WO2000053234A1 - Lipid soluble radioactive metal chelates for tumor therapy - Google Patents
Lipid soluble radioactive metal chelates for tumor therapy Download PDFInfo
- Publication number
- WO2000053234A1 WO2000053234A1 PCT/US2000/006207 US0006207W WO0053234A1 WO 2000053234 A1 WO2000053234 A1 WO 2000053234A1 US 0006207 W US0006207 W US 0006207W WO 0053234 A1 WO0053234 A1 WO 0053234A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- indium
- radioactive metal
- lipid soluble
- metal chelate
- tumor
- Prior art date
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Classifications
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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
-
- 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 generally relates to the field of oncology and a method of injecting radionuclides for tumor therapy, and more particularly to the use of a class of lipid soluble radioactive metal chelate compounds for treatment of malignant, benign, or inoperable tumors.
- Intratumoral injection of certain radionuclides for therapy is drawing increasing attention.
- Investigators have begun to use intratumoral therapy, especially where tumors are inoperable or where incision of tumors is associated with high risks to the patient.
- Radionuclide therapy is particularly useful for treating a variety of tumors, including inoperable tumors; prostate tumors, for example, which are confined but are associated with high risk following surgical intervention; and brain tumors such as glioma.
- radioactive metal chelates in general, and Indium-I l l lipid soluble complexes, in particular, is based upon work with such agents in the diagnostic imaging field, especially for labelling cellular blood elements.
- two of the lipid soluble chelates of IndiumJ l l have been prepared previously. These compunds are Indium-l l l-oxine (8-hydroxyquinoline; see ML Thakur, RE Coleman, and MJ Welch.
- Indium-l l l-oxine has a higher thermodynamic stability and is smaller in size than Indium-l l l-oxine. These differences result in the more efficient labeling of cells under physiologic conditions by Indium-l l l-Merc. Whereas Indium-l l l-Merc can label cells in the presence of plasma, Indium-l l l-oxine cannot efficiently label cells unless such cells are suspended in balanced salt solutions, such as isotonic saline.
- Indium-I l l also decays by the emission of two ⁇ -rays of 173 Kev (89%) and 247 Kev (94%). These two ⁇ -rays are useful for scintigraphic imaging.
- the present invention takes advantage of the lipid soluble nature of Indium- 111 complexes, along with the radioactive properties of these complexes, and utilizes the radioactive metal chelate as a means of treating tumors.
- the present invention is distinct from receptor-specific agents, such as radiolabeled antibodies or radiolabeled peptides and is distinct from metabolic agents, such as radiodeoxyuridine.
- IndiumJ l l is one example of an appropriate radioactive metal chelate for tumor therapy
- other lipid soluble radioactive chelate could be used, so long as such compounds bind tightly to cell cytoplasmic components.
- Such alternative lipid soluble compounds include Indium-l l l-tropolone (2-hydroxy-2,4,6- cylcoheptatrienone), Rhenium- 186 or Rhenium- 188 chelated with sesta-MIBI (methoxy isobutyl isonitrile), HMPAO, or tetrofosnine. (Holman BL, Jones AG, Lister-James J. et al.
- radioactive metal chelates could be directed against a variety of other tumors, including hepatoma, melanoma, breast cancer, pancreatic cancer, lung cancer, sarcomas, and carcinoids.
- Known metastatic tumors can also be treated similarly.
- the success of the agent used depends upon its homogeneous distribution into the tumor mass. Such a homogeneous distribution is dependent upon the skill and judgment of a physician injecting the agent. As is customary with many therapeutic agents, repeated injections of the agent may be necessary, depending upon the individual patient and the size, location, and type of tumor targeted for therapy.
- lmCi of Indium-I l l injected into a 1 cc tumor 1.3 X 10 13 atom and 10 9 cells
- the emission of gamma rays by such radioactive metal chelates may lead to delivery of some radiation to normal organs and tissue within vicinity of the targeted tumor.
- Such expected radiation dose the normal organs and tissue will have to be determined prior to administration of the therapeutic dose.
- To arrest tumor cell proliferation means to inhibit cell proliferation, to slow the rate of cell proliferation, to arrest cell proliferation, or to kill tumor cells.
- the present invention is a method of injecting a class of lipid soluble radioactive metal chelate compounds for intratumoral treatment of malignant, benign, metastatic, or inoperable tumors.
- the present invention also involves a multisquirter device used to inject the lipid soluble radioactive metal chelate compounds for intratumoral treatment, where the device is designed such that a compound injected with said needle is distributed radially in a uniform volume.
- FIG. 1 A polaroid picture of two mice bearing human colorectal cancer (LS174T). The mouse on the right received Indium-l l l-oxine (648 ⁇ Ci) 22 days previously, and the mouse on the left (control) received only placebo. Excessive tumor growth in the control animal is visible.
- Figure 3 A schematic drawing of a needle that will permit more homogeneous distribution of radioactivity in the tumor than using a conventional, single, open-ended needle.
- the end of the needle in question is sharp for penetration but is blocked.
- the part of the needle has microholes on its surface that will cause a "spray" of the radiaoctive agent, thereby resulting in more homogeneous distribution of the radioactive solution.
- mice Four athymic nude mice weighing between 15-18 g were injected intramuscularly in the right flank with approximately 5xl0 6 viable human colorectal carcinoma cells LS174T, human prostate tumor DU145 (male mice), or human breast tumor T74D (female mice). Tumors were allowed to grow to approximately 0.5 cm in diameter.
- Indium- 111 -oxine is available commercially (Amersham Int. , Arlington Heights, IL). For this procedure, however, Indium-l l l-oxine was prepared by using a procedure published previously (Thakur ML et al, J Lab Clin Med 89: 217-228, 1977). Indium-I l l in chloride form was obtained from MDS Nordion, Vancouver, Canada. Briefly, to the 10 ⁇ l Indium-111-Ch Solution (1 mCi, 0.05 N HC1), 1 ml of 0.3 M acetate buffer pH-5.4 was added, followed by 50-100 ⁇ g 8-hydroxyquinoline in 50 ⁇ l ethanol.
- reaction mixture was then extracted twice with 1 ml chloroform or methylene chloride.
- the organic layer was separated each time and combined. Greater than 95 % of the activity was extracted.
- Organic solvent was evaporated, and the residue was taken up in 100 ⁇ l ethanol. which was then diluted to 400 ⁇ l with 0.9% NaCl.
- the agent was prepared as follows. To one mCi Indium-I l l -chloride solution in 10 ⁇ l (0.05 M HC1), 150 ⁇ l of 0.05 M phosphate buffer (pH-7.4) was added followed by 50 ⁇ g of Merc in 50 ⁇ l phosphate buffer pH-7.4. This reaction mixture was not extracted in CHCh and used as such. Alternatively the resultant complex could also be extracted in chloroform or methylene chloride and be subsequently treated as in the preparation of Indium- 11 1-oxine.
- Injecting agents On day one, two of the four tumor-bearmg mice received a single intratumoral injection of approximately 100 ⁇ l Indium-l l l-oxme Mice were placed in an lonization chamber, and radioactivity was recorded after the injection and then daily for 28 days On each day, radioactivity was corrected for decay, and the percent of injected dose retained in the animal was calculated and recorded. Animals were also weighed daily in a calibrated balance.
- mice On day one, all four mice were lightly anesthetized and photographs taken. Mice receiving Indium-l l l-oxine were also imaged with a gamma camera 28 days later. This qualitatively recorded the distribution of radioactivity, 28 days after it was injected.
- the control animals received a single intratumoral injection of 100 ⁇ l of 25% ethanol m 0.9% NaCl Two radioactive animals and the control animals were then cared for m two separated cages and allowed to eat and drink at liberty.
- mice treated with Indium-l l l-oxine received 100 ⁇ l of Indium-l l l-Merc each in two places in tumors
- the control animals also received two intratumoral injection of 0.05 M phosphate buffer pH-7.4.
- mice were weighed daily and radioactivity remaining in their bodies was measured for an additional 10 days
- Fig. 1 is a photograph of two mice, one receiving Indium-l l l-oxine (right) and
- the tumor in the control mouse at right has grown substantially larger (3.2 cm), but the one m the treated animal has not grown Results were similar in the remaining two mice.
- Fig. 2 shows gamma camera image (left) taken on day 22 after Indium-l l l-oxine injection
- Gamma camera images show that nearly all of the radioactivity was retained in the tumor.
- Ten days after the injection of Indium-l l l-Merc all of the radioactivity was also retained in each animal body (right). Both mice treated with Indium-I l l agents had neither gained nor lost body weight. The control animals gained 20.4% and 20.5 % body weight.
- Fig. 3 shows a needle designed for intratumoral injection, which will permit more homogeneous distribution of radioactivity in the tumor than by using a conventional needle.
- mice Human prostate and human breast tumors were grown in two separate groups of nude mice. Six mice in each group were divided in two subgroups of 3 mice each. Three mice were treated with intratumoral injections of either Indium-l l l-oxine or Indium-l l l-Merc. Each group of mice was then placed in rodent cages separately and cared for with regular diet and water ad lib. Each day the animals were weighed, and tumor diameter was measured three times with a Vernier caliper.
- Radioactivity received by each animal was carefully measured, and each day the amount of radioactivity retained in the animal body was measured using an energy calibrated radiation dose calibrator.
- a second dose of the same agent was readministered, also intratumorally and the procedure was followed as described above, for the next two weeks.
- the animals were sacrificed, and organs such as the liver, spleen, lungs, kidneys, and bladder were harvested together with the tumor. These organs were then weighed. Indium-I l l associated with each tissue was counted, and the radioactivity distributed in each organ was calculated as the percent of the total radioactivity retrained in each animal.
- Indium- I l l was obtained as a radiochemical in chloride form from MDS Nordion in Canada and converted into Indium-l l l-oxine using the procedure described previously. (Thakur et al, J Lab Clin Med 89: 217-228, 1977). It should be noted that while studies with Indium-l l l-oxine have been done previously to assess cytotoxicity, these preparations of Indium-l l l-oxine were diluted in 0.9% NaCl excessively, stored and used.
- the organic solvent containing greater than 95 % of the radioactivity was then separated, and the solvent was evaporated with a gentle stream of nitrogen. After a complete evaporation, 50 ⁇ l of ethanol was added followed by 150 ⁇ l of 0.9 % NaCl. Fifty ⁇ l doses were then withdrawn, measured for radioactivity, and administered intratumorally in one or more places. Control animals received a similar volume of 25 % ethanol in 0.9% saline in the tumors. Radioactivity received by each animal was then determined by placing the animal in the radioactivity dose calibrator and then measured daily.
- Indium-l l l-Merc was prepared also by a method described previously.
- Human prostate cancer cells DU145 (5x 10 6 ) were implanted in the thigh of nude mice and allowed to grow to less than 0.5 cm in size. These were treated with Indium-l l l-oxine.
- human breast cancer cells (5 x 10 6 ) T47D were implanted similarly. These were also allowed to grow to up to 0.5 cm in diameter.
- the average radiation dose with Indium-l l l-oxine received by each animal was estimated to be approximately 131 Gy.
- the average tumor growth during the treatment period in the treated mice was 117% as compared to 200% in the untreated mice (Fig. 4). On the average, none of the treated or untreated mice either gained or lost body weight. At sacrifice, the tumor retained 86.5% of the injected activity corrected for decay.
- the kidney uptake was 7.5 % , and the liver 5.4% .
- the average radiation dose received by animals with Indium-l l l-Merc was estimated to be approximately 127 Gy.
- the average tumor growth in the treated mice was 172% , as compared to 477% in the untreated control animals (Fig. 5). All animals gained some body weight.
- the Merc treated tumors had retained 92.97% of the injected activity.
- the kidney had 4.03 % and the liver 1.02% .
- Indium- 111 is a cyclotron produced radionuclide that decays by electron capture with a physical half-life of 2.83 d. This decay processes, and the atomic and nuclear transitions that ensue to reach the ground state of u l Cd, result in the emission of two gamma rays (171 keV - 90% and 245 keV - 94%), x-rays, 3-27 keV), conversion electrons (145-171 keV - 9.7% and 219-245 keV - 6.0%), and several Auger electrons (0.5 to 25 keV). Using the techniques and computer code described by Howell et al. (Howell RW,
- the mean absorbed dose to the tumor is 10-20 times higher than the dose to adjacent healthy tissues or the absorbed dose to the adjacent healthy organs is only 5% - 10% of the dose to the tumor.
- This radiation dosimetry compares highly favorably to the brachytherapy in which radiation dose to the bladder and rectal wall are 100% to that of the prostate tumor and to that of the external beam therapy in which, on the average, 25 % of the bladder wall and 35 % of the rectal wall receive 100% of the dose to the tumor (Waterman FM, Yue N, Corn BW, Dicker AP. Edema associated with 1-125 or Pd-103 prostate brachytherapy and its impact on post- implant dosimetry: An analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 43:447-54, 1999).
- a multi-squirter (multiple outlet) needle can spray the activity in the entire tumor and can produce even better results.
Abstract
Description
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002366593A CA2366593A1 (en) | 1999-03-09 | 2000-03-09 | Lipid soluble radioactive metal chelates for tumor therapy |
JP2000603723A JP2002538225A (en) | 1999-03-09 | 2000-03-09 | Lipid-soluble radiometal chelates for tumor treatment |
EP00921373A EP1165146A4 (en) | 1999-03-09 | 2000-03-09 | Lipid soluble radioactive metal chelates for tumor therapy |
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---|---|---|---|
US12348399P | 1999-03-09 | 1999-03-09 | |
US60/123,483 | 1999-03-09 |
Publications (1)
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WO2000053234A1 true WO2000053234A1 (en) | 2000-09-14 |
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ID=22408928
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Application Number | Title | Priority Date | Filing Date |
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PCT/US2000/006207 WO2000053234A1 (en) | 1999-03-09 | 2000-03-09 | Lipid soluble radioactive metal chelates for tumor therapy |
Country Status (4)
Country | Link |
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EP (1) | EP1165146A4 (en) |
JP (1) | JP2002538225A (en) |
CA (1) | CA2366593A1 (en) |
WO (1) | WO2000053234A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000059550A2 (en) * | 1999-04-02 | 2000-10-12 | Ut-Battelle Llc | Indium-114m and related compositions applicable in brachytherapie |
WO2019243419A1 (en) * | 2018-06-19 | 2019-12-26 | Danmarks Tekniske Universitet | Brachygel for treatment of cancer and/or for guidance of surgery |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4017596A (en) * | 1975-03-03 | 1977-04-12 | Research Corporation | Radiopharmaceutical chelates and method of external imaging |
US5130118A (en) * | 1987-11-06 | 1992-07-14 | Abbott Laboratories | Methods and materials for the preparation of metal labelled antibody solutions |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0225409A1 (en) * | 1985-12-02 | 1987-06-16 | The Dow Chemical Company | Organic amine phosphonic acid complexes for the treatment of calcific tumors |
US4925925A (en) * | 1988-06-15 | 1990-05-15 | University Of Cincinnati | Radioactive rhenium ligated to 2-hydroxy isobutyric acid and method of use |
US5192526A (en) * | 1989-05-02 | 1993-03-09 | Mallinckrodt Medical, Inc. | Kit for preparation of rhenium therapeutic agents for bone cancer without purification |
US5460785A (en) * | 1989-08-09 | 1995-10-24 | Rhomed Incorporated | Direct labeling of antibodies and other protein with metal ions |
US5840859A (en) * | 1995-07-06 | 1998-11-24 | Research Corporation Technologies, Inc. | (Aminostyryl)pyridinium compounds for radiolabelling cell membranes |
DE19632052C2 (en) * | 1996-08-08 | 2003-05-28 | Michael Eisenhut | Benzamide derivatives and their use for the diagnosis and treatment of tumors, in particular melanomas |
-
2000
- 2000-03-09 JP JP2000603723A patent/JP2002538225A/en active Pending
- 2000-03-09 CA CA002366593A patent/CA2366593A1/en not_active Abandoned
- 2000-03-09 EP EP00921373A patent/EP1165146A4/en not_active Withdrawn
- 2000-03-09 WO PCT/US2000/006207 patent/WO2000053234A1/en active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4017596A (en) * | 1975-03-03 | 1977-04-12 | Research Corporation | Radiopharmaceutical chelates and method of external imaging |
US5130118A (en) * | 1987-11-06 | 1992-07-14 | Abbott Laboratories | Methods and materials for the preparation of metal labelled antibody solutions |
Non-Patent Citations (2)
Title |
---|
HONG, S. S. ET. AL.: "Radiation toxicity of indium-111- 2-mercaptopyridine-N-oxide and HeLa S-3 cells.", THE BRITISH JOURNAL OF RADIOLOGY, vol. 62, May 1989 (1989-05-01), pages 468 - 472, XP002928275 * |
See also references of EP1165146A4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000059550A2 (en) * | 1999-04-02 | 2000-10-12 | Ut-Battelle Llc | Indium-114m and related compositions applicable in brachytherapie |
WO2000059550A3 (en) * | 1999-04-02 | 2001-04-05 | Ut Battelle Llc | Indium-114m and related compositions applicable in brachytherapie |
WO2019243419A1 (en) * | 2018-06-19 | 2019-12-26 | Danmarks Tekniske Universitet | Brachygel for treatment of cancer and/or for guidance of surgery |
Also Published As
Publication number | Publication date |
---|---|
CA2366593A1 (en) | 2000-09-14 |
EP1165146A1 (en) | 2002-01-02 |
JP2002538225A (en) | 2002-11-12 |
EP1165146A4 (en) | 2003-09-17 |
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