Breast Cancer Research and Treatment

, Volume 32, Issue 1, pp 119–135 | Cite as

New magnetic resonance imaging techniques for the detection of breast cancer

  • Kourosh Orang-Khadivi
  • Brian L. Pierce
  • Callise M. Ollom
  • L. Jean Floyd
  • Robert L. Siegle
  • Robert F. Williams


The importance of contrast agents in enhancing diagnoses from magnetic resonance images has been established in numerous cases. However, the development of a potent tissue-specific contrast agent, as a sensitive probe for early detection and investigation of the physiological characteristics of a tumor, has not yet been realized in MR imaging (MRI). In nuclear scintigraphy the technique has been demonstrated; however, the poor spacial resolution inherent to the modality and the substantial dose of radioactivity administered to the patient has hindered its widespread use. This article will review the different classes of contrast agents in MRI, with special focus on the strategies involved in the development of targeted tissue-specific MRI contrast agents for the early detection of breast cancer. The features of a new class of contrast agents for targeted MR imaging will be described. Gadolinium-containing melanin polymers (GMP's) have been synthesized as MR contrast agents in our laboratory. These GMP's demonstrate significantly higher relaxivities than any other paramagnetic contrast agents reported; consequently, they are extremely effective contrast enhancing, imaging agents by themselves. The successful coupling of these potent GMP's to a monoclonal antibody specific for breast carcinoma, the 323/A3 monoclonal antibody, suggests thatin vivo tissue-specific MR imaging, at the receptor level, will become feasible in the near future.

Key words

magnetic resonance imaging (MRI) magnetic resonance mammography (MRM) site-specific MR contrast agents breast cancer targeted MR imaging gadolinium-melanin polymer (GMP) contrast agents MR magnetopharmaceutical agents 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    The Ontario Cancer Treatment and Research Foundation: Cancer in Ontario 1987. Toronto, Canada, 1987Google Scholar
  2. 2.
    Kelsey JL, Gammon MD: The epidemiology of breast cancer. Cancer J Clin 41:146–165, 1991Google Scholar
  3. 3.
    Boring CC, Squires TS, Tong T: Cancer statistics 1992. Cancer J Clin 42:19–38, 1992Google Scholar
  4. 4.
    Doll R, Petro R: The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66:1192–1308, 1981Google Scholar
  5. 5.
    Softlas AF, Syklo M: Mammographic parenchymal patterns and breast cancer risk. Epidemiol Rev 9:146–174, 1979Google Scholar
  6. 6.
    Goodwin PJ, Boyd NF: Mammographic parenchymal pattern and breast cancer risk: a critical appraisal of the evidence. Am J Epidemiol 127:1097–1108, 1988Google Scholar
  7. 7.
    Warner E, Boyd NF: A meta-analysis of the evidence that the parenchymal pattern of the breast is a risk factor for breast cancer. Cancer Detect Prev 16:67–72, 1992Google Scholar
  8. 8.
    Winchester DP, Bernstein JR, Paige ML, Christ ML: The Early Detection and Diagnosis of Breast Cancer. Am Cancer Soc, Atlanta, 1988Google Scholar
  9. 9.
    Baker LH: Breast cancer detection demonstration project: five-year summary report. Cancer 32:194–225, 1982Google Scholar
  10. 10.
    Schwartz GF, Patchesfsky AS, Fieg SA, Shaber GS, Schwartz AB: Multicentricity of nonpalpable breast cancer. Cancer 45:2913–2916, 1980Google Scholar
  11. 11.
    Rosen PP, Braun DW, Kinne DE: The clinical significance of pre-invasive breast carcinoma. Cancer 46:919–925, 1980Google Scholar
  12. 12.
    Kirsh JE: Basic principles of magnetic resonance contrast agents. Mag Reson Imaging 3:1–18, 1991Google Scholar
  13. 13.
    Gore JC, Kennan RP, Zhong J: MRI contrast agents: Principles and constraints.In: Sprawls P, Bronskill MJ (eds) The Physics of MRI: Proceedings of AAPM Summer School 1992. American Association of Physicists in Medicine, AIP, New York, 1993, pp 299–319Google Scholar
  14. 14.
    Schwaighofer BW, Klein MV, Wesbey G, Hesselink JR: Clinical experience with routine Gd-DTPA administration for MR imaging of the brain. J Comput Assis Tomog 14:11–17, 1990Google Scholar
  15. 15.
    Damadian R: Tumor detection by nuclear magnetic resonance. Science 171:1151–1153, 1971Google Scholar
  16. 16.
    Damadian R, Zamer K, Hor D, DiMaio T: Human tumors by NMR. Physical Chem Phys 5:381–402, 1973Google Scholar
  17. 17.
    Damadian R, Zamer K, Hor D, DiMaio T: Human tumors detected by nuclear magnetic resonance. Proc Natl Acad Sci 71:1471–1473, 1974Google Scholar
  18. 18.
    Wesbey GE: Magnetopharmaceuticals.In: Wehrli FW, Shaw D, Kneeland JB (eds) Biomedical Magnetic Resonance Imaging: Principles, Methodology, and Applications. VCH Publishers, New York, 1988, pp 157–188Google Scholar
  19. 19.
    Poon CS, Bronskil MJ, Henkelman RM, Boyd NF: Quantitative magnetic resonance imaging parameters and their relationship to mammographic pattern. J Natl Cancer Inst 84:777–781, 1992Google Scholar
  20. 20.
    Heywang-Koebrunner SH, Murphy WA, Gohagan JK: Breasts. In: Stark DD, Bradley WG (eds) Magnetic Resonance Imaging, 2nd ed. Mosby, 1992, pp 1401–1428Google Scholar
  21. 21.
    Kaiser WA: MRM promises earlier breast cancer diagnosis. Diagnostic Imaging 8:88–93, September, 1992Google Scholar
  22. 22.
    Harms SE, Flamig DP, Hesley KL, Evans WP, Cheek JH, Peters GW, Knox SM, Savino DA, Netto GJ, Wells RB, Jones SE: Fat-suppressed three-dimensional MR imaging of the breast. Radiographics 131:247–267, 1993Google Scholar
  23. 23.
    Folkman J: Tumor angiogenesis. Adv Cancer Res 43:175–199, 1985Google Scholar
  24. 24.
    Presta M, Rifkin DB: New aspects of blood vessel growth: tumor and tissue-derived angiogenesis factors. Haemostasis 18:6–17, 1988Google Scholar
  25. 25.
    Lauffer RB, Brady TJ: Preparation and water relaxation properties of proteins labeled with paramagnetic metal chelates. Mag Reson Imaging 3:11–16, 1985Google Scholar
  26. 26.
    Unger EC, Totty WG, Neufeld DM, Otsuka FL, Murphy WA, Welch MS, Connet JM, Philpott GW: Magnetic resonance imaging using gadolinium labeled monoclonal antibody. Invest Radiol 20:693–700, 1985Google Scholar
  27. 27.
    Shreve P, Aisen AM: Monoclonal antibodies labeled with polymeric paramagnetic ion chelates. Mag Reson Med 3:336–340,1986Google Scholar
  28. 28.
    Lauffer RB, Brady TJ, Brown RD III, Baglin C, Koenig SH: 1/T1 NMRD profiles of the solutions of Mn2+ and Gd3+ protein-chelate conjugates. Mag Reson Med 3:541–548, 1986Google Scholar
  29. 29.
    Geralds CFGC, Sherry AD, Brown III RD, Koenig SH: Magnetic field dependence of solvent protein relaxation rates induced by Gd3+ and Mn2+ complexes of various polyazamacrocyclic ligands: implications of NMR imaging. Mag Reson Med 3:242–250, 1986Google Scholar
  30. 30.
    Goldstein EJ, Burnett KR, Hansell JR, Casaia J, Dizon J, Farrar B, Gelblum D, Wolf GL: Gadolinium DTPA (an NMR proton imaging contrast agent): chemical structure, paramagnetic properties and pharmacokinetics. Physiol Chem Phys Med NMR 16:97–104, 1984Google Scholar
  31. 31.
    Prato FS, Wisenberg G, Marshal TP, Uksik P, Zabel P: Comparison of the biodistribution of Gd-153 DTPA and Technetium-99m DTPA in rats. J Nuc Med 29:1683–1687, 1988Google Scholar
  32. 32.
    Dean PB, Niemi P, Kivisarri L, Kormano M: Comparative pharmacokinetics of gadolinium DTPA and gadolinium chloride. Invest Radiol 23 (Suppl 1): S258-S260, 1988Google Scholar
  33. 33.
    Tweedle MF, Eaton SM, Eckelman WC, Gaughan GT, Hagan JJ, Wedeking PW, Yost FJ: Comparative chemical structure and pharmacokinetics of MRI contrast agents. Invest Radiol 23 (Suppl 1): S236-S239, 1988Google Scholar
  34. 34.
    Weinmann HJ, Brasch RC, Press WR, Waesbey GE: Characteristics of gadolinium-DTPA complex: A potential NMR contrast agent. Am J Radiol 142:619–624, 1984Google Scholar
  35. 35.
    Gries H, Micklautz H: Some physicochemical properties of the gadolinium-DTPA complex, a contrast agent for MRI. Physiol Chem Phys Med NMR 16:105–112, 1984Google Scholar
  36. 36.
    Allard MD, Doucet P, Kien B, Bonnemain B, Caille JM: Experimental study of DOTA-gadolinium: Pharmacokinetics and pharmacologic properties. Invest Radiol 23 (Suppl 1): S271-S274, 1988Google Scholar
  37. 37.
    Meyer D, Schaefer M, Bonnemain B: Gd-DOTA, a potential MRI contrast agent: Current status of physiochemical knowledge. Invest Radiol 23 (Suppl 1): S232-S235, 1988Google Scholar
  38. 38.
    Rozenman Y, Zou X, Kantor HL: Magnetic resonance imaging with super-paramagnetic iron oxide particles for the detection of myocardial reperfusion. Mag Reson Imaging 9:933–939, 1991Google Scholar
  39. 39.
    Pouliquen D, Perdrisot R, Ermias A, Akoka S, Jallet P, Le Jeune JJ: Superparamagnetic iron oxide nanoparticles as a liver MRI contrast agent: contribution of microencapsulation to improve biodistribution. Mag Reson Imaging 7:619–627, 1989Google Scholar
  40. 40.
    Renshaw PF, Owen CS, Evans AE, Leigh JS Jr: Immunospecific NMR contrast agents. Mag Reson Imaging 4:351–357, 1986Google Scholar
  41. 41.
    Williams RF: U.S. Patent 5,310,539, Notice of Allowance, 5/10/94Google Scholar
  42. 42.
    Proctor PH, Reynolds ES: A review: Free radicals and disease in man. Physiol Chem Phys Med NMR 16:175–195, 1984Google Scholar
  43. 43.
    Williams RF, Pierce BL, Siegle RL, Floyd LJ, Floyd LA: Gadolinium-melanin, a new contrast agent for magnetic resonance imaging. J Mag Reson, submitted for publication (1994)Google Scholar
  44. 44.
    Erickson JG, Ogan MD, Peng CT, Brasch RC, Tozer TN: Metabolic fate in the dog of the nitroxide moiety in a compound with potential utility as a contrast agent in MRI. Mag Reson Med 5:73–77, 1987Google Scholar
  45. 45.
    Lauffer RB, Vincent AC, Padmanabhan S, Villringer A, Saini S, Elmaleh DR, Brady TJ: Hepatobiliary MR contrast agents: 5-substituted iron-EHPG derivatives. Mag Reson Med 4:582–596, 1987Google Scholar
  46. 46.
    Greif WL, Buxton RB, Lauffer RB, Saini S, Stark DD, Wedeen VJ, Rosen BR, Brady TJ: Pulse sequence optimization for MR imaging using a paramagnetic hepatobiliary contrast agent. Radiol 157:461–466, 1985Google Scholar
  47. 47.
    Paik CH, Murphy PR, Eckelman WC, Volkert WA, Reba RC: Optimization of the DTPA mixed-anhydride reaction with antibodies at low concentration. J Nuc Med 24:932–936, 1983Google Scholar
  48. 48.
    Lauterbur PC, Mendonca-Dias MH, Rudin AM: Augmentation of tissue water proton spin-lattice relaxation rates by thein vivo addition of paramagnetic ions.In: Duton PC (ed) Frontiers of Biological Energetics. Academic Press, New York, 1978, pp 752–759Google Scholar
  49. 49.
    Pitt CG: The design of chelating agents for the treatment of iron overload.In: Pitt CG, Martel AE (eds) Inorganic Chemistry and Biology in Medicine, 1980, pp 279–291Google Scholar
  50. 50.
    Cotzias GC, Borg DC, Bertinchamps AJ: Clinical experiences with manganese.In: Metal-Binding in Medicine. JB Lippincott, Philadelphia, 1960, pp 87–101Google Scholar
  51. 51.
    Maynard LS, Fink S: The influence of chelation on radiomanganese excretion in man and mouse. J Clin Invest 35:831–842, 1956Google Scholar
  52. 52.
    Wisenberg G, Schelbert HR: Radionuclide techniques in the diagnosis of cardiovascular disease. Curr Prob in Cardiol 4(7):1–58, 1979Google Scholar
  53. 53.
    Wolf GL, Baum L: Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dogs and rabbits. Am J Roentgenol 141:193–199, 1983Google Scholar
  54. 54.
    Haley TJ: Toxicity.In: Gschneidner KA, Eyring L (eds) Handbook on the Physics and Chemistry of Rare Earths. Elsevier, New York, 1978, pp 78–109Google Scholar
  55. 55.
    Kaminsky S, Laniado M, Kaminsky S, Laniado M, Felix R: Gadolinium-DTPA as an oral contrast medium for magnetic resonance imaging of the abdomen. Mag Reson Med Biol 1:271–278, 1988Google Scholar
  56. 56.
    Corbett JR, Lewis M, Willerson JT, Nicod PH, Huxley RL, Simon T, Rude RE, Henderson E, Parkey R, Rellas JS: Comparison of planar images with single photon tomography with blood pool overlay. Circulation 69:1120- 1128, 1984Google Scholar
  57. 57.
    Maurer AH, King LC, Siegel JA, Elfenbein IB, Adler LP: Paramagnetic pyrophosphate: Preliminary studies in MR contrast enhancement of acute myocardial infarction. Invest Radiol 25:153–163, 1990Google Scholar
  58. 58.
    Thrall JH: Adverse reactions to contrast media: etiology, incidence, treatment and prevention.In: Swanson DP, Chilton HM, Thrall JH (eds) Pharmaceuticals in Medical Imaging. Macmillan, New York, 1990, pp 88–101Google Scholar
  59. 59.
    Katayama H, Yamaguchi K, Kozuka T, Takashima T, Seez P, Matsuura K: Adverse reactions to ionic and non-ionic contrast media. Radiol 175:621–628, 1990Google Scholar
  60. 60.
    Davis SS, Frier M, Ilum L: Colloidal particles as radiodiagnostic agents.In: Guiot P, Couvreur P (eds) Polymeric Nanoparticles and Microspheres. CRC Press, Boca Raton FL, 1990Google Scholar
  61. 61.
    Jendrasiak GL, Frey GD, Heim RC: Liposomes as carriers of iodolipid radiocontrast agents for CT scanning of the liver. Invest Radiol 20:995–1002, 1985Google Scholar
  62. 62.
    Smith-Jones PM, Fridrich R, Kaden TA, Novak-Hofer I, Siebold K, Tschudin D, Maecke HR: Antibody labeling with copper-67 using the bifunctional macrocycle [(1,4,8,11-tetraazacyclotetradec-1-yl)methyl]benzoic acid. Bioconj Chem 2:415–421, 1991Google Scholar
  63. 63.
    Rainsbury RM, Westwood JH, Coombes RC, Neville AM, Ott RJ, Kalirai TS, McCready VR, Gazet JC: Location of metastatic breast carcinoma by a monoclonal antibody chelate labeled with indium-111. Lancet ii:934–938, 1983Google Scholar
  64. 64.
    Carrasquillo JA, Bunn PA, Keenan AM, Reynolds JC, Schroff RW, Foon KA, Ming-Hus S, Gazdar AF, Mushine JL, Oldham RK, Perentesis P, Horowitz M, Eddy J, James JP, Larson S: Radioimmunodetection of cutaneous T-cell lymphoma with In111-labeled T 101 monoclonal antibody. N Engl J Med 315:673–680, 1986Google Scholar
  65. 65.
    Macklis RM, Kinsey BM, Kassis AI, Ferrara JLM, Atcher RW, Hines JJ, Coleman CN, Adelstein SJ, Burakoff SJ: Radioimmunotherapy with alphaparticle-emitting immunoconjugates. Science 240:1024–1026, 1988Google Scholar
  66. 66.
    Eisenberg AD, Contury TE, Mitchell MR, Schwartzberg MS, Price FS, Rich MS, Partain CL, James AE Jr: Enhancement of red blood cell proton relaxation with chromium labeling. Invest Radiol 21:137–143, 1986Google Scholar
  67. 67.
    Lonnemark M, Hemmingsson A, Carlsten J, Ericsson A, Hotz E, Klaveness J: Superparamagnetic particles as an MRI contrast agent for the gastrointestinal tract. Acta Radio 29:599–602, 1989Google Scholar
  68. 68.
    Moseley ME, White PL, Wang SC, Wikstrom MG, Dupon JW, Gobbel G, Roth K, Brasch RC: Vascular mapping using albumin-(Gd-DTPA), an intravascular MR contrast agent, and projection MR imaging. J Comput Assist Tomogr 13:215–221, 1985Google Scholar
  69. 69.
    Ranney DF, Huffaker HH: Magnetic microspheres for the targeted controlled release of drugs and diagnostic agents. Ann NY Acad Sci 507:104–119, 1987Google Scholar
  70. 70.
    Weissleder R, Elizandro G, Wittenberg J, Rabito CA, Bengel HH, Josephson L: Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiol 175:489–493, 1990Google Scholar
  71. 71.
    Weissleder R, Elizandro G, Wittenberg J, Lee AS, Josephson L, Brady TJ: Ultrasmall superparamagnetic iron oxide: an intravenous contrast agent for assessing lymph nodes with MR imaging. Radiol 175:494–498, 1990Google Scholar
  72. 72.
    Kent TA, Quact MJ, Kaplan BJ, Lifsey RS, Eisenberg HM: Assessment of a superparamagnetic iron oxide (AMI-25) as a brain contrast agent. Mag Reson Med 13:433–443, 1990Google Scholar
  73. 73.
    Saini S, Stark DD, Hahn PF, Wittenberg J, Brady TJ, Ferrucci JT Jr: Ferrite particles: a superparamagnetic MR contrast agent for the reticuloendothelial system. Radiol 162:211–216, 1987Google Scholar
  74. 74.
    Rinck PA, Smevik O, Nilsen G: Oral magnetic particles in abdominal and pelvic MRI. Soc of Mag Reson Med, Abstracts, 9th Annual Meeting, New York, 1990Google Scholar
  75. 75.
    Reimer P, Weissleder R, Brady TJ, Yeager AE, Baldwin BH, Tennant BC, Wittenberg J: Experimental hepatocellular carcinoma: MR receptor imaging. Radiol 180:641–645, 1991Google Scholar
  76. 76.
    Reimer P, Weissleder R, Wittenberg J, Brady TJ: Receptor-directed contrast agents for MR imaging: preclinical evaluation with affinity assays. Radiol 182:565–569, 1992Google Scholar
  77. 77.
    Reimer P, Weissleder R, Lee AS, Buettner S, Wittenberg J, Brady TJ: Asialoglycoprotein receptor function in benign liver disease: evaluation with MR imaging. Radiol 178:769–74, 1991Google Scholar
  78. 78.
    Weissleder R, Reimer P, Lee AS, Wittenberg J, Brady TJ: MR receptor imaging: ultrasmall iron oxide particles targeted to asialoglycoprotein receptors. Am J Roentgenol 155:1161–1167, 1990Google Scholar
  79. 79.
    Grant CWM, Karlik S, Flono E: A liposomal MRI contrast agent: phosphatidylethanolamine-DTPA. Mag Reson Med 11:236–244, 1989Google Scholar
  80. 80.
    Bulte JW, Ma LD, Magin RL, Kamman RL, Hulstaert Ce, Go KG, The TH, de Leij L: Selective MR imaging of labeled human peripheral blood mononuclear cells by liposome mediated incorporation of dextran-magnetite particles. Mag Reson Med 29:32–37, 1993Google Scholar
  81. 81.
    Navon G, Panigel R, Valensin G: Liposomes containing paramagnetic macromolecules as MRI contrast agents. Mag Reson Med 3:876–880, 1986Google Scholar
  82. 82.
    Miesman MR: Liposome encapsulatd MnCl2 as a liver specific contrast agent for magnetic resonance imaging. Invest Radiol 25:545–552, 1990Google Scholar
  83. 83.
    Unger E, Tilcock C, Ahkong QF, Fritz T: Paramagnetic liposomes as magnetic resonance contrast agents. Invest Radiol 1:S65-S66, 1990Google Scholar
  84. 84.
    Barry CD: Quantitative determination of conformations of flexible molecules in solution using lanthanide ions as a nuclear magnetic resonance probe: application to adenosine-5'-monophosphates. J Mol Biol 84:471–479, 1974Google Scholar
  85. 85.
    Dechter JJ, Levy GC: Aqueous relaxation reagents in nitrogen-15 NMR. J Mag Reson 39:207–214, 1980Google Scholar
  86. 86.
    Lauffer RB: Paramagnetic metal complexes as water proton relaxation reagents for NMR imaging: Theory and design. Chem Rev 87:901–911, 1987Google Scholar
  87. 87.
    Sieving PF, Watson AD, Rocklage SM: Preparation and characterization of paramagnetic polychelates and their protein conjugates. Bioconjugate Chem 1:65–71, 1990Google Scholar
  88. 88.
    Pierce BL, Floyd LJ, Floyd LA, Cortinas NC, Ollom CM, Jurena KR, Simmons AM, Siegle RL, Williams RF: (unpublished observations)Google Scholar
  89. 89.
    Edwards DP, Grzyb KT, Dressler LG, Mansel RE, Zava DT, Sledge GW Jr, McGuire WL: Monoclonal antibody identification and characterization of a Mr 43,000 membrane glycoprotein associated with human breast cancer. Cancer Res 46:1306–1317, 1986Google Scholar
  90. 90.
    LeMaistre CF, Edwards DP, Krolick KA, McGuire WL: An immunotoxin cytotoxic for breast cancer cellsin vitro. Cancer Res 47:730–734, 1987Google Scholar
  91. 91.
    Hanna SL, Reddick WE, Parham DM, Gronemeyer SA, Taylor JS, Fletcher BD: Automated pixel-by-pixel mapping of dynamic contrast-enhanced MR images for evaluation of osteosarcoma response to chemotherapy: Preliminary results. J Mag Reson Imag 3:849–853, 1993Google Scholar

Copyright information

© Kluwer Academic Publishers 1994

Authors and Affiliations

  • Kourosh Orang-Khadivi
    • 1
  • Brian L. Pierce
    • 1
  • Callise M. Ollom
    • 1
  • L. Jean Floyd
    • 1
  • Robert L. Siegle
    • 1
  • Robert F. Williams
    • 1
  1. 1.Research Imaging Center and the Department of RadiologyThe University of Texas Health Science CenterSan AntonioUSA

Personalised recommendations