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Biocatalytic Polymerization of Naturally Occurring Green Tea Flavonoids for Cancer TherapyEPA Grant Number: SU833204
Title: Biocatalytic Polymerization of Naturally Occurring Green Tea Flavonoids for Cancer Therapy
Investigators: Kumar, Jayant , Braunhut, Susan J. , Nagarajan, Subhalakshmi
Institution: University of Massachusetts - Lowell
EPA Project Officer: Nolt-Helms, Cynthia
Project Period: September 1, 2006 through August 31, 2008
Project Amount: $75,000
RFA: P3 Awards: A National Student Design Competition for Sustainability Focusing on People, Prosperity and the Planet - Phase 2 (2006) Recipients Lists
Research Category: Nanotechnology , P3 Challenge Area - Materials & Chemicals , Pollution Prevention/Sustainable Development , P3 Awards , Sustainability
Cancer is the second leading cause of death in the world, with more than 20 million people living with it and seven million dying annually. Existing drugs have proven to be effective in controlling some forms of cancer; however, most of these drugs are toxic to the normal healthy cells and are often prepared using complex synthetic procedures generating huge amounts of carcinogenic waste. For example, one of the most popular drugs (Taxol®) was, until recently, manufactured through a multi-step synthetic process with approximately 32 metric tons of waste generated in the synthetic route from synthesis to purification. A large number of drugs that are used currently in the treatment of cancer are not affordable for the vast majority of the population in developing countries. There is clearly an urgent need for a dramatic shift in the discovery and development of anti-cancer drugs towards using less toxic methods and using naturally occurring materials.
The primary objective of the proposed research is to develop a simple eco-friendly technology for the polymerization of naturally occurring compounds like ‘green tea catechins’ resulting in a new class of compounds that would be effective in treating cancer. To accomplish this goal, various isomers of catechins were polymerized using naturally occurring plant peroxidases like Horseradish peroxidase (HRP) in biocompatible solvents such as water-ethanol mixtures. This one-pot synthesis is carried out at room temperature and the polymers obtained can be used as such with minimal purification. Another important objective of this effort is to evaluate the efficacy of these polymers on arresting the growth of various types of cancer cells. The inhibitory activities of these polymeric catechins are compared to the monomeric forms as well as other green tea flavanols like epigallocatechin gallate (EGCG).
Sustainability and P3: The project directly benefits the three pillars of sustainability - people, prosperity and planet. The method proposed here could greatly reduce the high costs associated with waste disposal in most countries, besides creating healthier work environments. More importantly, this project is of enormous significance to the better part of the under-developed and developing world, which cannot afford most of the drugs that are effective in treating cancer owing to the exorbitant costs associated with them. The simplicity of the synthetic route combined with the wide availability of raw materials and low waste generation make it ideal for implementation in most countries in the developing world. This route will definitely prove to be much more economical and will use renewable resources for treatment of cancer.
- The primary goal of Phase II is to separate the polymeric mixture into its constituent polymers using High Performance Liquid Chromatography (HPLC). Organix, our partners in this research effort will assist us with their expertise in separating the polymers through HPLC.
- After the isolation of the individual fractions, in-vitro studies will be used to evaluate and determine the most active component or to determine if the fractions have a synergistic mechanism by which they prevent cancer cells from proliferation.
- Another important objective is to conduct mechanistic studies to identify the mechanism of action through which the poly (catechin) inhibits the growth of cancer cells.
- Scaling up of the reaction (to gram quantities) will also be one of the important objectives of the project.
- Organix will also assist us in identifying structure-activity relationship in these polymers by synthesizing model compounds.
- In continuation of our efforts from phase I, we would also like to test the efficacy of these polymers on other lethal kinds of cancer including the more aggressive and less treatable head and neck cancer.
- Phase I results clearly indicated that more economical catalysts like Hematin can catalyze the polymerization of the green tea catechins. Attempts will be made to transition the synthetic route to these cost effective processes. In addition, in-vitro studies will also be performed on these polymers.
Value of the Phase II Work: The Phase II research will be of immense importance to take this project to the next step. Separation, characterization of the polymers, and identifying the mechanism of action will be crucial as it would impart a better understanding of the technology and set the stage up for invivo studies. Scaling up is the natural step forward towards commercialization of this technology and hence is equally important. Identifying structural-activity relationships will help us in designing a library of monomers and polymers and arrive at an optimum structure where the polymers formed will exhibit very high inhibitory activity. Our long-term experimental plan will be to test the most potent polymeric catechins identified in these in vitro studies in a study of human breast cancer tumor-bearing nude mice, delivering these stable poly(catechins) in the drinking water of mice or via venous administration.
- HPLC separation of the polymeric mixture into its constituent fractions
- Anti-proliferation assays will be performed to identify the most active component.
- In-vitro studies to determine the effectiveness of the poly(catechins) against human esophagus-pharyngeal, tongue cancers, colorectal cancer and the more lethal cancers like the head and neck cancer.