CA2701537A1 - Compositions for treatment of tumors by direct administration of a radioisotope - Google Patents
Compositions for treatment of tumors by direct administration of a radioisotope Download PDFInfo
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- CA2701537A1 CA2701537A1 CA2701537A CA2701537A CA2701537A1 CA 2701537 A1 CA2701537 A1 CA 2701537A1 CA 2701537 A CA2701537 A CA 2701537A CA 2701537 A CA2701537 A CA 2701537A CA 2701537 A1 CA2701537 A1 CA 2701537A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/025—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus inorganic Tc complexes or compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
- A61K51/048—DTPA (diethylenetriamine tetraacetic acid)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
This invention provides a safer and more effective treatment for undesirable tissue masses, especially bone cancer and soft tissue tumors. The method involves a composition for direct administration of a therapeutic, radioisotope formulation nearby or directly into the tissue mass. Administration of the dose for bone cancer may be done through a hole created in the bone using a miniature drill. Delivery of the dose directly into a tumor may be accomplished using microsyringe or a miniature pump capable of accurately delivering microliter amounts of material. A chelating agent capable of removing activity from the bloodstream is also an aspect of this invention.
Description
COMPOSITIONS FOR TREATMENT OF TUMORS BY DIRECT
ADMINISTRATION OF A RADIOISOTOPE
Cross Reference to Related Applications This application claims priority from US Provisional Patent Applications 60/997,856 and 60/997,873, both filed on October 5, 2007. This application is related to US Provisional Patent Applications 60/890,831 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 20, 2007 and 60/891,183 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 22, 2007.
Field of the Invention The present invention concerns treatment of undesirable tissue masses, such as bone cancer or soft tissue tumors, in mammals and humans by direct administration of a radioisotope formulation directly to the area of the tissue mass, i.e., via intratumural, intramedullary or intraosseous injection.
Background of the Invention The treatment of cancerous tumors or masses of undesirable tissue has been of concern for many years with various attempts to have effective treatment to prolong the quality of life of the mammal or human. Various compositions have been tried and the following discussion of bone tumor and soft tissue tumor are discussed below.
Bone Cancer According to the American Academy of Orthopaedic Surgeons, "More than 1.2 million new cancer cases are diagnosed each year [in the US], and approximately 50 percent of these tumors can spread or metastasize to the skeleton."
Metastatic bone cancer therefore afflicts over 500,000 patients in the US alone. Bone is the third most common site of metastatic disease. Cancers most likely to metastasize to bone include breast, lung, prostate, thyroid and kidney. In many cases there are multiple bone metastatic sites making treatment more difficult. Pain, pathological fractures and hypercalcemia are the major source of morbidity associated with bone metastasis.
Pain is the most common symptom found in 70% of patients.
Primary bone cancer is much less prevalent (2,370 new cases and 1330 deaths estimated in the US for 2007) but it is much more aggressive. This type of cancer is more likely to occur in young patients. In contrast to people, primary bone cancer is more prevalent in dogs than metastatic bone cancer. Large dogs frequently present with primary bone cancer. Because of the aggressive nature of the disease, primary bone cancer is often treated by amputation of the area affected to prevent the cancer from spreading. In addition, chemotherapeutic agents are then used to decrease the chance of metastatic disease, especially to the lungs.
The pain associated with bone cancer, especially metastatic bone cancer, is often treated with narcotics. However, the patients have need for increasing amounts of narcotics to control the pain. The side effects of the narcotics result in a significant decrease in the patient's quality of life.
Another method for treatment is external beam radiation or more recently stereotactic radiotherapy of bone metastatic sites. However, current treatments with high energy electromagnetic radiation do not exclusively deliver radiation to the tumor. This treatment results in the necessity to administer the dose over about a week and has the difficultly of giving high doses of radiation to a tumor without significant damage to surrounding tissue.
Intraoperative Radiation Therapy (TORT) has permitted localized tumor destruction, but this is expensive and associated with significant trauma due to surgery.
Certain bone seeking radiopharmaceuticals which can be used in the present invention do not require the use of a chelating agent. For example P-32 can be used alone as a bone seeking radiopharmaceutical without a chelant present. Also, Sr-89 as the chloride can be used, as indicated in Robinson R G, Spicer J A, Preston D
F, et al., "Treatment of Metastatic Bone Pain With Strontium-89," Nucl. Med. Biol. 14:219-(1987).
The ability to target bone tumors has been exploited in the field of radiopharmaceuticals for many years. Both diagnostic and therapeutic radiopharmaceuticals capable of targeting bone tumors generally use phosphonic acid functionality as the targeting moiety. For example, pyrophosphates have been used to deliver Tc-99m, a gamma-emitting diagnostic radioisotope, to bone. This technology was displaced by the bisphosphonates because of their increased stability in vivo. In addition, therapeutic radiopharmaceuticals for bone tumors were developed in the 1980's and 1990's. Of these, a series of chelates based on aminomethylenephosphonic acids offer another type of functionality useful for targeting bone tumors. Thus ethylenediaminetetramethylenephosphonic acid (EDTMP) has been shown to be a very good chelating agent for delivering metals such as Sm, Gd, Ho, and Y to the bone.
Two radiopharmaceuticals, both based on radioactive metals, are marketed in the United States for the treatment of bone metastases. Metastron is an injectable solution of strontium-89 (Sr-89) given as the chloride salt. Quadramet is a phosphonic acid (EDTMP) chelate of samarium-153 (Sm-153). Both of these agents concentrate in normal bone as well as in the metastatic lesions. This gives a radiation dose to the bone marrow resulting in temporary but significant suppression of the immune system. For that reason these agents are contraindicated when chemotherapeutic agents are planned. Thus a patient may suffer from bone pain while waiting to receive a chemotherapeutic regimen for the primary cancer.
When these available chelates are injected intravenously, about 50% of the injected dose concentrates in the bone. The rest is efficiently cleared by the kidneys and into the bladder; however, because of this clearance, toxicity to these organs has been observed when administering large therapeutic doses of bone seeking radiopharmaceuticals. The amount of radiometal deposited at the site of a bone tumor is significantly higher that in normal bone. Although the chelate concentration in the site of a tumor is as much as 20 times that of normal bone, significant amounts of radioactivity are taken up by normal bone. The dose from the bone to the bone marrow can suppress bone marrow. Even though this effect is usually temporary and marrow cells recover, the use of these agents are contraindicated when used with chemotherapeutic agents that also suppress bone marrow. Therefore therapeutic bone agents are typically not used at the same time chemotherapeutic agents are used. In addition, only a small fraction of the radiation dose is associated with the tumor.
Because of the fast kidney clearance and uptake in normal bone, only about 0.1% of the dose goes to the site of the tumor. Administration of larger doses of bone agents is limited by the dose to the bone marrow.
ADMINISTRATION OF A RADIOISOTOPE
Cross Reference to Related Applications This application claims priority from US Provisional Patent Applications 60/997,856 and 60/997,873, both filed on October 5, 2007. This application is related to US Provisional Patent Applications 60/890,831 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 20, 2007 and 60/891,183 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 22, 2007.
Field of the Invention The present invention concerns treatment of undesirable tissue masses, such as bone cancer or soft tissue tumors, in mammals and humans by direct administration of a radioisotope formulation directly to the area of the tissue mass, i.e., via intratumural, intramedullary or intraosseous injection.
Background of the Invention The treatment of cancerous tumors or masses of undesirable tissue has been of concern for many years with various attempts to have effective treatment to prolong the quality of life of the mammal or human. Various compositions have been tried and the following discussion of bone tumor and soft tissue tumor are discussed below.
Bone Cancer According to the American Academy of Orthopaedic Surgeons, "More than 1.2 million new cancer cases are diagnosed each year [in the US], and approximately 50 percent of these tumors can spread or metastasize to the skeleton."
Metastatic bone cancer therefore afflicts over 500,000 patients in the US alone. Bone is the third most common site of metastatic disease. Cancers most likely to metastasize to bone include breast, lung, prostate, thyroid and kidney. In many cases there are multiple bone metastatic sites making treatment more difficult. Pain, pathological fractures and hypercalcemia are the major source of morbidity associated with bone metastasis.
Pain is the most common symptom found in 70% of patients.
Primary bone cancer is much less prevalent (2,370 new cases and 1330 deaths estimated in the US for 2007) but it is much more aggressive. This type of cancer is more likely to occur in young patients. In contrast to people, primary bone cancer is more prevalent in dogs than metastatic bone cancer. Large dogs frequently present with primary bone cancer. Because of the aggressive nature of the disease, primary bone cancer is often treated by amputation of the area affected to prevent the cancer from spreading. In addition, chemotherapeutic agents are then used to decrease the chance of metastatic disease, especially to the lungs.
The pain associated with bone cancer, especially metastatic bone cancer, is often treated with narcotics. However, the patients have need for increasing amounts of narcotics to control the pain. The side effects of the narcotics result in a significant decrease in the patient's quality of life.
Another method for treatment is external beam radiation or more recently stereotactic radiotherapy of bone metastatic sites. However, current treatments with high energy electromagnetic radiation do not exclusively deliver radiation to the tumor. This treatment results in the necessity to administer the dose over about a week and has the difficultly of giving high doses of radiation to a tumor without significant damage to surrounding tissue.
Intraoperative Radiation Therapy (TORT) has permitted localized tumor destruction, but this is expensive and associated with significant trauma due to surgery.
Certain bone seeking radiopharmaceuticals which can be used in the present invention do not require the use of a chelating agent. For example P-32 can be used alone as a bone seeking radiopharmaceutical without a chelant present. Also, Sr-89 as the chloride can be used, as indicated in Robinson R G, Spicer J A, Preston D
F, et al., "Treatment of Metastatic Bone Pain With Strontium-89," Nucl. Med. Biol. 14:219-(1987).
The ability to target bone tumors has been exploited in the field of radiopharmaceuticals for many years. Both diagnostic and therapeutic radiopharmaceuticals capable of targeting bone tumors generally use phosphonic acid functionality as the targeting moiety. For example, pyrophosphates have been used to deliver Tc-99m, a gamma-emitting diagnostic radioisotope, to bone. This technology was displaced by the bisphosphonates because of their increased stability in vivo. In addition, therapeutic radiopharmaceuticals for bone tumors were developed in the 1980's and 1990's. Of these, a series of chelates based on aminomethylenephosphonic acids offer another type of functionality useful for targeting bone tumors. Thus ethylenediaminetetramethylenephosphonic acid (EDTMP) has been shown to be a very good chelating agent for delivering metals such as Sm, Gd, Ho, and Y to the bone.
Two radiopharmaceuticals, both based on radioactive metals, are marketed in the United States for the treatment of bone metastases. Metastron is an injectable solution of strontium-89 (Sr-89) given as the chloride salt. Quadramet is a phosphonic acid (EDTMP) chelate of samarium-153 (Sm-153). Both of these agents concentrate in normal bone as well as in the metastatic lesions. This gives a radiation dose to the bone marrow resulting in temporary but significant suppression of the immune system. For that reason these agents are contraindicated when chemotherapeutic agents are planned. Thus a patient may suffer from bone pain while waiting to receive a chemotherapeutic regimen for the primary cancer.
When these available chelates are injected intravenously, about 50% of the injected dose concentrates in the bone. The rest is efficiently cleared by the kidneys and into the bladder; however, because of this clearance, toxicity to these organs has been observed when administering large therapeutic doses of bone seeking radiopharmaceuticals. The amount of radiometal deposited at the site of a bone tumor is significantly higher that in normal bone. Although the chelate concentration in the site of a tumor is as much as 20 times that of normal bone, significant amounts of radioactivity are taken up by normal bone. The dose from the bone to the bone marrow can suppress bone marrow. Even though this effect is usually temporary and marrow cells recover, the use of these agents are contraindicated when used with chemotherapeutic agents that also suppress bone marrow. Therefore therapeutic bone agents are typically not used at the same time chemotherapeutic agents are used. In addition, only a small fraction of the radiation dose is associated with the tumor.
Because of the fast kidney clearance and uptake in normal bone, only about 0.1% of the dose goes to the site of the tumor. Administration of larger doses of bone agents is limited by the dose to the bone marrow.
An example of the bisphosphonate chelant, methylenediphosphonic acid (MDP), is shown in the structure below.
H
H) / O
/ C \ ~
HO -P P--, I I OH
O OH
MDP
Two aminomethylenephosphonic acid chelants, ethylenediaminetetra-methylenephosphonic acid (EDTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid) (DOTMP), are shown in the structures below.
H O P N N PO H
EDTMP
H203P---\\ F-~ / P03H2 N N
I:N N
H2O3P~ \_j \-PO3H2 DOTMP
To date even combinations of treatments have not been effective at resolving bone tumors. Thus it is still common practice to amputate a limb to stop the spread of bone cancers. In the case of metastatic bone cancer, pain palliation and maintaining quality of life is often the goal in contrast to resolution of the tumors.
There clearly is a need for more effective therapy to treat bone cancer.
Brachytherapy In contrast to external beam radiotherapy, where an external beam of radiation is directed to the treatment area (such as discussed above for bone tumors), brachytherapy is a form of radiotherapy where a radioactive source is placed inside or next to the area requiring treatment. Brachytherapy is also known as sealed source radiotherapy or endocurietherapy and is commonly used to treat localized prostate cancer and cancers of the head and neck. Superficial tumors can be treated by placing sources close to the skin. Interstitial brachytherapy is where the radioactive source is inserted into tissue. Intracavitary brachytherapy involves placing the source in a pre-existing body cavity. Intravascular brachytherapy places a catheter with the source inside blood vessels.
In most of these cases the radioactive material is encapsulated in a metal casing. Because of this casing, most of the radioactive sources are electromagnetic radiation (X-rays and gamma photons) emitting radionuclides such that the radiation can penetrate the outer casing and deliver a radiation dose to surrounding tissue.
Administration of the radioisotope without this encapsulation may result in migration of the radioisotope to other areas of the body creating side effects in the patient.
Particle emitting radionuclides such as beta ((3) and alpha (a) emitters are rarely used in this application because a significant portion of the dose would not penetrate the casing within which the isotope is contained. However, in many cases the gamma photons penetrate beyond the desired treatment area resulting in significant side effects. Therefore, a more specific method to deliver radiation is needed.
The prostate is a gland in the male reproductive system located just below the urinary bladder and in front of the rectum. It is about the size of a walnut and surrounds the urethra. In 2007 the American Cancer Society estimated 218,890 new cases and 27,050 deaths due to prostate cancer in the U.S. Treatment options include surgery, external radiation therapy, and brachytherapy. In many cases brachytherapy is the preferred choice due to less trauma to surrounding tissues. However since the radioisotopes selected for this application are gamma (y) emitters, delivering an undesired radiation dose to surrounding tissue remains a problem.
The radioactive sources used for brachytherapy are sealed in "seeds" or wires.
Permanent prostate brachytherapy involves implanting between 60 and 120 rice-sized radioactive seeds into the prostate. One type of radioactive seed is based on which has a 59.4 day half life and emits multiple X-rays around 30 keV.
Recently a shorter half life alternative has been proposed with Cs-131 which has a 9.7 day half life and emits X-rays of about 30 keV. Alternatively, Pd-103 is used which has a 17 day half life and emits X-rays of about 20 keV. Another option is Ir-192 which has a half life of 73.8 days and gamma emissions at 468 keV. Ir-192 can be used to give different doses to different parts of the prostate. All these isotopes emit electromagnetic radiation that penetrates beyond the prostate and into normal tissue causing problems such as impotence, urinary problems, and bowel problems.
Although in most cases the seeds stay in place, seed migration does occur in a portion of patients. Usually the seeds migrate to the urethra or bladder.
In some cases, brachytherapy is used to destroy cancer cells left over after a surgical procedure. For example breast cancer patients can be treated with a technology by the name of MammoSite Radiation Therapy System. This involves a balloon catheter that is inserted into the area of the breast where a tumor was removed. The balloon is expanded and radiation is delivered via a small bead attached to a wire. Similarly, the space surrounding a resected brain tumor can be treated using a balloon catheter inflated with a radioactive solution of 1-125. This technology is called G1iaSite Radiation Therapy System (e.g. U.S. Patent 6,315,979).
In these cases the balloon prevents the radioactivity from going systemic.
Again, the radioisotopes used are those emitting penetrating electromagnetic radiation such as X-rays or gamma rays.
Beta emitting radioisotopes are being used in what could be categorized as brachytherapy. For example, liver cancer has been treated with a form of brachytherapy. This technology called Selective Internal Radiation Therapy (SIRT) delivers radioactive particles to a tumor via the blood supply. The radioactive particles are positioned via a catheter in the hepatic artery, the portal vein, or a branch of either of these vessels. The catheter is guided to the branch of the blood vessel that feeds the tumor, and then the microspheres are infused. The radioactive microspheres become trapped in the capillary beds of the tumor and the surrounding tissues which results in a more targeted radiation dose to the tumor. There are currently two products that take this approach, both are microspheres labeled with Y-90, TheraSphere (MDS Nordion, Inc.), and SIR-Spheres (SIRTeX Medical).
TheraSpheres are glass microspheres which have a diameter of 25 10 m so they are trapped mainly within tumor terminal arterioles, which are estimated to have a diameter of 8-10 m. SIR-Spheres are resin-based microspheres that are approximately 32 pm in diameter. One issue with both of these products is that a portion of the radioactive microspheres can migrate to other tissues such as the lungs and cause undesired side effects.
Ho-166 bound to chitosan has also been proposed to treat cancer cells. Thus J.
Nucl. Med. 1988 Dec; 39(12):2161-6 describes a method to treat liver cancer by administering the compound via the hepatic artery. However, "shunting" of radioactivity to the lung has again been a problem. In addition, it is a cumbersome technique to determine the blood supply to the tumor and to deliver the particles in the selected blood vessels.
US Patent 5,320,824 describes the use of rare earth isotopes such as Sm-153 and Ho-166 bound to hydroxyapatite for the treatment of rheumatoid arthritis.
In this process, the most of the radioisotope bound to hydroxyapatite either remains in the injected joint or is taken up by the synovial membrane surrounding the joint.
Localization to the target tissue depends on phagocytosis of the hydroxyapatite particles into the synovial membrane. One major problem with this approach is leakage of radioisotope from the synovial cavity to other parts of the body.
As is evident from the discussion above, better technology to ablate undesirable cells is needed. In the field of brachytherapy, more effective methods of delivering radioisotopes to tumors are needed that give a radiation dose specifically to the treatment area with little to no dose to non-target tissues.
Summary of the Invention An aim of this invention is to provide a therapy that that can deliver relatively large radiation doses from a radioisotope in a minimal volume to the site of an undesired tissue mass, including infections and cancerous tumors in both soft tissue and bone, for the purpose of killing said undesirable tissue. A further aim of this invention is to minimize the amount of radiation dose to non-target tissues in order to minimize side effects.
One aspect of this invention concerns a composition comprising a therapeutically-effective amount of a radioisotope formulation having a pH
greater than about 7 together with a pharmaceutically-acceptable liquid carrier, for the treatment of an undesirable tissue mass in an animal or human in need of such treatment, wherein the composition is administered directly to or nearby the tissue mass, and the composition is such that less than about 15% of the radioisotope migrates away from the site of administration within two half lives of radioactive decay.
A second aspect of this invention relates a composition for direct administration of a therapeutically-effective amount of a radioisotope formulation wherein the radioisotope is bound to a binder, for the treatment of an undesirable tissue mass in an animal or human in need of such treatment, such that greater than about 5% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
Both of these aspects are accomplished by the direct injection of a very small volume of a liquid formulation mixture to the desired site. The radioactivity delivered to the site remains at the site of administration for a sufficient time to give a therapeutic radiation dose to that area. Compared to systemic administration approaches, the total amount of radioactivity administered is very small and the amount of radioisotope that leaches out of the treatment area is minimal, thus little to no radiation dose to normal tissues is realized.
Administration of the radioisotope formulation can be via a microsyringe or another device capable of delivering small volumes of fluid such as a small pump. In one embodiment of the invention for treating bone tumors, a miniature drill is used to create a hole by which a catheter can be inserted through the hole and a device capable of delivering small volumes of fluid is used to deliver the dose. In other embodiments, a microsyringe can be used for delivery.
H
H) / O
/ C \ ~
HO -P P--, I I OH
O OH
MDP
Two aminomethylenephosphonic acid chelants, ethylenediaminetetra-methylenephosphonic acid (EDTMP) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylenephosphonic acid) (DOTMP), are shown in the structures below.
H O P N N PO H
EDTMP
H203P---\\ F-~ / P03H2 N N
I:N N
H2O3P~ \_j \-PO3H2 DOTMP
To date even combinations of treatments have not been effective at resolving bone tumors. Thus it is still common practice to amputate a limb to stop the spread of bone cancers. In the case of metastatic bone cancer, pain palliation and maintaining quality of life is often the goal in contrast to resolution of the tumors.
There clearly is a need for more effective therapy to treat bone cancer.
Brachytherapy In contrast to external beam radiotherapy, where an external beam of radiation is directed to the treatment area (such as discussed above for bone tumors), brachytherapy is a form of radiotherapy where a radioactive source is placed inside or next to the area requiring treatment. Brachytherapy is also known as sealed source radiotherapy or endocurietherapy and is commonly used to treat localized prostate cancer and cancers of the head and neck. Superficial tumors can be treated by placing sources close to the skin. Interstitial brachytherapy is where the radioactive source is inserted into tissue. Intracavitary brachytherapy involves placing the source in a pre-existing body cavity. Intravascular brachytherapy places a catheter with the source inside blood vessels.
In most of these cases the radioactive material is encapsulated in a metal casing. Because of this casing, most of the radioactive sources are electromagnetic radiation (X-rays and gamma photons) emitting radionuclides such that the radiation can penetrate the outer casing and deliver a radiation dose to surrounding tissue.
Administration of the radioisotope without this encapsulation may result in migration of the radioisotope to other areas of the body creating side effects in the patient.
Particle emitting radionuclides such as beta ((3) and alpha (a) emitters are rarely used in this application because a significant portion of the dose would not penetrate the casing within which the isotope is contained. However, in many cases the gamma photons penetrate beyond the desired treatment area resulting in significant side effects. Therefore, a more specific method to deliver radiation is needed.
The prostate is a gland in the male reproductive system located just below the urinary bladder and in front of the rectum. It is about the size of a walnut and surrounds the urethra. In 2007 the American Cancer Society estimated 218,890 new cases and 27,050 deaths due to prostate cancer in the U.S. Treatment options include surgery, external radiation therapy, and brachytherapy. In many cases brachytherapy is the preferred choice due to less trauma to surrounding tissues. However since the radioisotopes selected for this application are gamma (y) emitters, delivering an undesired radiation dose to surrounding tissue remains a problem.
The radioactive sources used for brachytherapy are sealed in "seeds" or wires.
Permanent prostate brachytherapy involves implanting between 60 and 120 rice-sized radioactive seeds into the prostate. One type of radioactive seed is based on which has a 59.4 day half life and emits multiple X-rays around 30 keV.
Recently a shorter half life alternative has been proposed with Cs-131 which has a 9.7 day half life and emits X-rays of about 30 keV. Alternatively, Pd-103 is used which has a 17 day half life and emits X-rays of about 20 keV. Another option is Ir-192 which has a half life of 73.8 days and gamma emissions at 468 keV. Ir-192 can be used to give different doses to different parts of the prostate. All these isotopes emit electromagnetic radiation that penetrates beyond the prostate and into normal tissue causing problems such as impotence, urinary problems, and bowel problems.
Although in most cases the seeds stay in place, seed migration does occur in a portion of patients. Usually the seeds migrate to the urethra or bladder.
In some cases, brachytherapy is used to destroy cancer cells left over after a surgical procedure. For example breast cancer patients can be treated with a technology by the name of MammoSite Radiation Therapy System. This involves a balloon catheter that is inserted into the area of the breast where a tumor was removed. The balloon is expanded and radiation is delivered via a small bead attached to a wire. Similarly, the space surrounding a resected brain tumor can be treated using a balloon catheter inflated with a radioactive solution of 1-125. This technology is called G1iaSite Radiation Therapy System (e.g. U.S. Patent 6,315,979).
In these cases the balloon prevents the radioactivity from going systemic.
Again, the radioisotopes used are those emitting penetrating electromagnetic radiation such as X-rays or gamma rays.
Beta emitting radioisotopes are being used in what could be categorized as brachytherapy. For example, liver cancer has been treated with a form of brachytherapy. This technology called Selective Internal Radiation Therapy (SIRT) delivers radioactive particles to a tumor via the blood supply. The radioactive particles are positioned via a catheter in the hepatic artery, the portal vein, or a branch of either of these vessels. The catheter is guided to the branch of the blood vessel that feeds the tumor, and then the microspheres are infused. The radioactive microspheres become trapped in the capillary beds of the tumor and the surrounding tissues which results in a more targeted radiation dose to the tumor. There are currently two products that take this approach, both are microspheres labeled with Y-90, TheraSphere (MDS Nordion, Inc.), and SIR-Spheres (SIRTeX Medical).
TheraSpheres are glass microspheres which have a diameter of 25 10 m so they are trapped mainly within tumor terminal arterioles, which are estimated to have a diameter of 8-10 m. SIR-Spheres are resin-based microspheres that are approximately 32 pm in diameter. One issue with both of these products is that a portion of the radioactive microspheres can migrate to other tissues such as the lungs and cause undesired side effects.
Ho-166 bound to chitosan has also been proposed to treat cancer cells. Thus J.
Nucl. Med. 1988 Dec; 39(12):2161-6 describes a method to treat liver cancer by administering the compound via the hepatic artery. However, "shunting" of radioactivity to the lung has again been a problem. In addition, it is a cumbersome technique to determine the blood supply to the tumor and to deliver the particles in the selected blood vessels.
US Patent 5,320,824 describes the use of rare earth isotopes such as Sm-153 and Ho-166 bound to hydroxyapatite for the treatment of rheumatoid arthritis.
In this process, the most of the radioisotope bound to hydroxyapatite either remains in the injected joint or is taken up by the synovial membrane surrounding the joint.
Localization to the target tissue depends on phagocytosis of the hydroxyapatite particles into the synovial membrane. One major problem with this approach is leakage of radioisotope from the synovial cavity to other parts of the body.
As is evident from the discussion above, better technology to ablate undesirable cells is needed. In the field of brachytherapy, more effective methods of delivering radioisotopes to tumors are needed that give a radiation dose specifically to the treatment area with little to no dose to non-target tissues.
Summary of the Invention An aim of this invention is to provide a therapy that that can deliver relatively large radiation doses from a radioisotope in a minimal volume to the site of an undesired tissue mass, including infections and cancerous tumors in both soft tissue and bone, for the purpose of killing said undesirable tissue. A further aim of this invention is to minimize the amount of radiation dose to non-target tissues in order to minimize side effects.
One aspect of this invention concerns a composition comprising a therapeutically-effective amount of a radioisotope formulation having a pH
greater than about 7 together with a pharmaceutically-acceptable liquid carrier, for the treatment of an undesirable tissue mass in an animal or human in need of such treatment, wherein the composition is administered directly to or nearby the tissue mass, and the composition is such that less than about 15% of the radioisotope migrates away from the site of administration within two half lives of radioactive decay.
A second aspect of this invention relates a composition for direct administration of a therapeutically-effective amount of a radioisotope formulation wherein the radioisotope is bound to a binder, for the treatment of an undesirable tissue mass in an animal or human in need of such treatment, such that greater than about 5% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
Both of these aspects are accomplished by the direct injection of a very small volume of a liquid formulation mixture to the desired site. The radioactivity delivered to the site remains at the site of administration for a sufficient time to give a therapeutic radiation dose to that area. Compared to systemic administration approaches, the total amount of radioactivity administered is very small and the amount of radioisotope that leaches out of the treatment area is minimal, thus little to no radiation dose to normal tissues is realized.
Administration of the radioisotope formulation can be via a microsyringe or another device capable of delivering small volumes of fluid such as a small pump. In one embodiment of the invention for treating bone tumors, a miniature drill is used to create a hole by which a catheter can be inserted through the hole and a device capable of delivering small volumes of fluid is used to deliver the dose. In other embodiments, a microsyringe can be used for delivery.
This invention concerns a better therapeutic approach to the treatment of cancer by the administration of a very small volume of therapeutic radioisotope directly to the tissue to be treated. Radioisotopes of this invention include particle-emitting isotopes such as alpha (a) emitters or beta (0) emitters that can deposit therapeutic amounts of ionizing radiation at the site of the tissue. The radioisotopes can be used by themselves or attached to a binder, such as phosphonic acid chelating agents (that have affinity for calcific tissue) or other binders such as solid supports like hydroxyapatite.
The systemic administration of chelating agents to scavenge radioactivity that does leach to non-target areas of the body is another aspect of this invention. The compositions of this invention allow higher target to non-target ratios using lower total amounts of radioisotopes, thus increasing the possibility of delivering significantly more radioactivity to the site of the target tissue without dosing normal tissue.
Detailed Description of the Invention This invention involves the delivery of a therapeutic amount of a formulated radioisotope composition directly to an undesired tissue mass, including infections (e.g., osteomyelitis) and cancerous tumors, especially inoperable cancerous tumors, in both soft tissue and bone. Because these formulations are very small in volume and the amount of radioactivity administered is effectively directed to the desired site, the administration is not by means that involve other body areas, e.g., no systemic administration (such as I.V. administration) is intended. Non-target, normal tissue is spared because only a very small amount of radioisotope is administered and the majority of the radioisotope mixture is immobilized at the administration site. Thus the majority of the radioactive decay of the isotope occurs at the site of injection with only small amounts of radioactivity leaching out of the injection site before a significant amount of the radioisotope decays. This results in a high radiation dose to the target area and extremely small doses to non-target tissues. The composition can be used to treat a variety of conditions, particularly cancerous tumors.
Radioisotopes used in this invention are particle emitters (beta ((3) emitters or alpha (a) emitters). Preferred radioisotopes are ions of rare earth-type metals including Pm, Sin, Gd, Dy, Ho, Yb, Lu, and Y; especially preferred are Sm, Ho, Lu, and Y. Preferred radioactive isotopes include: Sm-153, Ho-166, Y-90, Pm-149, Gd-159, Lu-177, Yb-175, Pb-212, Bi-212, Bi-213, and Ac-225. Especially preferred are Sm-153, Ho-166, Y-90, Bi-213, Ac-225, and Lu-177. Most preferred are isotopes with a relatively short half life of less than about 3 days and that emit energetic beta particles. Examples include Y-90, Ho-166, and Sm-153. It is understood that often the radioisotopes contain non-radioactive carrier isotopes as a mixtures.
In one aspect of this invention, the radioisotopes are administered in an aqueous formulation without a chelating agent or other binder after the pH of the solution has been raised. A preferred pH of the formulation is wherein the metallic radioisotopes are in a hydroxide form which usually results in a suspension.
This pH
varies from metal to metal and is known to one skilled in the art. Preferred pH
formulations include a pH greater than about 7. More preferred formulations are a pH
greater than about 8. A pH range from about 8 to about 14 is desirable for most of these radioactive metals, and preferred is a range from about 8 to about 11.
The pH is attained by the addition of a suitable base such as sodium hydroxide. While not wishing to be bound by theory, it is believed that the metallic radioisotopes form insoluble hydroxides that precipitate and remain in the tissue longer than if the dose is administered in neutral or acidic solution (pH less than about 7) or if the radioisotope is bound to a soluble binder such as a chelating agent. To facilitate the precipitation it is possible to add another non-radioactive metal such as iron that could co-precipitate with the radioisotope.
In another aspect of this invention, the radioisotope is bound to a phosphonic acid chelating agent (that has an affinity for bone) or other binder such as hydroxyapatite that helps retain it at the injection site. When a binder is used then greater than about 75% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
The various radioisotopes discussed above are administered as a formulation in a liquid that is pharmaceutically-acceptable, such as water, saline, or an oil such as sesame seed oil, corn oil and others. The formulated liquid may be a suspension, a slurry or an emulsion. Optionally other usual ingredients can be present such as excipients, suspension aids, preservatives, base or buffers for pH adjustment, and others.
In yet another aspect of this invention, the amount of the radioisotope administered is very low. Preferred volumes of administered radioisotope are less than about 50 microliters per cubic centimeter of tissue (50 gL/cm). More preferred are doses of less than 20 microliters per cubic centimeter of tissue (20 gL/cm).
Delivery of the dose can be done using a microsyringe or a pump capable of accurately delivering microliter volumes (e.g. Valco Instrument Company, Inc.
model CP-DSM) to provide flow to the proximal end of a catheter which may be placed within or next to the tissue to be treated. The flow may be either continuous or may be pulsed to enhance complete penetration of the tissue mass by the radioisotope.
In another aspect of this invention a chelating agent is administered systemically to the patient before and for a time after the administration of the radioactive dose. Preferred chelating agents including EDTA and DTPA that serve to scavenge systemic radioactivity and remove it from the body via the kidneys and into the bladder. These agents are used when desired to ensure more complete removal of the administered radioisotope that may have migrated from the injection site.
As usually only a low amount of such migration occurs, this treatment is optional.
In one embodiment of the invention, the radioisotope may be delivered to a bone tumor using a miniature pump. Access to the tumor may be effected by the use of a bone biopsy tool or a miniature drill capable of making a curved or angled hole through bone and either upstream of the tumor (so to guide the catheter towards it) or directly into the bone or tumor in the bone. The insertion of the catheter using fluoroscopy, as is known in the art, may help to position the distal end of the catheter in close proximity to the tumor. The delivery of the radioisotope upstream of the tumor may reduce the risk of spreading cancer cells potentiated by approaching the tumor directly or downstream from the blood flow.
The drill used in the present examples is discussed in US Provisional Patent Applications 60/890,831 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 20, 2007 and 60/891,183 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 22, 2007, but this invention is not limited to the use of this drill as any device that can provide a suitable hole in the bone, such as a syringe needle or biopsy tool will suffice.
In another aspect of this invention the radioisotopes are combined with a binder that is a solid support, such as hydroxyapatite. This form of calcium phosphate has the ability to bind metal ions such as radioactive rare earth metals. The hydroxyapatite/metal ion combination can be administered into tissues and a therapeutically significant amount of the radioisotope remains at the site of injection.
In another aspect of the invention, the radioisotopes may have binder molecules that have affinity for bone such as phosphonic acid chelating agents.
Preferred chelating agents include those selected from aminomethylenephosphonic acids such as ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylene-triaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediamine-trimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP), 1-carboxyethylenediaminetetramethylenephosphonic acid (CEDTMP), bis(amino-ethylpiperazine)tetramethylenephosphonic acid (AEPTMP), ethylenediaminetetra-acetic acid (EDTA), 1,4,7,1 0-tetraazacyclododecane-N, N',N",N"'-tetramethylene-phosphonic acid (DOTMP), hydroxyethyldiphosphonic acid (HEDP), methylene-diphosphonic acid (MDP), diethylenetriaminepentaacetic acid (DTPA), hydroxyethyl-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA). More preferably, the chelating agent is 1,4,7, 1 0-tetraazacyclododecane-N, N',N",N"'-tetramethylenephosphonic acid (DOTMP).
In one aspect of this invention, the bone seeking radiopharmaceutical complex is chosen from the group consisting of Sm-153-EDTMP, Sm-153-DOTMP, Ho-166-EDTMP, Ho-166-DOTMP, Gd-159-EDTMP, Gd-159-DOTMP, Dy-165-EDTMP, Dy-165-DOTMP, Lu-177-EDTMP and Lu-177-DOTMP. Most preferred radiopharmaceutical complexes for use with the present invention include Sm-DOTMP, Ho-166-DOTMP, Lu-177-DOTMP, and Gd-159-DOTMP. Examples of these complexes and their preparation are described in U.S. Patents 4,976,950, 4,882,142, 5,059,412, 5,066,478, 5,064,633, 4,897,254, 4,898,724 and 5,300,279, which are incorporated herein by reference.
The systemic administration of chelating agents to scavenge radioactivity that does leach to non-target areas of the body is another aspect of this invention. The compositions of this invention allow higher target to non-target ratios using lower total amounts of radioisotopes, thus increasing the possibility of delivering significantly more radioactivity to the site of the target tissue without dosing normal tissue.
Detailed Description of the Invention This invention involves the delivery of a therapeutic amount of a formulated radioisotope composition directly to an undesired tissue mass, including infections (e.g., osteomyelitis) and cancerous tumors, especially inoperable cancerous tumors, in both soft tissue and bone. Because these formulations are very small in volume and the amount of radioactivity administered is effectively directed to the desired site, the administration is not by means that involve other body areas, e.g., no systemic administration (such as I.V. administration) is intended. Non-target, normal tissue is spared because only a very small amount of radioisotope is administered and the majority of the radioisotope mixture is immobilized at the administration site. Thus the majority of the radioactive decay of the isotope occurs at the site of injection with only small amounts of radioactivity leaching out of the injection site before a significant amount of the radioisotope decays. This results in a high radiation dose to the target area and extremely small doses to non-target tissues. The composition can be used to treat a variety of conditions, particularly cancerous tumors.
Radioisotopes used in this invention are particle emitters (beta ((3) emitters or alpha (a) emitters). Preferred radioisotopes are ions of rare earth-type metals including Pm, Sin, Gd, Dy, Ho, Yb, Lu, and Y; especially preferred are Sm, Ho, Lu, and Y. Preferred radioactive isotopes include: Sm-153, Ho-166, Y-90, Pm-149, Gd-159, Lu-177, Yb-175, Pb-212, Bi-212, Bi-213, and Ac-225. Especially preferred are Sm-153, Ho-166, Y-90, Bi-213, Ac-225, and Lu-177. Most preferred are isotopes with a relatively short half life of less than about 3 days and that emit energetic beta particles. Examples include Y-90, Ho-166, and Sm-153. It is understood that often the radioisotopes contain non-radioactive carrier isotopes as a mixtures.
In one aspect of this invention, the radioisotopes are administered in an aqueous formulation without a chelating agent or other binder after the pH of the solution has been raised. A preferred pH of the formulation is wherein the metallic radioisotopes are in a hydroxide form which usually results in a suspension.
This pH
varies from metal to metal and is known to one skilled in the art. Preferred pH
formulations include a pH greater than about 7. More preferred formulations are a pH
greater than about 8. A pH range from about 8 to about 14 is desirable for most of these radioactive metals, and preferred is a range from about 8 to about 11.
The pH is attained by the addition of a suitable base such as sodium hydroxide. While not wishing to be bound by theory, it is believed that the metallic radioisotopes form insoluble hydroxides that precipitate and remain in the tissue longer than if the dose is administered in neutral or acidic solution (pH less than about 7) or if the radioisotope is bound to a soluble binder such as a chelating agent. To facilitate the precipitation it is possible to add another non-radioactive metal such as iron that could co-precipitate with the radioisotope.
In another aspect of this invention, the radioisotope is bound to a phosphonic acid chelating agent (that has an affinity for bone) or other binder such as hydroxyapatite that helps retain it at the injection site. When a binder is used then greater than about 75% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
The various radioisotopes discussed above are administered as a formulation in a liquid that is pharmaceutically-acceptable, such as water, saline, or an oil such as sesame seed oil, corn oil and others. The formulated liquid may be a suspension, a slurry or an emulsion. Optionally other usual ingredients can be present such as excipients, suspension aids, preservatives, base or buffers for pH adjustment, and others.
In yet another aspect of this invention, the amount of the radioisotope administered is very low. Preferred volumes of administered radioisotope are less than about 50 microliters per cubic centimeter of tissue (50 gL/cm). More preferred are doses of less than 20 microliters per cubic centimeter of tissue (20 gL/cm).
Delivery of the dose can be done using a microsyringe or a pump capable of accurately delivering microliter volumes (e.g. Valco Instrument Company, Inc.
model CP-DSM) to provide flow to the proximal end of a catheter which may be placed within or next to the tissue to be treated. The flow may be either continuous or may be pulsed to enhance complete penetration of the tissue mass by the radioisotope.
In another aspect of this invention a chelating agent is administered systemically to the patient before and for a time after the administration of the radioactive dose. Preferred chelating agents including EDTA and DTPA that serve to scavenge systemic radioactivity and remove it from the body via the kidneys and into the bladder. These agents are used when desired to ensure more complete removal of the administered radioisotope that may have migrated from the injection site.
As usually only a low amount of such migration occurs, this treatment is optional.
In one embodiment of the invention, the radioisotope may be delivered to a bone tumor using a miniature pump. Access to the tumor may be effected by the use of a bone biopsy tool or a miniature drill capable of making a curved or angled hole through bone and either upstream of the tumor (so to guide the catheter towards it) or directly into the bone or tumor in the bone. The insertion of the catheter using fluoroscopy, as is known in the art, may help to position the distal end of the catheter in close proximity to the tumor. The delivery of the radioisotope upstream of the tumor may reduce the risk of spreading cancer cells potentiated by approaching the tumor directly or downstream from the blood flow.
The drill used in the present examples is discussed in US Provisional Patent Applications 60/890,831 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 20, 2007 and 60/891,183 entitled, "Directional Bone Drilling and Methods of Treatment" filed on February 22, 2007, but this invention is not limited to the use of this drill as any device that can provide a suitable hole in the bone, such as a syringe needle or biopsy tool will suffice.
In another aspect of this invention the radioisotopes are combined with a binder that is a solid support, such as hydroxyapatite. This form of calcium phosphate has the ability to bind metal ions such as radioactive rare earth metals. The hydroxyapatite/metal ion combination can be administered into tissues and a therapeutically significant amount of the radioisotope remains at the site of injection.
In another aspect of the invention, the radioisotopes may have binder molecules that have affinity for bone such as phosphonic acid chelating agents.
Preferred chelating agents include those selected from aminomethylenephosphonic acids such as ethylenediaminetetramethylenephosphonic acid (EDTMP), diethylene-triaminepentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediamine-trimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP), 1-carboxyethylenediaminetetramethylenephosphonic acid (CEDTMP), bis(amino-ethylpiperazine)tetramethylenephosphonic acid (AEPTMP), ethylenediaminetetra-acetic acid (EDTA), 1,4,7,1 0-tetraazacyclododecane-N, N',N",N"'-tetramethylene-phosphonic acid (DOTMP), hydroxyethyldiphosphonic acid (HEDP), methylene-diphosphonic acid (MDP), diethylenetriaminepentaacetic acid (DTPA), hydroxyethyl-ethylenediaminetriacetic acid (HEDTA), and nitrilotriacetic acid (NTA). More preferably, the chelating agent is 1,4,7, 1 0-tetraazacyclododecane-N, N',N",N"'-tetramethylenephosphonic acid (DOTMP).
In one aspect of this invention, the bone seeking radiopharmaceutical complex is chosen from the group consisting of Sm-153-EDTMP, Sm-153-DOTMP, Ho-166-EDTMP, Ho-166-DOTMP, Gd-159-EDTMP, Gd-159-DOTMP, Dy-165-EDTMP, Dy-165-DOTMP, Lu-177-EDTMP and Lu-177-DOTMP. Most preferred radiopharmaceutical complexes for use with the present invention include Sm-DOTMP, Ho-166-DOTMP, Lu-177-DOTMP, and Gd-159-DOTMP. Examples of these complexes and their preparation are described in U.S. Patents 4,976,950, 4,882,142, 5,059,412, 5,066,478, 5,064,633, 4,897,254, 4,898,724 and 5,300,279, which are incorporated herein by reference.
This invention will be further clarified by a consideration of the following examples, which are intended to be purely exemplary of the present invention.
The following numbered examples illustrate this invention; and the lettered examples are illustrating comparative examples.
Examples General Information All percentages are weight/weight (w/w) unless stated otherwise.
MURR is University of Missouri Research Reactor (Columbia, MO) that has a service to provide radioisotopes.
It is understood that often the radioisotopes contain non-radioactive carrier isotopes as a mixtures.
Example 1: High pH Lu-177 mixture A high pH Lu-177 solution was prepared by adding of 2.0 gL of 50% w/w NaOH to 10 L of a Lu- 177 solution (obtained from MURR, 1.09 Ci/mL in 0.05 M
HCI) followed by the addition of 8.0 L of water. The mixture was allowed to stand for 30 minutes prior to injection. The pH of the mixture was greater than about 10.
Example A: Low pH Lu-177 solution (comparative) A solution of Lu-177 in 0.05 M HCl was obtained from MURR containing about 1.09 Ci/mL. The injectate was prepared by mixing equal volumes of the Lu-solution and 0.05 M HCI. The pH was less than about 2.
Example 2: In vivo Xenograft Test - High pH Lu-177 An athymic mouse bearing an HT-29 xenograft was anesthetized and 2-3 L
of the mixture of Example 1 was diluted with about 20 L of water and administered directly into the tumor. Multiple injections were made at several. different sites around the periphery of the tumor as well as directly into the tumor mass. The amount of injected activity was determined to be 0.924 mCi Lu- 177. Gamma camera images 13 days post-treatment showed the majority of the activity remaining at the injection site. Less than 1 pCi of the Lu-177 was found in the urine or feces on any of the 13 days post-injection. The size of the tumor was measured and compared to a similar mouse injected with saline as a control. The tumor in the saline control mouse increased in size while the tumor in the mouse of this Example 2 decreased in size.
These results are shown in the Table 1 below:
Table 1 Tumor size in cubic millimeters for treated and control mice Days Post 1 2 3 6 7 8 9 10 11 12 13 Treatment Mouse of 405 447 816 282 721 282 237 211 144 181 154 Example Control Mouse 527 1362 1332 1499 2673 2847 3621 3589 3357 3748 4573 Example B: In vivo Xenograft Test - Low pH Lu-177 (comparative) An athymic mouse bearing an HT-29 (human colorectal carcinoma) xenograft was anesthetized and 2-3 pL of the solution of Example A was administered directly into the tumor. The amount of injected activity was determined using a dose calibrator to be 1.08 mCi of Lu- 177.
The fate of the Lu- 177 in the mouse body was determined using a gamma camera. In addition, a dose calibrator was used to measure the amount of radioactivity collected in the urine as a function of time. After 1 day, 50 ICi of Lu-177 was found in the collected urine and feces. In addition, significant migration of radioisotope from the tumor area was observed. Over time, the mouse showed signs of increasing morbidity. The mouse was euthanized due to morbidity after a 20% loss in body weight 9 days post-injection.
Example 3: In vivo Prostate Test A volume of about 6-8 pL of the solution of Example 1 was administered to the left lobe of the prostate of a normal Sprague Dawley rat while the rat was under anesthesia. The rat received a Lu-177 dose of 0.924 mCi.
The following numbered examples illustrate this invention; and the lettered examples are illustrating comparative examples.
Examples General Information All percentages are weight/weight (w/w) unless stated otherwise.
MURR is University of Missouri Research Reactor (Columbia, MO) that has a service to provide radioisotopes.
It is understood that often the radioisotopes contain non-radioactive carrier isotopes as a mixtures.
Example 1: High pH Lu-177 mixture A high pH Lu-177 solution was prepared by adding of 2.0 gL of 50% w/w NaOH to 10 L of a Lu- 177 solution (obtained from MURR, 1.09 Ci/mL in 0.05 M
HCI) followed by the addition of 8.0 L of water. The mixture was allowed to stand for 30 minutes prior to injection. The pH of the mixture was greater than about 10.
Example A: Low pH Lu-177 solution (comparative) A solution of Lu-177 in 0.05 M HCl was obtained from MURR containing about 1.09 Ci/mL. The injectate was prepared by mixing equal volumes of the Lu-solution and 0.05 M HCI. The pH was less than about 2.
Example 2: In vivo Xenograft Test - High pH Lu-177 An athymic mouse bearing an HT-29 xenograft was anesthetized and 2-3 L
of the mixture of Example 1 was diluted with about 20 L of water and administered directly into the tumor. Multiple injections were made at several. different sites around the periphery of the tumor as well as directly into the tumor mass. The amount of injected activity was determined to be 0.924 mCi Lu- 177. Gamma camera images 13 days post-treatment showed the majority of the activity remaining at the injection site. Less than 1 pCi of the Lu-177 was found in the urine or feces on any of the 13 days post-injection. The size of the tumor was measured and compared to a similar mouse injected with saline as a control. The tumor in the saline control mouse increased in size while the tumor in the mouse of this Example 2 decreased in size.
These results are shown in the Table 1 below:
Table 1 Tumor size in cubic millimeters for treated and control mice Days Post 1 2 3 6 7 8 9 10 11 12 13 Treatment Mouse of 405 447 816 282 721 282 237 211 144 181 154 Example Control Mouse 527 1362 1332 1499 2673 2847 3621 3589 3357 3748 4573 Example B: In vivo Xenograft Test - Low pH Lu-177 (comparative) An athymic mouse bearing an HT-29 (human colorectal carcinoma) xenograft was anesthetized and 2-3 pL of the solution of Example A was administered directly into the tumor. The amount of injected activity was determined using a dose calibrator to be 1.08 mCi of Lu- 177.
The fate of the Lu- 177 in the mouse body was determined using a gamma camera. In addition, a dose calibrator was used to measure the amount of radioactivity collected in the urine as a function of time. After 1 day, 50 ICi of Lu-177 was found in the collected urine and feces. In addition, significant migration of radioisotope from the tumor area was observed. Over time, the mouse showed signs of increasing morbidity. The mouse was euthanized due to morbidity after a 20% loss in body weight 9 days post-injection.
Example 3: In vivo Prostate Test A volume of about 6-8 pL of the solution of Example 1 was administered to the left lobe of the prostate of a normal Sprague Dawley rat while the rat was under anesthesia. The rat received a Lu-177 dose of 0.924 mCi.
The rat was monitored daily for Lu-177 in urine and feces. Only minimally measurable Lu-177 (-1.0 .tCi) was found on any individual day. Gamma images showed the Lu- 177 remaining at the injection site throughout the 7 day study with very little systemic radioactivity. The rat was euthanized seven days post-treatment, organs and tissues were excised and the presence of Lu-177 in each was determined.
Less than 10% of the dose was found outside the prostate after 7 days.
Examination of the prostate revealed the injected lobe of the prostate to be atrophied compared to the opposite lobe of the prostate.
Example 4: Lu-177 Injectate preparation Lu-177 was received from MURR in 0.1 M HCl at 0.71 mCi/ L upon arrival.
Activity was measured using a CapintecTM CRC-15 dose calibrator. To 3.0 gL of this solution was added 3.0 gL of 1.0 N NaOH (Fisher). Water was added to give a final volume of 10.0 L.
Example 5: Lung Test - Lu- 177 Injection into a male Sprague Dawley Rat A 364 g male Sprague Dawley rat, under anesthesia, was injected with 3-5 L
(-1.0 mCi) of the preparation in Example 4 directly into the lung using an insulin syringe. The dose was deposited in the left lobe of the lung via needle insertion through the skin.
Images of the rat using a gamma camera were taken at 30 minutes post injection, 18 hours, 2, 5, 7 and 9 days post injection. Feces and urine excretions were collected daily and analyzed for the presence of radioactivity. At 9 days the rat was euthanized and organs/tissues obtained for gamma counting.
All gamma images showed one a single spot at the site of injection with no detectable activity in any other part of the body.
Gamma counting of low activity tissues was accomplished using a WizardTM
1480 gamma counter (Packard); highest activity samples, which were the urine and lung, were evaluated on a CapintecTM CRC-15 dose calibrator.
Evaluation of the data indicate 76.2% of the injected Lu-177 remained in the lung at 9 days post injection. About 15% was excreted in the feces/urine. The rat skeleton (Bone) had 3.6%, and liver about 0.4%. Less than 1 % of the injected radioactivity was found in any other organ or tissue.
Example 6: Ho-166 Administered to Bone as the Hydroxide Holmium-166 (Ho-166) was obtained from MURR. The solution was 52.4 mCi in 350 L for a specific activity of 0.15 mCi/IL in 0.1 M HCI. The Ho-166 solution (10 L) was placed in a vial and 5 L of 0.1 M NaOH was added. The pH
was measured with pH paper showing a pH of about 10.
A miniature drill was used to create a hole in the femur of an anesthetized Sprague Dawley rat. A miniature pump was used to deliver 3 L of this high pH
Ho-166 solution into the hole created by the drill.
Two hours after the injection of the dose the rat was sacrificed and dissected.
Tissues/organs excised and counted included bone (opposite femur), liver, kidneys, spleen, muscle, blood, heart, lung, pancreas as well as the injected femur.
Counting was done by the use of a Nal gamma detector to determine the presence of radioactivity.
The amount of activity found in the site of injection was 92 % of the injected dose. Less than 2% of the dose was found in the liver or in the rest of the bone. Total skeletal dose was determined by multiplying the % dose in the opposite femur by 25.
No urine activity was evident.
Example C (comparative): Ho-166 Administered to Bone as the Chloride Ho-166 in O.1M HCl was obtained from MURR. The pH was measured with pH paper showing a pH of about 1. The miniature drill described above in Example 6 was used to create a hole in the femur of an anesthetized Sprague Dawley rat.
The miniature pump described above was used to deliver 3 pL of Ho-166 solution into the hole created by the drill. Two hours after the injection of the dose the rat was sacrificed and dissected. The amount of activity found in the site of injection was 5 %
of the injected dose. However 52% of the dose was found in the liver and 23%
of the dose was found in the rest of the bone. Total skeletal dose was determined by multiplying the % dose in the opposite femur by 25. The high amount of the dose found in non-target areas shows that this form of Ho-166 is not an effective way to dose patients.
Example 7: Ho-166 Administered to Bone with Hydroxyapatite Hydroxyapatite (6 mg) was placed in a vial and 600 L of water was added.
The mixture was shaken to form a slurry and 15 pL of the slurry were taken and placed in a separate tube. To this was added 3 gL of Ho-166 in 0.1M HCI. The miniature drill described in Example 6 was used to create a hole in the femur of an anesthetized Sprague Dawley rat. The miniature pump described in Example 6 was used to deliver 3 pL of Ho- 166 labeled hydroxyapatite solution into the hole created by the drill. Three hours after the injection of the dose the rat was sacrificed and dissected. The amount of radioactivity found in or directly around the site of injection was 94% of the injected dose. Less than 1% of the dose was found in the liver or in the rest of the bone. Total skeletal dose was determined by multiplying the %
dose in the opposite femur by 25.
Example 8: Sm-153-DOTMP
Sm-153 in 0.1 M HCI was obtained from MURR. The complex formed between Sm-153 and DOTMP was prepared by combining 5 pL of Sm-153 with 5.6 L of a solution containing 13 mg/mL of DOTMP (previously adjusted to pH 7-8) and 4 L of water. An additional 5 pL of DOTMP solution was added to obtain high complex yields. The amount of Sin found as a complex was 99% by ion exchange chromatography. DOTMP was prepared and purified by known synthetic techniques.
The chelant was greater than 99% pure.
The miniature drill described in Example 6 was used to create a hole in the femur of an anesthetized Sprague Dawley rat. The miniature pump described in Example 6 was used to deliver 2 pL of Sm-153-DOTMP solution into the hole created by the drill. Two hours after the injection of the dose the rat was sacrificed and dissected. The amount of activity found in the site of injection was 9 % of the injected dose. None of the radioactivity was found in the liver and about 20%
was found in the rest of the bone. Total skeletal dose was determined by multiplying the % dose in the opposite femur by 25. An average of 65% of the injected dose was found in the urine.
Summary The examples above are illustrative of the present invention. When compositions of radioisotope solutions at high pH are administered in small volume, the vast majority of the isotope remains at the site of administration, even 13 days post injection (e.g. Example 2), compared with a similar administration of radioisotopes at low pH where a significant portion of the radioactivity migrates away from the site of administration (e.g. Example B). When direct injections of isotopes are made directly into the bone, a significantly higher percentage of radioactivity can be delivered to bone compared to I.V. administration of a bone-seeking radiopharmaceutical where only about 0.1 % of the radioactivity is taken up by a bone tumor. This allows a much lower total amount of radioactivity injected to deliver a much greater radiation dose to the target tissue.
The use of the compositions of this invention show in some cases, greater than 90% of the radioactivity at the desired site with little to no activity in non-target organs or tissues. As stated above, in addition to practically eliminating the dose to non-target tissues and organs, much less radioisotope is needed. Finally, since more activity can be delivered to the tumor, resolution of the tumor is possible.
In comparing the tumor growth rate in Example 2 to that of Example B, a therapeutic effect was clearly demonstrated.
Although the invention and processes have been described with reference to these embodiments, those of ordinary skill in the art may, upon reading this application, appreciate changes and modifications which may be made which do not depart from the scope and spirit of this invention as described above or claimed hereafter.
Less than 10% of the dose was found outside the prostate after 7 days.
Examination of the prostate revealed the injected lobe of the prostate to be atrophied compared to the opposite lobe of the prostate.
Example 4: Lu-177 Injectate preparation Lu-177 was received from MURR in 0.1 M HCl at 0.71 mCi/ L upon arrival.
Activity was measured using a CapintecTM CRC-15 dose calibrator. To 3.0 gL of this solution was added 3.0 gL of 1.0 N NaOH (Fisher). Water was added to give a final volume of 10.0 L.
Example 5: Lung Test - Lu- 177 Injection into a male Sprague Dawley Rat A 364 g male Sprague Dawley rat, under anesthesia, was injected with 3-5 L
(-1.0 mCi) of the preparation in Example 4 directly into the lung using an insulin syringe. The dose was deposited in the left lobe of the lung via needle insertion through the skin.
Images of the rat using a gamma camera were taken at 30 minutes post injection, 18 hours, 2, 5, 7 and 9 days post injection. Feces and urine excretions were collected daily and analyzed for the presence of radioactivity. At 9 days the rat was euthanized and organs/tissues obtained for gamma counting.
All gamma images showed one a single spot at the site of injection with no detectable activity in any other part of the body.
Gamma counting of low activity tissues was accomplished using a WizardTM
1480 gamma counter (Packard); highest activity samples, which were the urine and lung, were evaluated on a CapintecTM CRC-15 dose calibrator.
Evaluation of the data indicate 76.2% of the injected Lu-177 remained in the lung at 9 days post injection. About 15% was excreted in the feces/urine. The rat skeleton (Bone) had 3.6%, and liver about 0.4%. Less than 1 % of the injected radioactivity was found in any other organ or tissue.
Example 6: Ho-166 Administered to Bone as the Hydroxide Holmium-166 (Ho-166) was obtained from MURR. The solution was 52.4 mCi in 350 L for a specific activity of 0.15 mCi/IL in 0.1 M HCI. The Ho-166 solution (10 L) was placed in a vial and 5 L of 0.1 M NaOH was added. The pH
was measured with pH paper showing a pH of about 10.
A miniature drill was used to create a hole in the femur of an anesthetized Sprague Dawley rat. A miniature pump was used to deliver 3 L of this high pH
Ho-166 solution into the hole created by the drill.
Two hours after the injection of the dose the rat was sacrificed and dissected.
Tissues/organs excised and counted included bone (opposite femur), liver, kidneys, spleen, muscle, blood, heart, lung, pancreas as well as the injected femur.
Counting was done by the use of a Nal gamma detector to determine the presence of radioactivity.
The amount of activity found in the site of injection was 92 % of the injected dose. Less than 2% of the dose was found in the liver or in the rest of the bone. Total skeletal dose was determined by multiplying the % dose in the opposite femur by 25.
No urine activity was evident.
Example C (comparative): Ho-166 Administered to Bone as the Chloride Ho-166 in O.1M HCl was obtained from MURR. The pH was measured with pH paper showing a pH of about 1. The miniature drill described above in Example 6 was used to create a hole in the femur of an anesthetized Sprague Dawley rat.
The miniature pump described above was used to deliver 3 pL of Ho-166 solution into the hole created by the drill. Two hours after the injection of the dose the rat was sacrificed and dissected. The amount of activity found in the site of injection was 5 %
of the injected dose. However 52% of the dose was found in the liver and 23%
of the dose was found in the rest of the bone. Total skeletal dose was determined by multiplying the % dose in the opposite femur by 25. The high amount of the dose found in non-target areas shows that this form of Ho-166 is not an effective way to dose patients.
Example 7: Ho-166 Administered to Bone with Hydroxyapatite Hydroxyapatite (6 mg) was placed in a vial and 600 L of water was added.
The mixture was shaken to form a slurry and 15 pL of the slurry were taken and placed in a separate tube. To this was added 3 gL of Ho-166 in 0.1M HCI. The miniature drill described in Example 6 was used to create a hole in the femur of an anesthetized Sprague Dawley rat. The miniature pump described in Example 6 was used to deliver 3 pL of Ho- 166 labeled hydroxyapatite solution into the hole created by the drill. Three hours after the injection of the dose the rat was sacrificed and dissected. The amount of radioactivity found in or directly around the site of injection was 94% of the injected dose. Less than 1% of the dose was found in the liver or in the rest of the bone. Total skeletal dose was determined by multiplying the %
dose in the opposite femur by 25.
Example 8: Sm-153-DOTMP
Sm-153 in 0.1 M HCI was obtained from MURR. The complex formed between Sm-153 and DOTMP was prepared by combining 5 pL of Sm-153 with 5.6 L of a solution containing 13 mg/mL of DOTMP (previously adjusted to pH 7-8) and 4 L of water. An additional 5 pL of DOTMP solution was added to obtain high complex yields. The amount of Sin found as a complex was 99% by ion exchange chromatography. DOTMP was prepared and purified by known synthetic techniques.
The chelant was greater than 99% pure.
The miniature drill described in Example 6 was used to create a hole in the femur of an anesthetized Sprague Dawley rat. The miniature pump described in Example 6 was used to deliver 2 pL of Sm-153-DOTMP solution into the hole created by the drill. Two hours after the injection of the dose the rat was sacrificed and dissected. The amount of activity found in the site of injection was 9 % of the injected dose. None of the radioactivity was found in the liver and about 20%
was found in the rest of the bone. Total skeletal dose was determined by multiplying the % dose in the opposite femur by 25. An average of 65% of the injected dose was found in the urine.
Summary The examples above are illustrative of the present invention. When compositions of radioisotope solutions at high pH are administered in small volume, the vast majority of the isotope remains at the site of administration, even 13 days post injection (e.g. Example 2), compared with a similar administration of radioisotopes at low pH where a significant portion of the radioactivity migrates away from the site of administration (e.g. Example B). When direct injections of isotopes are made directly into the bone, a significantly higher percentage of radioactivity can be delivered to bone compared to I.V. administration of a bone-seeking radiopharmaceutical where only about 0.1 % of the radioactivity is taken up by a bone tumor. This allows a much lower total amount of radioactivity injected to deliver a much greater radiation dose to the target tissue.
The use of the compositions of this invention show in some cases, greater than 90% of the radioactivity at the desired site with little to no activity in non-target organs or tissues. As stated above, in addition to practically eliminating the dose to non-target tissues and organs, much less radioisotope is needed. Finally, since more activity can be delivered to the tumor, resolution of the tumor is possible.
In comparing the tumor growth rate in Example 2 to that of Example B, a therapeutic effect was clearly demonstrated.
Although the invention and processes have been described with reference to these embodiments, those of ordinary skill in the art may, upon reading this application, appreciate changes and modifications which may be made which do not depart from the scope and spirit of this invention as described above or claimed hereafter.
Claims (21)
1. A composition comprising a therapeutically-effective amount of a radioisotope formulation having a pH greater than about 7 together with a pharmaceutically-acceptable liquid carrier, for the treatment of an undesirable tissue mass in an animal or human in need of such treatment, wherein the composition is administered directly to or nearby the tissue mass, and the composition is such that less than about 15% of the radioisotope migrates away from the site of administration within two half lives of radioactive decay.
2. The composition of Claim 1 where the pH greater than about 8.
3. The composition of Claim 1 or 2 wherein another non-radioactive metal is added to co-precipitate with the radioisotope.
4. The composition of Claim 1 wherein the undesirable tissue mass is a cancer.
5. The composition of Claim 1, wherein the volume of the administered formulation is less than about 50 µL/cm3 of treated tissue mass.
6. The composition of Claim 5 wherein the volume of the administered formulation is less than about 20 µL/cm3 of treated tissue mass.
7. The composition of Claim 4 or 5 wherein the cancer is bone cancer and a miniature drill is used to create a hole in the bone by which a needle or catheter can be inserted through the hole and a device capable of delivering small volumes of fluid is used to deliver the formulation.
8. The composition of Claim 1 or 5 wherein the dose is delivered via a pump or syringe.
9. The composition of Claim 1 wherein the radioisotope is Sm-153, Ho-166, Y-90, Pm-149, Gd-159, Lu-177, Yb-175, Pb-212, Bi-212, Bi-213 or Ac-225
10. The composition of Claim 9 wherein the radioisotope is Sm-153, Ho-166, Y-90, Bi-213, Ac-225 or Lu-177.
11. A composition for direct administration of a therapeutically-effective amount of a radioisotope formulation wherein the radioisotope is bound to a binder, for the treatment of an undesirable tissue mass in an animal or human in need of such treatment, such that greater than about 5% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
12. The composition of Claim 11 wherein the binder is a phosphonic acid chelating agent.
13. The composition of Claim 12 wherein the radioisotope is chelated to DOTMP
and the radioisotope is Sm-153, Lu-177, Ho-166 or Ac-225.
and the radioisotope is Sm-153, Lu-177, Ho-166 or Ac-225.
14. The composition of Claim 11 wherein the binder is a solid support and greater than about 75% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
15. The composition of Claim 14 wherein the solid support is hydroxyapatite.
16. The composition of Claim 1 or 11 wherein the formulation is a liquid in the form of a solution, suspension, slurry or emulsion.
17. The composition of Claim 1 or 11 wherein an intravenous administration of an aminomethylenecarboxylic acid is used to scavenge and remove radioactivity that becomes systemic.
18. The composition of Claim 17 wherein the aminomethylenecarboxylic acid is EDTA or DTPA.
19. The composition of Claim 1 or 11 wherein the radioisotope is administered by a micro-pump which can accurately deliver microliter volumes of the formulation.
20. A method for direct administration of a therapeutically-effective amount of a radioisotope formulation as defined in Claim 1 to an undesirable tissue mass of bone cancer or soft tissue tumor in an animal or human in need of such treatment, wherein the composition is such that less than about 15% of the radioisotope migrates away from the site of administration within two half lives of radioactive decay.
21. A method for direct administration of a therapeutically-effective amount of a radioisotope formulation as defined in Claim 11 to an undesirable tissue mass of bone cancer or soft tissue tumor in an animal or human in need of such treatment, wherein the radioisotope is bound to a binder, such that greater than about 5% of the radioisotope remains at the site of administration within two half lives of radioactive decay.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US99787307P | 2007-10-05 | 2007-10-05 | |
| US99785607P | 2007-10-05 | 2007-10-05 | |
| US60/997,873 | 2007-10-05 | ||
| US60/997,856 | 2007-10-05 | ||
| PCT/US2008/002026 WO2009045230A1 (en) | 2007-10-05 | 2008-02-15 | Compositions for treatment of tumors by direct administration of a radioisotope |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2701537A1 true CA2701537A1 (en) | 2009-04-09 |
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ID=40526495
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2701537A Abandoned CA2701537A1 (en) | 2007-10-05 | 2008-02-15 | Compositions for treatment of tumors by direct administration of a radioisotope |
Country Status (4)
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| EP (1) | EP2195036A4 (en) |
| JP (1) | JP2010540627A (en) |
| CA (1) | CA2701537A1 (en) |
| WO (1) | WO2009045230A1 (en) |
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|---|---|---|---|---|
| WO2007008232A2 (en) | 2004-09-03 | 2007-01-18 | Board Of Regents, The University Of Texas System | Locoregional internal radionuclide ablation of abnormal tissues. |
| DOP2010000279A (en) * | 2009-09-18 | 2012-06-15 | Sari Asher Llc | NON-SEALED NON-SEALED RADIOPHARMACEUTICAL COMPOSITIONS AND METHODS FOR TREATMENT OF ABNORMAL FABRIC |
| CA2986337C (en) | 2010-03-09 | 2020-06-02 | Kurion, Inc. | Isotope-specific separation and vitrification using ion-specific media |
| GB2490317A (en) * | 2011-04-19 | 2012-10-31 | Dspi Ltd | Radioactive solution undergoing in situ precipitation at a tumour site for cancer therapy |
| EP2793955B1 (en) * | 2011-12-21 | 2018-04-11 | IsoTherapeutics Group, LLC | Radioactive compositions and methods for their therapeutic use |
| EP2831889B1 (en) | 2012-03-26 | 2018-11-21 | Kurion, Inc. | Selective regeneration of isotope-specific media resins in systems for separation of radioactive isotopes from liquid waste materials |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4849209A (en) * | 1985-06-07 | 1989-07-18 | Cadema Medical Products, Inc. | Treatment of arthritis, including rheumatoid arthritis with 166 Holmium radionuclide |
| EP0313273B1 (en) * | 1987-10-14 | 1992-01-29 | Australian Nuclear Science And Technology Organisation | Macroaggregates for radiation synovectomy |
| US20030003048A1 (en) * | 2001-04-26 | 2003-01-02 | Chun Li | Diagnostic imaging compositions, their methods of synthesis and use |
| WO2004050168A2 (en) * | 2002-11-27 | 2004-06-17 | Board Of Regents, The University Of Texas System | Radiopharmaceuticals and radioactive microspheres for locoregional ablation of abnormal tissues |
| US8388955B2 (en) * | 2003-03-03 | 2013-03-05 | Xencor, Inc. | Fc variants |
| WO2007008232A2 (en) * | 2004-09-03 | 2007-01-18 | Board Of Regents, The University Of Texas System | Locoregional internal radionuclide ablation of abnormal tissues. |
| EP1796737B1 (en) * | 2004-09-24 | 2018-10-24 | Biosphere Medical, Inc. | Microspheres capable of binding radioisotopes, optionally comprising metallic microparticles, as well as methods of use thereof |
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2008
- 2008-02-15 EP EP08725637A patent/EP2195036A4/en not_active Withdrawn
- 2008-02-15 CA CA2701537A patent/CA2701537A1/en not_active Abandoned
- 2008-02-15 WO PCT/US2008/002026 patent/WO2009045230A1/en active Application Filing
- 2008-02-15 JP JP2010527928A patent/JP2010540627A/en active Pending
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| JP2010540627A (en) | 2010-12-24 |
| WO2009045230A1 (en) | 2009-04-09 |
| EP2195036A1 (en) | 2010-06-16 |
| EP2195036A4 (en) | 2011-03-09 |
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