Patents & Publications

1) PATENTS: [As an employee of 3M Company until 2001 these were assigned to 3M]

4,509,506 "Shielding Device For Radioactive [I-125] Seed", DC Windorski and D. O. Kubiatowicz, 4/9/85 [Abstract: This invention describes a method of packaging radioactive iodine-125 Seeds carried in absorbable suture within a curved tube of dense material having two open ends. This placement is both convenient for the physician and useful in preventing unwanted release of radiation.]

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4,323,055 "Radioactive Iodine [I-125] Seed" D.O. Kubiatowicz, April 6, 1982 [Abstract: This invention discloses an improvement in the design of radioactive iodine-125 Seeds in which the isotope is carried on an elongated silver rod sealed within a (e.g.) titanium container. Seeds made in this way are easier to assemble. They also have increased radiopacity, potential for improved dosimetry calculation and offer a more reproducible calibration. I-125 Seeds are used largely for treatment of prostate cancer]

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4,208,398 "Technetium [Tc-99m] labeled Complexes, Production and Use Thereof", D.O. Kubiatowicz and T.F. Bolles, June 17, 1980 [Abstract: This invention describes chemical complexes of the radioactive metastable isotope technetium-99m where the complexing agents are selected from certain water-soluble mercaptans (e.g. -SH) These complexes are pharmacologically suited to the performance of kidney structure studies. 3M sold this patent to Hoffman-LaRoche, Inc]

3,758,678 "Biodegradable Radioactive Polysaccharide Particles", T.W. Lindsay and D.O. Kubiatowicz, September 11, 1973 [Abstract: This invention describes the manufacture of substantially spherical particles having a smooth outer surface and consisting essentially of solid, cold-water insoluble parenterally metabolizable radioactive polysaccharide. There particles are useful in diagnosis and therapy, are easier to handle than prior art materials, and are cleared from the body in a more predictable fashion.]

3,707,353 "Radioactive Labeling Kit", D.O. Kubiatowicz, December 26, 1972 [Abstract: This invention describes a glass vial "kit" which facilitates "tagging" biodegradable human serum albumin microspheres with radioactive technitium-99m and the like. The invention advanced the prior art in being more convenient and consisting of a single contained unit. The "kit" was non-radioactive as shipped and was made radioactive in the hospital when needed. Tc-99m labeled microspheres were used for diagnostic lung imaging.]

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Labeling Kit	Minneapolis Tribune article from 9/11/1972 describing the Kit as winning one of the prestigious "IR-100" Awards in Chicago	At IR-100 Awards the evening of 9/21/1972 from left to right: Dave Kubiatowicz, Ivan M. Grotenhuis; Dr. Roger L. Evans and Dr. John P. Ryan

3,663,686 "Biodegradable Radioactive Particles" .M. Grotenhuis and D.O. Kubiatowicz, 5/16/72 [Abstract: Particles, preferably substantially spherical particles having a smooth outer surface and essentially void-free interior are produced, consisting essentially of solid, cold-water insoluble vehicle comprising a physiologically acceptable, parenterally metabolizable radioactive protein, said particles being substantially non-leachable upon short term exposure to cold water. The particles can be administered parenterally for diagnostic, prophylactic or therapeutic purposes. On administration in this way, they are broken down or solubilized by the body fluids over a predeterminable period ranging from minutes to several days, whereupon the radioisotopic material is excreted from the body thus limitining exposure to the radiation.]

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Mouse in a crucible	Human Serum Albumin Microspheres	Stay healthy!

1. "Two-Dimensional Dose Distribution Of I-125 Seeds." C.C. Ling, M.C. Schell, E.D. Yorke, B.B. Palos, D.O. Kubiatowicz, MEDICAL PHYSICS 12, 652(1985)

2. "Measurement of Dose Distribution Around Fletcher-Suit-Delclos Colpostat Using a Therados Radiation Field Analyzer (RFA-3)." C.C. Ling, I.J. Spiro, D.O. Kubiatowicz, J.G. Gergen, R.K. Peksens, J.D. Bennett, and W.F. Gagnon, MEDICAL PHYSICS 11,326 (1984)

3. "Physical Dosimetry of I-125 Seeds of a New Design For Interstitial Implant." C.C. Ling, E.D. Yorke, I.J. Spiro, D.O. Kubiatowicz, D. Bennett, INT. J. RADIATION ONCOLOGY BIOL. PHYS. 9, 1747 (1983)

4. (ABSTRACT) "Dosimetric Comparison of Two I-125 Seed Designs." C. Ling, T. Fewell, D.O. Kubiatowicz, J.A. Roseland, M.C. Etter, in MEDICAL PHYSICS 8, 570 (1981)

5. "Calibration of Cesium-137 Brachytherapy Sources." D.O. Kubiatowicz, in RECENT ADVANCES IN BRACHYTHERAPY PHYSICS, edited by D.R. Shearer (American Institute of Physics, New York, NY, 1981) p 57.

6. "Room Temperature Radioassay for B-12 With Oyster Toadfish (Opsanus tau) Serum as Binder." D.S. Ithakissios, D.O. Kubiatowicz and J.H. Wicks, CLIN. CHEM. 26, 323 (1980)

7. "Localization of Low Molecular Weight 99m-Tc-Labeled Dimercaptodicarboxylic Acids in Kidney Tissue." D.O. Kubiatowicz, T.F. Bolles, J.C. Nora and D.S. Ithakissios, J. PHARM. SCI. 68, 621 (1979)

8. "Semi-automated T-3 Uptake Test That Uses Magnetic Albumin Microparticles." D.O. Kubiatowicz, D.S. Ithakissios, J.H. Wicks, and P.E. Heerwald, J. NUCL. MED.,19,854 (1978)

9. "Immune and Non-Immune T-4 Uptake Test That Uses Magnetic Albumin Microparticles." D.S. Ithakissios, D.O. Kubiatowicz, DC Windorski and J.H. Wicks, CLIN. CHEM. ACTA. 84 (1978)

10. "Use of Protein Containing Magnetic Microparticles in Radioassays." D.S. Ithakissios and D.O. Kubiatowicz, CLIN. CHEM. 23, 2072 (1977)

11. "Binding Proteins From Fish Sera and Intrinsic Factor Compared in Vitamin B-12 Radioassay." D.S. Ithakissios, D.O. Kubiatowicz, DC Windorski and J.H. Wicks, CLIN. CHEM. 23, 2043 (1977)

12. (ABSTRACT) "Additional Observations on the Binding of B-12 to Oyster Toadfish Serum and Development of a Radioassay for B-12. D.O. Kubiatowicz.", D.S. Ithakissios, J.H. Wicks, D.C. Windorski and B. Hapke, presented at the Proceedings of the 3rd Annual Meeting of the Clinical Radioassay Society, P 30 (1977)

13. (ABSTRACT) "Radioassay of Vitamin B-12 Using Fish Serum Binding Proteins." D.S. Ithakissios, D.O. Kubiatowicz, J.H. Wicks, DC Windorski and B. Hapke, in CLIN. CHEM. 23, 1124 (1977)

14. (ABSTRACT) "Preparation of Composite Protein Magnetic Microparticles and Their Utilization in Radioassays." D.O. Kubiatowicz and D.S. Ithakissios, in CLIN. CHEM. 23, 1163 (1977)

15. (ABSTRACT) "Thyroxin Radioassays Utilizing Albumin Magnetic Microparticles." D.S. Ithakissios and D.O. Kubiatowicz, in J. NUCL. MED., 18, 622 (1977)

16. "Vitamin B-12 Radioassay with Oyster Toadfish (Opsanus tau) Serum as Binder." D.O. Kubiatowicz, Dionyssis S. Ithakissios and DC Windorski, CLIN. CHEM., 23, 1037 (1977)

17. (ABSTRACT) "Evaluation of Kidney Imaging Agent 99m-Tc Dimercaptosuccinic Acid and Two Higher Homologs in Mice." D.O. Kubiatowicz, T.F. Bolles, and J.C. Nora, presented at the Central Chapter, Nuclear Medicine Society Meeting; Minneapolis, MN in October 17-19, 1974)

18. "Tc-99m Labeled Albumin (Human) Microspheres (15-30 um): Their Preparation, Properties and Uses." T.F. Bolles, D.O. Kubiatowicz, R.L. Evans, I.M. Grotenhuis and J.C. Nora, SYMPOSIUM ON RADIOPHARMACEUTICALS AND LABELED COMPOUNDS, INTERNATIONAL ATOMIC ENERGY AGENCY, VIENNA, 151(1973)

19. (ABSTRACT) "Technetium-Mercaptide Complexes and Their Potential Application as a Liver Specific Agent." R.A. Jackson, T.F. Bolles, D.O. Kubiatowicz, G.E. Krejcarek, in J. NUCL. MED., 14,411 (1973)

The paragraphs and references below are excerpted from Chapter 30 "Albumin Microspheres: Current Methods of Preparation and Use" by Buck A. Rhodes and Theodore F. Bolles pp 282-291 in the book Radiopharmaceuticals, edited by Gopal Subramanian, PhD., Buck A. Rhodes, PhD., James F. Cooper, Pharm. D, Vincent J. Sodd, PhD, Soc Nucl Medicine, Inc., 1975

The idea of using microspheres "two to three times the diameter of capillaries" to study circulation apparently originated with physiologists interested in blood flow through arteriovenous communications (1, 2). The earliest investigators used spores; later investigators used wax or glass beads. The particles were injected intra-arterially, and venous outflow was collected and sieved so that the shunted particles could be retrieved and counted. To eliminate the problem of having to filter the spheres from the blood and count them one by one, Emmenegger, et al (3) produced the First radiolabeled microspheres. They placed wax microspheres in a nuclear reactor to produce radiosodium from the natural traces of sodium in wax. To eliminate the problems caused by using particles with specific gravities grossly different from blood, Doby (4) developed agar microspheres. In addition to these developments, two other lines of research were also in the background that ultimately led to the idea of albumin microspheres.

The first was the development of inert radiolabeled particles for blood flow studies. Ceramic radiolabeled microspheres were developed by Lahr and Ryan (5). The first lung scans were performed by Haynie (6) and Ariel (7) using these microspheres. Later, radiolabeled carbonized resin microspheres (8) were developed that more closely matched the density of the blood.

However, since these microspheres were not biodegradable, investigators began a second approach, searching for a biodegradable particle. This led to the development of 131-I-macroaggregated albumin (9) and its introduction as a lung-scanning radiopharmaceutical (10).

The concept of how to make albumin microspheres originated in experiments by Evans (11) and Grotenhuis and Kubiatowicz (12). who demonstrated that protein solutions dispersed in oil and then heated produced solid, spheroidized protein panicles. At the suggestion of Wagner this principle was applied to human serum albumin to produce microspheres that could be used in clinical studies in man (13). While the 3M Company developed albumin microspheres as a commercial radiopharmaceutical (14). investigators at the Johns Hopkins Medical Institutions (15, 16). Baylor College of Medicine (17, 18). and other institutions established the clinical usefulness of the microspheres as a lung-scanning agent and as a tracer that could be used to study circulatory problems previously limited to animals or specimens of human organs (19, 20).

The concept of how to label the preformed albumin microspheres with short-lived tracers just before their use originated in experiments at 3M (11) and Johns Hopkins (21) which demonstrated that inorganic precipitates occluded within the matrix of the spheroidized protein would exchange radioactive ions in solution. Iron hydroxide was first used as the occluded precipitate (11, 22). Subsequently. Stern suggested the use of the thiosulfate method for 99mTc labeling, and that procedure was later adapted (12) to non-iron-containing microspheres (23). This method proved to be clinically useful (24) and was used through 1974 in the commercial kits developed by Kubiatowicz (12, 14). Later, methods were developed for labeling iron-free microspheres with 113mIn (25) and 203Pb (26). Returning to the principle of adding inorganic salts to the microspheres, Berger and Johannsen (27) demonstrated that microspheres could be rapidly labeled with 99mTc following pretreatment of the particles with stannous chloride.

1. Prinzmetal M. Simkin B. Bergman HL. et al: Studies of the coronary circulation. Am Heart J 33: 420-422, 1947

2 Doby T Arteriovenous shunt measurements. Letter " to the editor. J Nucl Med 14: 247, 1973

3. Emmenegger N. Wurlimann A, and Bucher K; A simple method of producing radioactive spheres for f the investigation of circulatory problems. Helv Physiol Pharmacol Acta 9: 254-258. 1951

4. Doby T: Method for the quantitative estimation of anteriovenous anastomoses in organs. Acta Med Acad Set Hung 3: 201-205, 1952

5. Lahr TN and Ryan JP: Medical uses of ceramic microspheres. Presented at the Central Chapter Meeting of the Nuclear Medical Society. Rochester. Minnesota, Oct 29. 1961

6. Haynie TP. Calhoon JH, Nasjleti CE. et al: Visualization of pulmonary infarcts and tumors by photo- scanning, J Lab Clin Med 60: 881-882, 1962

7. Ariel 1: Quoted in "Highlights" of the Society of Nuclear Medicine Meeting. JAMA 183:32-33, 1963

8. Grotenhuis IM: Properties and uses of radiating microspheres. In Radioactive Pharmaceuticals, Andrews GA. Kniseley, RM, Wagner HN, eds. Chapter II. AEC Symposium Series 6. CONF-651111. Springfield. Va. National Bureau of Standards. 1966. pp 205-209

9. Taplin GV. Dore EK. Johnson DE. et al: Colloidal radio-albumin aggregates for organ scanning. Exhibit at 10th Annual Meeting of the Nuclear Medicine Society, Montreal, Canada, 1963

10. Wagner HN Jr: Discussion. In Dynamic Clinical Studies with Radioisotopes, Kniseley RM, Tauxe WN. Andersen EP. eds. USAEC Report TID- 7678, 1964, p 225

12. Kubiatowicz DO. Grotenhuis IM: U.S. Patents 3,707,353 and 3,663,686. issued 1972

13. Rhodes BA. Zolle ". Wagner HN Jr: Properties and uses of radioactive albumin microspheres. Clin Res 16: 245, 1968

14. Bolles TF. Kubiatowicz, DO. Evans RL, et al: 99mTc-labeled albumin (human) microspheres (15 30 um): their preparation, properties and uses. International Symposium on Radiopharmaceuticals, Copenhagen. Denmark 1973. IAEA-SM-171/37. pp 151-165

15. Rhodes BA, Zolle I, Buchanan JW, et al: Radioactive microspheres for studies of the circulation. Radiology 92: 1453-1460, 1969

16. Zolle 1. Rhodes BA, Wagner HN Jr: Preparation of metabolizable radioactive human serum albumin microspheres for studies of the circulation. Int J Appl Radiat Isot 21: 155- 167. 1970

17. Burdine JA, Sonnemaker RE. Ryder, LA. el al: Perfusion studies with technettum-99m human albumin microspheres (HAM). Radiology 95: 101-107, 1970

18. Burdine JA. Ryder LA. Sonnemaker RE. et al: 99mTc-human albumin microspheres (HAM) for lung imaging. J Nuc Med 12: 127-130,1971

19. Wagner HN Jr. Rhodes BA: Radioactive tracers in the diagnosis of cardiovascular disease. Prog Cardiovasc Dis 15: 1-24. 1972

21. Zolle I: Radioactive albumin microspheres. Masters of Science thesis. The Johns Hopkins University. 1970

22. Buchanan JW. Rhodes BA. Wagner HN Jr: Labeling albumin microspheres with indium-113m. J Nucl Med 10: 487-490. 1969

24. Rhodes BA. Stern HS. Buchanan JW. el al: Lung scanning with 99mTc-microspheres. Radiology 99: 613-621, 1971

25. Buchanan JW, Rhodes BA, Wagner HN Jr: Labeling iron-free albumin microspheres with indium-l 13m. J Nucl Med 12: 616-619, 1971

26. Rhodes BA: Radiopharmaceuticals for nuclear cardiology. In Cardiovascular Nuclear Medicine. Strauss HW, James AE Jr, Pitt B, eds, St. Louis. C V Mosby, 1974, pp36-51

27. Berger R. Johannsen B: Technelium-99m labeling of spherical human serum albumin particles. Isotopenpraxis 7: 188-189, 1971

28. Pasqualini R, Plassio G. and Sosi S: The preparation of albumin microspheres. J Nucl Biol Med 13: 80-84, 1969

29. Mayron LW, Lopez-Majano V, Kaplan E: Sieving of albumin microspheres with sonification. J Nucl Med 14: 511-513. 1973

30. Zolle I, Hosain F, Rhodes BA. et al: Human serum albumin millimicrospheres for studies of the reticuloendothelial system. J Nucl Med 11: 379. 1970

31. Scheffel U. Rhodes BA. Natarajan TK. et al: Albumin microspheres for study of the reticuloendothelial system. J Nucl Med 13: 498-503. 1972

1965: Use of iodine-125 Seeds originated at memorial Sloan-Kettering Cancer Center where the first implant took place in 1965. Memorial recognized the need for a low-energy brachytherapy source, the use of which would result in reduced radiation exposure to medical personnel, patients and their families. (1,2)

I-125 Seeds were conceived by Don Lawrence, a health Physicist in California. He wrote and received a U.S. Patent #3,351,049 entitled "Therapeutic Metal Seed Containing Within a Radioactive Isotope Disposed on a Carrier and Method of Manufacture." The patent was filed April 12, 1965 and issued November 7, 1967.

1968: Don Lawrence organized Lawrence Soft-Ray Corporation (LSR). Model 6701 I-125 Seeds became commercially available. Model 6701 Seeds consisted of I-125 absorbed on two resin spheres separated by one gold sphere X-ray marker and were encased in a welded titanium can. Seed strength was less than 1 mCi I-125. Model 6702 Seeds were made available some time after 1968 and were of similar construction to the Model 6701 Seeds but without the gold sphere. Deletion of the gold sphere was necessary to achieve the higher I-125 activity. Seed strengths ranged from 1 to about 40 mCi I-125. Model 6701 Seeds enjoyed the majority of sales.

1975-76: Lawrence Soft-Ray manufactured and sold I-125 Seeds in absorbable suture. This material was useful for shallow plane implants (3,4,5,6) 3M reintroduced the product in 1982 as Model 6720 I-125 Seeds in Carrier.

1978: 3M Company acquired Lawrence Soft-Ray on May 8, 1978. And began marketing I-125 Seeds.

1979: 3M moved I-125 Seed production from Sunnyvale, CA to New Brighton, MN in May 1979

1983: 3M replaced Model 6701 Seeds with Model 6711 I-125 Seeds having improved X-ray visibility (silver rod instead of gold sphere). Seed strengths ranged from .07 mCi to 1 mCi. These Seeds were protected under patent 4,323,055 issued April 6, 1982 [D.O. Kubiatowicz]. Also in 1983, 3M began assaying all production I-125 Seeds against I-125 Seeds calibrated by the National Bureau of Standard (currently the NIST).

1983-91: The upper limit of Model 6711 Seed strength was increased to 5 mCi so the Seeds could be loaded into nylon tubes and used as an Ir-192 replacement for temporary implants in brain, breast and eye tumors. Also during these years, techniques for the transperineal implant of low activity Model 6711 Seeds into prostates were being developed.

1991: 3M sold (divested) the I-125 Seed business to Medi-Physics (An Amersham subsidiary) in April 1991.

1. Hilaris, B.S., Holt, G.J, St. Germain, Jl, "The use of Iodine-125 for Interstitial Implants," U.S. Department of Health, Education and Welfare Publications (FDA), 76-8022 (1975)

2. Kim, J.H., Hilaris, B.S. "Iodine-125 Source in Interstitial Tumor Therapy. Clinical and Biologic Consideration," American journal of Roentgenolgy, Radium Therapy and Nuclear Medicine, 123, No. 1: 163-169 (1975)

3.Harter, D.J., Delclos, L., and Johns, M.F., "Sealed Sources in Synthetic Absorbable Suture," Radiology, 116: 721-723 (1975)

4. Scott, W.P., "Interstitial Therapy Using Non-Absorbable (Ir-192 Nylon Ribbon) and Absorbable (I-125 Vicryl) Suturing Techniques," American journal of Radiology, 124: 560-564 (1975)

5. Goode, R.L., Fee, W., Goffinet, D.R. and Martinez, A., "Radioactive Suture in the Treatment of Head and Neck Cancer," Laryngoscope, 89: 349-354 (1979)

6. Palos, B.B., Pooler, D., Goffinet, D.R., and Martinez, A., "A Method for Inserting I-125 Seeds into Absorbable Sutures for Permanent Implantation in Tissue," Int. J. Radiation Oncology Biol. Phys., 6: 381-385 (1980)