2. Metals in Medicine Dr Steve Archibald Department of Chemistry University of Hull SWOSU 26 th May 2009

5. Periodic table with elements highlighted

6. Concepts you need to know! Metals and ligands. How does nature use metals?

7. Metal + Ligand Control of the properties properties of the metal through the use of new metal/ligand combinations

8. Metals in disease There are a number of diseases that can be cured by the administration of metals. Diseases can also be caused by the lack of metal ions.

9. Topics 1.Preventing heart injuries 2.Imaging the body 3.Anti-cancer drugs –Radiation emitters –DNA binders 4.Anti-HIV drugs

10. 1.Preventing heart injuries

11. Heart attack- how is the tissue damaged?

12. The majority of tissue damage is actually caused after a heart attack.

13. Superoxide is a radical anion and is quite toxic Normally SOD enzymes destroy it (Superoxide Dismutase)

14. Pentaazamacrocycle Mn 2+ complexes act as therapeutic SOD mimics Riley, Nature Reviews Drug Discovery, 2002, 367-374.

15. 2.Diagnosis- Imaging the body

16. Radiation emitters and MRI agents

17. Types of metal drugs: Radiopharmaceutical0.0001 mmol MRI contrast0.1 mmol

18. Metal isotopes that emit radiation are used (short half life!). High energy radiation required. The ligand can direct the metal to specific areas of the body.

19. Targeted Imaging

20. Magnetic resonance imaging Analysing the water in the tissues of the body. Humans are approx. 70% water. The patient is placed within a large superconducting magnet and pulsed with radiowaves and the resulting signals analysed by computer.

25. Do you need a metal? No… but it helps. Gadolinium is used because of its unique properties. However it is toxic! The magnetism of the Gd disrupts the signal from the water resulting in an improved image.

26. None Contrast agent used

27. 1,4,7,10-tetraazacyclododecane -1,4,7,10-tetraacetic acid diethylene triamine pentaacetic acid Gd(DOTA) -

28. 3.Anti-cancer drugs

29. Curing cancer with radioactive metals Drugs for delivery of therapeutic doses of radiation to specific disease sites.

30. “The first dose uses 111 In (indium-111) ibritumomab for imaging. Indium-111 emits gamma radiation, which can be picked up by the gamma camera. A scan is done to assess biodistribution of the drug. This test dose is used to determine that no excess amounts go to the marrow, liver, etc. in this particular patient. If the gamma scan shows no altered biodistribution, then the second dose is given, using 90 Y (yttrium-90) ibritumomab as the actual treatment. Yttrium-90 emits the cell-killing beta radiation.” http://en.wikipedia.org/wiki/Zevalin Tiuxetan chelator

31. Most expensive drug!! Uses an antibody to target the cancer taking a radioactive payload with it. Zevalin-licensed (US) in 2002. Can cost as much as $24,000 for treatment

33. Zevalin Utilised to combat B- cell non-hodgkins lymphoma. Antibody utilised for targeting. Ibritumomab mouse antibody

34. Killing cancer cells by binding to DNA

35. DNA double helix

36. History Platinum containing drug. 1978 cisplatin was proven and used in the clinic to treat cancer patients.

37. cisplatincarboplatin cisplatincarboplatin

39. What’s new with cisplatin? We know much more about why it works! Why doesn’t the DNA damage get repaired? Following administration, one of the chloride ligands is slowly displaced by water (an aqua ligand), in a process termed aquation. The aqua ligand in the resulting [PtCl(H 2 O)(NH 3 ) 2 ] + is itself easily displaced, allowing the platinum atom to bind to bases. Of the bases on DNA, guanine is preferred. Subsequent to formation of [PtCl(guanine-DNA)(NH 3 ) 2 ] +, crosslinking can occur via displacement of the other chloride ligand, typically by another guanine. Cisplatin crosslinks DNA in several different ways, interfering with cell division by mitosis. The damaged DNA elicits DNA repair mechanisms, which in turn activate apoptosis when repair proves impossible. http://en.wikipedia.org/wiki/Cisplatin

41. 4.Anti-HIV drugs

44. Blocking virus attack Cell Drug Receptor signalling protein

45. AMD3100 = Plerixafor = Mozobil

46. Where is my metal? The drug is not adminstered with a metal ion. New studies have shown that binding of a metal makes the drug work better. Where does the metal come from?

47. Zn 2+

48. Lewis, E. A.; Hubin, T. J.; Archibald, S.J. Patent WO2005121109, 2005.

49. Periodic table with elements highlighted

50. Where now? Lots of new drugs and new possibilities for metals in medicine. There is much research to be done! Back to the laboratory!