Patent Application
20080038190
a) is an illustration of a composition comprising a microparticle including a radioactive isotope and an imageable element in accordance with some embodiments.
b) is an illustration of a composition comprising a microparticle including a radioactive isotope, and a dopant included in the microparticle in accordance with some embodiments.
a) is a block diagram of an apparatus including an imaging system, a radioactive microparticle, shown in
b) is a block diagram of an apparatus including an imaging system, a microparticle that is not radioactive, and an enriched paramagnetic isotope in accordance with some embodiments.
a) is an illustration of a composition 100 comprising a microparticle 102 including a radioactive isotope 104 and an imageable element 106 in accordance with some embodiments. The microparticle 102 including the radioactive isotope 104 and the imageable element 106 is suitable for use in connection with the treatment of disease and imaging. For example, the radioactive isotope 104 can be used in cancer treatments, and the imageable element 106 can be used to identify the location of the microparticle 102 in a subject, such as a cancer patient, after infusion. Infusion includes infusion by a catheter or injection by a syringe. Methods of infusion are shown and described in U.S. Pat. No. 4,745,907 which is incorporated herein by reference. The imageable element 106 is also suitable for use as a diagnostic tool in pre-treatment assessments or in conjunction with treatment of a disease. For example, the imageable element 106 can be used to determine the distribution of the microparticles 102 within a subject after infusion. In applications in which the infused microparticles are intended for delivery to a human liver, the approximate percentage of microparticles delivered to the lung, which is sometimes referred to as a “lung shunt”, can be determined through imaging. “Lung shunt” can vary among individuals. Thus, “lung shunt” information obtained through pre-treatment infusion and imaging at a substantially zero radioactive dosage level can be used to customize a treatment for a particular individual. The information can also be used to determine the radiation dose delivered to diseased tissue versus the radiation dose delivered to healthy tissue in a target organ which is also helpful in treatment planning. In one embodiment, the target organ is a human liver.
The microparticle 102 is not limited to having a particular shape or size. The shape of the microparticle 102 is selected for compatibility with the application in which the microparticle 102 is employed. For example, in pre-treatment evaluation applications, the shape of the microparticle 102 is selected to be substantially the same as the shape of the microparticle used in the treatment. In some embodiments, such as embodiments suitable for use in connection with cancer treatments, the microparticle 102 is substantially spherical.
The microparticle 102 has a size on the order of microns and can range from a fraction of a micron to thousands of microns. The size of the microparticle is selected for compatibility with the intended application. For example, an exemplary microparticle suitable for use in connection with a cancer treatment, such as a treatment for liver cancer, can have a diameter between about 0.1 micron and about 1000 microns. For pre-treatment applications, such as pre-treatment evaluations performed on animals, including humans, the microparticle 102 is substantially spherical and has a diameter substantially equal to the diameter of the microspheres used in the treatment. For diagnostic applications, the size of the microparticle is selected to achieve the desired results of the intended application.
A radioactive isotope of an element is a form of the element having an unstable nucleus that stabilizes itself by emitting radiation. The radioactive isotope 104 included in the microparticle 102 is not limited to a particular radioactive isotope.
Exemplary radioactive isotopes suitable for use in connection with the microparticle 102 include the following therapeutic radioisotopes: As-211, P-32, Y-90, Cl-36, Re-186, Re-188, Au-198, Ho-166, 1-131, Lu-177, P-33, Pr-147, Sc-47, Sr-89, S-35, 1-125, Fe-55, and Pd-103.
The imageable element 106 is selected for compatibility with one or more imaging systems. For example, in some embodiments the imageable element 106 is selected for compatibility with a magnetic resonance imaging (MRI) system.
Exemplary materials suitable for use in connection with imaging in a magnetic resonance imaging (MRI) system include paramagnetic materials and enriched paramagnetic materials or isotopes. In a paramagnetic material the atomic magnetic dipoles of the material have a tendency to align with an external magnetic field. A paramagnetic material exhibits magnetic properties such as experiencing a force when placed in a magnetic field. Exemplary paramagnetic materials suitable for use in connection with the formation of the composition 100 include H-1, He-3, Li-7, B-7, B-9, N-15, O-17, F-19, Mg-27, Al-27, Si-29, S-33, Cl-37, Ca-43, Ti-47, V-51, Cr-53, Mn-55, Fe-57, Ni-61, Cu-63, Zn-67, Ga-69, Ge-73, Kr-83, Sr-87, Y-89, Zr-91, Mo-95, Mo-97, Ru-99, Rh-103, Pd-105, Cd-111, Sn-115, Te-125, I-127, Ba-135, Ba-137, Xe-129, Xe-131, Nd-145, Gd-155, Dy-161, Er-167, Yb-171, W-183, Os-187, Pt-195, Hg-199, Tl-205, Pb-207, Pt-198, and H-2. The imageable element 106 can be incorporated into microparticles including those described in U.S. Pat. No. 4,789,501 titled Glass Microspheres, U.S. Pat. No. 5,011,677 titled Radioactive Glass Microspheres, U.S. Pat. No. 5,011,797 titled Composition and Method for Radiation Synovectomy of Arthritic Joints, U.S. Pat. No. 5,039,326 titled Composition and Method for Radiation Synovectomy of Arthritic Joints, U.S. Pat. No. 5,302,369 Microspheres for Radiation Therapy, U.S. Pat. No. 6,379,648 titled Biodegradable Glass Compositions and Methods for Radiation Therapy, and U.S. Pat. No. 5,885,547 titled Particulate Material. These United States patents are incorporated herein by reference.
An enriched paramagnetic material is a paramagnetic material in which the concentration of one or more isotopes of the paramagnetic material has been increased above the naturally occurring concentration. For example, the naturally occurring concentration of Gd-155 is about 14.8% in nature. Gd-155 is enriched when the concentration is increased to a concentration greater than about 14.8%. Methods of enrichment known to those skilled in the art of nuclear physics and chemistry and suitable for use in connection with the formation of the composition 100 include gaseous diffusion, chemical separation, electromagnetic separation, and laser separation. The preparation of the composition 100 is not limited to a particular enrichment or isotope separation method. The enrichment method is selected for compatibility with the materials selected to be enriched and to achieve the desired level of enrichment
The degree of enrichment of the imageable element 106 is not limited to a particular value. A higher level of enrichment results in increased signal strength and a higher resolution image. To increase signal strength for magnetic resonance imaging, Fe-57 is enriched to reduce radioactive impurities, Fe-54 and Fe-58 are substantially eliminated. Fe-54 can become a radioactive impurity with a single neutron capture. Fe-58 can become a radioactive impurity with a single neutron capture. In some embodiments, the imageable element 106 is enriched to a concentration of about 90%. In some embodiments, Fe-57 is enriched to a concentration of greater than about 92%. In some embodiments, Fe-57 is enriched to a concentration of about 92.88%. Enriching Fe-57 to a concentration beyond 90% increases the signal strength when compared to enrichment to a concentration of less than about 90%. In combination with increasing the concentration of the desired isotope in order to increase imaging resolution it is desirable to reduce the concentration of non-enriched isotopes to substantially zero. This lowers the probability of producing harmful isotopes when the microparticle 102 is activated. A harmful isotope is an isotope that is harmful to a subject or decreases the signal of the enriched element.
In some embodiments, the imageable element 106 includes a radiopaque material. A radiopaque material is a material that is substantially opaque to at least some range of frequencies in the electromagnetic spectrum. Pb is one exemplary radiopaque material suitable for use as the imageable element 106 in the microparticle 102. Pb is substantially opaque to X-rays. Radiopaque materials, such as Pb, are imageable using computer-aided tomography (CT), fluoroscopy, and X-rays. In some embodiments, the imageable element 106 includes Pb-206. Other exemplary radiopaque materials include enriched isotopes of Pb-207, Hg-198, Hg-199, Hg-200, Pt-195, Pt-198, Os-187, W-182, W-183, Yb-170, Yb-171, Yb-172, Er-166, Er-177, Dy-160, Dy-161, Dy-162, Dy-163, Gd-154, Gd-155, Gd-156, Cd-110, Cd-111, Sn-114, Sn-115, I-127, Ba-134, Ba-135, Ba-137, Ca-42, Ca-43, Mn-55, Fe-56, Fe-57, Ni-60, Ni-61, Zn-66, Zn-67, Zr-90, Zr-91, Mo-94, Mo-95, Mo-96, Mo-97, Ru-98, Ru-100, Rh-103, Pd-104, and Pd-105.
Pb-206 is an exemplary radiopaque isotope suitable for use as the detectable element 106 in the composition 100. Pb-206 is approximately 24% abundant in nature. Pb-206 is three neutron captures away from Pb-209 which is the first significant radioactive impurity. The neutron absorption cross-sections for Pb-206, Pb-207, and Pb-208 are low, so the probability of neutron capture causing a harmful radioactive impurity is low. Although Pb-207 has a meta-stable state, Pb-207 also has a short half-life of about 0.8 seconds. The short half-life renders the meta-stable state substantially harmless. Pb-204 is 1.4% abundant and should be eliminated because a single neutron capture will yield Pb-205, which is a radioactive impurity with a long half-life. Enrichment of Pb-206 substantially eliminates the undesired isotopes, Pb-204, Pb-207, and Pb-208, and thus avoids the production of radioactive impurities during the activation process.
b) is an illustration of a composition 150 comprising a material 152 including a radioactive isotope 104, and a dopant 156 included in the material in accordance with some embodiments. The material 152 is not limited to a particular material or material in a particular form. Materials suitable for use in connection with the composition 150 can be in the form of solids, liquids, or gases. A dopant is a second material added to first material to change the first material's properties. For example, a paramagnetic material or isotope is added to a glass or ceramic substrate, such as a microsphere, to form a microsphere having paramagnetic properties. In some embodiments, the dopant 156 includes an enriched paramagnetic isotope. Exemplary enriched paramagnetic isotopes suitable for use in connection with the formation of the material 152 include H-1, He-3, Li-7, B-7, B-9, N-15, O-17, F-19, Mg-27, Al-27, Si-29, S-33, Cl-37, Ca-43, Ti-47, V-51, Cr-53, Mn-55, Fe-57, Ni-61, Cu-63, Zn-67, Ga-69, Ge-73, Kr-83, Sr-87, Y-89, Zr-91, Mo-95, Mo-97, Ru-99, Rh-103, Pd-105, Cd-111, Sn-115, Te-125, I-127, Ba-135, Ba-137, Xe-129, Xe-131, Nd-145, Gd-155, Dy-161, Er-167, Yb-171, W-183, Os-187, Pt-195, Hg-199, Tl-205, Pb-207, Pt-198, and H-2. The dopant 156 can be incorporated into microparticles including those described in U.S. Pat. No. 4,789,501 titled Glass Microspheres, U.S. Pat. No. 5,011,677 titled Radioactive Glass Microspheres, U.S. Pat. No. 5,011,797 titled Composition and Method for Radiation Synovectomy of Arthritic Joints, U.S. Pat. No. 5,039,326 titled Composition and Method for Radiation Synovectomy of Arthritic Joints, U.S. Pat. No. 5,302,369 Microspheres for Radiation Therapy, U.S. Pat. No. 6,379,648 titled Biodegradable Glass Compositions and Methods for Radiation Therapy, and U.S. Pat. No. 5,885,547 titled Particulate Material.
Exemplary enriched paramagnetic isotopes suitable for use in connection with the method 200 include H-1, He-3, Li-7, B-7, B-9, N-15, O-17, F-19, Mg-27, Al-27, Si-29, S-33, Cl-37, Ca-43, Ti-47, V-51, Cr-53, Mn-55, Fe-57, Ni-61, Cu-63, Zn-67, Ga-69, Ge-73, Kr-83, Sr-87, Y-89, Zr-91, Mo-95, Mo-97, Ru-99, Rh-103, Pd-105, Cd-11, Sn-115, Te-125, I-127, Ba-135, Ba-137, Xe-129, Xe-131, Nd-145, Gd-155, Dy-161, Er-167, Yb-171, W-183, Os-187, Pt-195, Hg-199, Tl-205, Pb-207, Pt-198, and H-2. Exemplary particles suitable for use in irradiating the target isotope include neutrons, protons, and heavier particles, such as deuterium+, tritium+, and helium++.
The method 200 is not limited to forming particles of a particular shape. In some embodiments, forming the microparticle including the target isotope includes forming a substantially spherical microparticle. Substantially spherical microparticles are suitable for use in connection with the treatment of cancers, such as liver cancer.
The method 200 reduces radioactive impurities while maintaining or increasing the strength of the magnetic resonance imaging signal through enrichment of the paramagnetic isotope. Failure to reduce radioactive impurities can result in tissue damage through radiation burning or radiation induced cell damage resulting in cancer. The method 200 is not limited to a particular degree of enrichment. In some embodiments, doping the microparticle with the enriched paramagnetic isotope includes doping the microparticle with an enriched paramagnetic isotope having a concentration after enrichment of at least about 90%. In some embodiments, transforming the target isotope into the radioactive isotope includes transforming the target isotope into the radioactive isotope without forming a substantial number of impurity isotopes. The number of impurity isotopes are substantial for a particular treatment when the number prevents safe, convenient, and effective use of the treatment.
In some embodiments, the method 200 further includes infusing the microparticle into living tissue to form a distribution of microparticles in the living tissue, and imaging the hydrogen near the microparticles affected by the paramagnetic elements in the microparticles. Magnetic resonance imaging (MRI) scanning instruments can be setup to measure the response from the paramagnetic element in the microparticle, or to measure the response of adjacent hydrogen that has been affected by the paramagnetic element.
In the method 300, in some embodiments for neutron activated Y-90 microspheres the doping element is enriched with paramagnetic isotopes, such as Fe-57 or Gd-155. A result of the enrichment process is that radioactive impurities, isotopes other than the paramagnetic isotopes that would be activated if present at activation time, are substantially eliminated. This method is effective when the neutron absorption cross-section for the paramagnetic isotope in the doping material is close to or less than the cross-section of Y-89, and when more than one neutron capture is required for the creation of a radioactive impurity.
For example, Gd-155 is a paramagnetic isotope that is four neutron captures away from forming the harmful radioactive impurity Gd-159. Although the neutron absorption cross-sections for the Gd isotopes are higher than the neutron absorption cross-sections for Y-89, the probability of four neutron captures is low in the period of time it takes to convert the Y-89 into Y-90 in a nuclear reactor or other neutron source. In another example, Fe-57 is two neutron captures away from forming the harmful radioactive impurity Fe-59. The neutron absorption cross-section of Fe-57 and Fe-58 are low, so the probability of a double neutron capture is low in the time it takes to produce Y-90 from Y-89 in a nuclear reactor or other neutron source.
Y-89 is transformed to Zr-89 after a (p,n) reaction and provides an improved signal in positron emission tomography (PET). In some embodiments, the method 300 further includes transforming Y-89 to Zr-89 for use in connection with positron emission tomography (PET). Other useful PET isotopes that can be formed by absorbing a neutron particle include Cu-64 and Zr-89. Exemplary radioisotopes suitable for use in connection with positron emission tomograph (PET) include F-18, I-124, and Sr-85.
In some embodiments, the method 400 further includes introducing the composition into a subject, such as a human. In some embodiments, the method including introducing the composition into a subject further includes forming an image of the composition and the subject by magnetic resonance imaging (MRI). In other embodiments, the method including introducing the composition into the subject further includes forming and analyzing an image of the composition to determine whether a disease is present in the subject. The method 400 can also include treating a disease with the composition, and forming an image of the composition using an imaging system. In some embodiments, forming the composition including the material and the paramagnetic material includes activating the composition through nuclear particle absorption.
a) is a block diagram of an apparatus 500 including an imaging system 502 to image a subject 503, and a radioactive microparticle 504 suitable for infusion into the subject 503 for imaging by the imaging system and including an enriched paramagnetic isotope 505 that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. The imaging system 502 is not limited to a particular type of imaging system. Exemplary imaging systems and methods suitable for use in connection with the apparatus 500 include magnetic resonance imaging (MRI), computer-aided tomography (CT), single photon emission computed tomography (SPECT), positron emission tomography (PET), and fluoroscopy.
Magnetic resonance imaging (MRI) includes the use of a nuclear magnetic resonance spectrometer to produce electronic images of atoms and molecular structures in solids, including human cells, tissues, and organs. Computer-aided tomography (CT) includes the generation of a three-dimensional image of the internals of a subject or object from a plurality of two-dimensional X-ray images taken around a single axis of rotation. Single photon emission computed tomography (SPECT) includes a tomographic imaging technique using gamma rays and produces a set of image slices through a subject, showing the distribution of a radiopharmaceutical or radioactive particle. Positron emission tomography (PET) includes producing a three dimensional image or map of functional processes in the body. X-ray tomography produces a series of projection images used to calculate a three-dimensional reconstruction of an object. Fluoroscopy includes producing real-time images of the internal structures of a subject through the use of a fluoroscope. A fluoroscope produces fluorescent images of a patient on a fluorescent screen by imaging the subject using X-rays.
The apparatus 500 is not limited to use in connection with a particular type of subject. Organic and inorganic materials can be imaged by the apparatus 500. Exemplary subjects also include living tissue, including live animals, and dead tissue, including preserved tissue and non-preserved tissue. The enriched paramagnetic isotope is not limited to a particular paramagnetic isotope. In some embodiments, the enriched paramagnetic isotope includes a material capable of neutron activation having a first neutron absorption cross-section, and a paramagnetic isotope having a second neutron absorption cross-section within a factor of about 1000 of the first neutron absorption cross-section and which requires more than one neutron capture to create a radioactive impurity.
b) is a block diagram of an apparatus 506 including the imaging system 502 to image the subject 503, and a microparticle 507 suitable for infusion into the subject 503 for imaging by the imaging system 502 and including the enriched paramagnetic isotope 505 that is enriched to reduce generation of radioactive impurities while maintaining or improving imaging sensitivity. The imaging system 502 is not limited to a particular type of imaging system. Exemplary imaging systems and methods suitable for use in connection with the apparatus 506 include magnetic resonance imaging (MRI), computer-aided tomography (CT), single photon emission computed tomography (SPECT), positron emission tomography (PET), and fluoroscopy. The microparticle 507 is not radioactive.
