma jet through a suitable window material. Since the plasma is formed in a vacuum and the precursor is a condensed or gaseous phase with non-zero pressure, a material that is transparent to and undamaged by the quasi-neutral plasma and that does not leak or fail from the pressure difference between the precursor and the vacuum chamber is preferred. Transparent materials preferably have average atomic numbers less than about 12, for example poly-p-phenylene-benzo-bis-oxazole (PBO), or an aramid such as Kevlar™ which contain only C, H, O, and N. PBO and Kevlar are non-limiting examples of materials with large elastic moduli (315 GPa and 125 GPa, respectively) and tensile strengths, as well as low gas permeabilities. A thin film or foil of these and similar materials can provide an impermeable barrier between the precursor at high pressures and the plasma jet in the vacuum chamber while being transparent to the MeV ions and electrons that comprise the plasma jet.
In certain embodiments, radionuclides are formed directly in the microfluidic reactor that subsequently transforms the radionuclide into an injectable reagent through chemical reactions and purifications. This can eliminate the time required to transfer (ttransfer) radionuclides formed in cyclotrons to hot cells or microreactor systems, thereby increasing the specific activity of the product.
In certain embodiments, a reusable or, preferably, a disposable sterile microfluidic cartridge is provided that contains the window, precursor, and other chemical materials to complete transformation of a quasi-neutral plasma flux into an injectable reagent. Individual doses of various nuclear probe molecules can be conveniently prepared from the same system without requirements for cleaning, radioactive decontamination, or sterilization.
The ability to prepare useful quantities of short-lived radioisotopes incorporated into arbitrary molecular compositions gives rise to further embodiments in non-destructive testing of materials and systems, tagging, tracking, and locating, and other non-medical applications.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art.
This application claims the benefit of priority to U.S. Provisional Application No. 61/807,218, filed Apr. 1, 2013, which is herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61807218 | Apr 2013 | US |
