Light activated anticancer drug targeted to DNA using cisplatin like sub-units

March 26, 2006

One of the most effective chemotherapy drugs against cancer is cisplatin because it attaches to cancer DNA and disrupts repair. However, it also kills healthy tissue. Many scientists are creating alternative drugs or cisplatin analogs in attempts to find treatments without side effects. One approach to analog development is light activated drugs, or photodynamic therapy (PDT). Now a Virginia Tech chemistry-biology research team that has been working on both non-cisplatin drugs and cisplatin analogs has combined their findings to create a molecular complex (supramolecule) that exploits cisplatins tumor targeting to deliver a light activated drug.

The latest results from the group's research to create a DNA targeting, light activated anticancer drug will be presented at the 231st American Chemical Society national meeting in Atlanta on March 26-30.

Chemistry professor Karen J. Brewer reports that the group has developed supramolecular complexes that combine light-absorbing PDT agents and cisplatin like units. Previous anticancer molecules created by the group have contained platinum-based molecules that bind DNA. They have also developed new light activated systems able to photocleave DNA. This report combines these two approaches to target the drug to DNA using cisplatin like units, directing the light activation to tumor cells and the sub-cellular target, DNA.

"In the past, our light activated systems had to find the DNA within the cell, an often inefficient process. Now we have added the DNA targeting drug," Brewer said. "We were working on cisplatin analogs before, so we have tied it to light activated systems."

Cisplatin begins its interaction with cancer DNA by binding to the nitrogen atoms of the DNA bases, typically guanine. Our new supramolecules use this nitrogen-binding site to hold the light activated drug at the target until signaled to activate. Thus the new supramolecules can be delivered to the tumor site but remain inert until activated by a light signal. Light waves in the therapeutic range - that is, those that can penetrate tissue, are used to activate these new drugs. t The researchers are also appending other molecules that emit UV light to track the movement of these drugs within cells.

Virginia Tech chemistry graduate student Ran Miao will discuss how component identity dictates device properties. He will present the paper, "Synthesis and properties of mixed-metal Ru-Pt complexes: Coupling light absorbers to reactive metal centers" (INOR 105) at 3:30 p.m., Sunday, March 26, at the Georgia World Congress Center room B408. Co-authors are Matthew T. Mongelli, postdoctoral associate in chemistry at Virginia Tech, and Brewer.
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ACS Abstract:
Mixed-metal tetrametallic complexes [{(bpy)2M(dpp)}2M'(L)PtCl2](PF6)6 (M, M'= Os or Ru, L = dpp, dpq or dpb; bpy = 2,2'-bipyridine, dpp = 2,3-bis(2-pyridyl)pyrazine, dpq = 2,3-bis(2-pyridyl)quinoxaline, dpb = 2,3-bis(2-pyridyl)benzoquinoxaline) are of interest. These supramolecular complexes have a trimetallic {(bpy)2M(dpp)}2M'(L)6+ chromophore, which strongly absorbs visible light, possessing several metal-to-ligand charge transfer transitions throughout the visible region, coupled to a reactive Pt site. This unique design allows these complexes to display interesting properties. Photophysical studies reveal excited state energy or electron transfer is possible. This report will discuss how component identity dictates devices properties. This work is supported by the NSF (CHE-0408445).

Several Bioinorganic - Biological Applications of Inorganic Chemistry posters, to be displayed from 7 to 10 p.m. Sunday in the Georgia World Congress Center exhibit hall B4, will also discuss related issues:

DNA interaction and biological activity of Ru-Pt supramolecular complexes (INOR 125) authors are Miao, chemistry Ph.D. student R. Lee Williams , biology professor Brenda S. J. Winkel , and Brewer, all of Virginia Tech. This presentation will also be posted during the Sci-Mix from 8 to 10 p.m. Monday, March 27.

Probing DNA-metal complex interactions of Pt containing assemblies via electrochemistry and spectroscopy (INOR 122), authors are Mongelli , Winkel , and Brewer .

Variation of light absorbing units for rhodium centered trimetallic complexes as DNA photocleavage agents applicable in photodynamic therapy (INOR 606) authors are Emily Merola, chemistry undergraduate at Bucknell who worked in the summer at Virginia Tech, Shatara Mayfield, chemical engineering student at North Carolina A&T who worked at Virginia Tech for two summers), chemistry undergraduate Julie Heinecke, Winkel, and Brewer.

The National Science Foundation supports this research.

Learn more about the Brewer-Winkel group's research at http://www.chem.vt.edu/chem-dept/brewer/brewer.html and http://www.biology.vt.edu/faculty/winkel/.

Virginia Tech

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