Classifications

• • 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
• • 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
• • 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)
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• 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.
• 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.
• narcotics The pain associated with bone cancer, especially metastatic bone cancer, is often treated with narcotics.
• 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.
• 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 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.
• P-32 can be used alone as a bone seeking radiopharmaceutical without a chelant present.
• 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 14:219-222 (1987).
• Both diagnostic and therapeutic radiopharmaceuticals capable of targeting bone tumors generally use phosphonic acid functionality as the targeting moiety.
• phosphonic acid functionality 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.
• therapeutic radiopharmaceuticals for bone tumors were developed in the 1980's and 1990's.
• a series of chelates based on aminomethylenephosphonic acids offer another type of functionality useful for targeting bone tumors.
• 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.
• 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.
• therapeutic bone agents are typically not used at the same time chemotherapeutic agents are used.
• 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.
• ETMP ethylenediaminetetra- methylenephosphonic acid
• DOTMP lATJO-tetraazacyclododecane-lATjlO- tetra(methylenephosphonic acid)
• 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 preexisting body cavity.
• Intravascular brachytherapy places a catheter with the source inside blood vessels.
• 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 ( ⁇ ) and alpha ( ⁇ ) 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.
• electromagnetic radiation X-rays and gamma photons
• 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.
• 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 ( ⁇ ) 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 1-125 which has a 59.4 day half life and emits multiple X-rays around 30 keV.
• Cs-131 which has a 9.7 day half life and emits X-rays of about 30 keV.
• Pd- 103 is used which has a 17 day half life and emits X-rays of about 20 keV.
• 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.
• brachytherapy is used to destroy cancer cells left over after a surgical procedure.
• breast cancer patients can be treated with a technology by the name of MammoSite ® Radiation Therapy System.
• 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.
• 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 GliaSite ® Radiation Therapy System (e.g. U.S. Patent 6,315,979).
• the balloon prevents the radioactivity from going systemic.
• 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.
• 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 ⁇ m in diameter.
• 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.
• 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.
• 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.
• 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
• 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.
• 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.
• 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
• 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 ( ⁇ ) emitters or beta ( ⁇ ) 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.
• 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.
• 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 LV. 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.
• infections e.g., osteomyelitis
• cancerous tumors especially inoperable cancerous tumors
• the composition can be used to treat a variety of conditions, particularly cancerous tumors.
• Radioisotopes used in this invention are particle emitters (beta ( ⁇ ) emitters or alpha ( ⁇ ) emitters).
• Preferred radioisotopes are ions of rare earth-type metals including Pm, Sm, 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.
• 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.
• 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.
• 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.
• a soluble binder such as a chelating agent.
• another non-radioactive metal such as iron that could co-precipitate with the radioisotope.
• 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.
• 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.
• 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.
• other usual ingredients can be present such as excipients, suspension aids, preservatives, base or buffers for pH adjustment, and others.
• 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 ⁇ L/cm 3 ). More preferred are doses of less than 20 microliters per cubic centimeter of tissue (20 ⁇ L/cm 3 ). 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.
• 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.
• 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 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 radioisotopes are combined with a binder that is a solid support, such as hydroxyapatite.
• 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.
• 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), /r ⁇ (2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP), 1- carboxyethylenediaminetetramethylenephosphonic acid (CEDTMP), Z>w(amino- ethylpiperazine)tetramethylenephosphonic acid (AEPTMP), ethylenediaminetetra- acetic acid (EDTA), 1,4,7,10-tetraazacyclododecane-N, N',N",N'"-tetramethylene- phospho
• 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-153- DOTMP, Ho-166-DOTMP, Lu-177-DOTMP, and Gd-159-DOTMP. Examples of these complexes and their preparation are described in U.S.
• 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.
• MURR is University of Missouri Research Reactor (Columbia, MO) that has a service to provide radioisotopes.
• 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 ⁇ L of 50% w/w
• 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-177 solution and 0.05 M HCl.
• the pH was less than about 2.
• Example 2 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 ⁇ Ci 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:
• 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 ⁇ L 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.
• a dose calibrator was used to measure the amount of radioactivity collected in the urine as a function of time. After 1 day, 50 ⁇ Ci 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.
• a volume of about 6-8 ⁇ L 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 ⁇ Ci) 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.
• 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 ⁇ L of this solution was added 3.0 ⁇ L 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
• 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.
• 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/ ⁇ L in 0.1 M HCl. The Ho-166 solution (10 ⁇ L) was placed in a vial and 5 ⁇ L of 0. IM 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.
• 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 NaI 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 Ho-166 Administered to Bone as the Chloride
• Ho-166 in 0.1M 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 ⁇ L 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 Hvdroxyapatite 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 ⁇ L of the slurry were taken and placed in a separate tube. To this was added 3 ⁇ L of Ho- 166 in 0.1 M HCl.
• 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 ⁇ L of Ho- 166 labeled hydroxyapatite solution into the hole created by the drill.
• Sm-153 in 0.1 M HCl was obtained from MURR.
• the complex formed between Sm-153 and DOTMP was prepared by combining 5 ⁇ L 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 ⁇ L of DOTMP solution was added to obtain high complex yields. The amount of Sm 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 ih Example 6 was used to deliver 2 ⁇ L 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.
• 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).
• Example 2 When direct injections of isotopes are made directly into the bone, a significantly higher percentage of radioactivity can be delivered to bone compared to LV.
• 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.
• 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.

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