Posted on | August 4, 2011 | No Comments
Millions of people around the world are either living with cancer or have a loved one who is living with cancer. According to the American Cancer Society, nearly half of all of the men and approximately one-third of all of the women in the United States will develop cancer. One of the most effective measures in treating the disease, depending upon the type of cancer involved, is chemotherapy. Yet, anyone who has gone through “chemo” or watched a loved one go through it knows the side effects all too well. Because in addition to killing diseased cells, chemotherapy destroys healthy ones. Researchers in the Department of Chemical and Biomolecular Engineering and the Advanced Diagnostics and Therapeutics initiative at Notre Dame are working to redesign already effective drugs to make them more selective in seeking and eliminating cancerous cells while bypassing healthy ones.
Cancer is the general name for more than 100 different diseases affecting cells in the body. Each type of cancer begins when a cell, or group of cells, does not follow the normal pattern of cell growth, division, and death. Instead of dying, these abnormal cells continue to grow and divide, forming new abnormal cells. This is the way cancer grows and spreads to other parts of the body. Pharmaceuticals used in chemotherapy treatments, individually or in combination with other drugs, attach to the cancerous cells and destroy their ability to multiply, eventually “killing” the cancer.
An expert in bioengineering, chemistry, medical oncology, and targeted drug delivery, Z. Basar Bilgicer, assistant professor of chemical and biomolecular engineering, has been focusing his efforts on better understanding the principles of multivalent biomolecular interactions in an effort to redesign chemotherapeutic drugs and increase their selectivity for targeting cancerous cells. This would increase the efficacy of a drug while lowering its affinity toward healthy cells and reducing associated side effects.
A highly effective anti-cancer drug, cisplatin was approved by the Food and Drug Administration in 1978. But because of its toxicity, its use has been limited. By studying the chemical properties of the molecule, Z. Basar Bilgicer and project collaborators — Abhimanyu S. Paraskar, Shivani Soni, Kenneth T. Chin, Padmaparna Chaudhuri, Katherine W. Muto, Julia Berkowitz, Michael W. Handlogten, Nathan J. Alves, Daniela M. Dinulescu, Raghunath A. Mashelkar, and Shiladitya Sengupta — were able to redesign the drug and change its interactions in the body. Bilgicer conducted additional studies to show that the newly designed drug collects in tumor tissue and not in the kidneys, where it had been prone to travel because of its size. This passive targeting of the cisplatin (whereby the team’s redesign of the drug ensures that it is able to be absorbed at the tumor site but not through healthy tissue) makes it a much more effective option in the fight against cancer.
One of the chemotherapeutic agents Bilgicer and his colleagues have been working on is cisplatin. Effective against many types of cancer, cisplatin is used primarily to fight testicular, ovarian, cervical, and lung cancer. However, it is extremely toxic to the kidneys. By adjusting the size of the particles carrying the chemo-therapeutic payload and changing the structure-activity relationship between the cisplatin molecule and the tumor, the team was able to prevent uptake of the drug by the kidneys, thereby reducing its toxicity.
Bilgicer has also been developing nanoparticles that encapsulate a cancer-killing drug, releasing it selectively when the nanoparticles attach to the cancerous cells that they have been designed to seek and find. In one project Bilgicer is working with an Indiana-based team — faculty from Notre Dame, the Indiana University School of Medicine, and Purdue University — to overcome drug resistance in multiple myeloma (MM). The second most common type of blood cancer in the United States, MM offers a median survival rate of four to five years. Because of its high drug resistance, Bilgicer and his team are working to design nanoparticles that will deliver chemotherapeutic agents to MM cells in blood plasma, bypassing the kidneys and liver. By creating special chemical receptors on the outside of a nanoparticle that recognize the receptors found on MM cells, the team hopes to increase drug effectiveness while lowering side effects and toxicity.
Bilgicer, who holds five patents, is using a similar approach for targeted drug delivery in collaboration with Kasturi Haldar, the Julius Nieuwland Chair of the Department of Biological Sciences and director of the Center for Rare and Neglected Diseases at Notre Dame, to develop new highly specific antibody therapeutics with increased valency to maximize efficacy in vivo for treating malaria and HIV infections.
Paraskar, Abhimanyu S.; Soni, Shivani; Chin, Kenneth T.; Chaudhuri, Padmaparna; Muto, Katherine W.; Berkowitz, Julia; Handlogten, Michael W.; Alves, Nathan J.; Bilgicer, Z. Basar; Dinulescu, Daniela M.; Mashelkar, Raghunath A.; Sengupta, Shiladitya, “Harnessing Structure-activity Relationship to Engineer a Cisplatin Nanoparticle for Enhanced Antitumor Efficacy,” Proceedings of the National Academy of Sciences of the United States of America, 2010, 28, 12435-40.
Bilgicer, Z. Basar; Thomas, Samuel W. III; Shaw, Bryan F.; Kaufman, George K.; Krishnamurthy, Vijay M.; Estroff, Lara A.; Yang, Jerry; and Whitesides, George M., “A Non-chromatographic Method for the Purification of a Bivalently Active Monoclonal IgG Antibody from Biological Fluids,” Journal of the American Chemical Society, 2009, 131, 9361-67.
Shaw, Bryan F.; Schneider, Gregory F.; Bilgicer, Z. Basar; Kaufman, George K.; Neveu, J.M.; Lane, W.S.; Whitelegge, J.P.; and Whitesides, George M., “Lysine Acetylation Can Generate Highly Charged Enzymes with Increased Resistance toward Irreversible Inactivation,” Protein Science, 2008, 17, 1446-1455.