Research Project
9464754
Abstract Green tea has received increased attention recently, due to several epidemiological and clinical studies showing a positive relationship between consumption and disease prevention. Benefits include reduced risk of cardiovascular diseases (e.g. myocardial infarction, hypertension, atherosclerosis), neurodegenerative diseases (e.g. Parkinson?s and Alzheimer?s disease), and certain cancers (e.g. gastric, breast and cervical cancer). Supplements can even help maintain healthy body weight and lipid profiles. Clinical activity has been demonstrated in leukemia and by our group in inflammatory bowel disease (IBD). These effects are attributed to the polyphenolic flavonoid compounds known as catechins (i.e., polyphenols) present in high amounts. Yet, poor stability, low oral bioavailability and inconsistent intestinal absorption remain problematic. If these shortcomings were overcome, the impact of green tea supplementation could be dramatically improved and novel, efficacious pharmaceutical products aimed at maintaining health developed. The hypothesis behind this application is that encapsulation into poly D,L-lactide-co-glycolide (PLGA) microspheres will improve the delivery and thus efficacy of green tea?s polyphenols via the oral route. Importantly, PLGA is already approved by the FDA and EMA for human use. Thus, PLGA-based micro-particles are in a good position for use in products intended for human consumption. Considering these observations, the proposed studies will test an oral PLGA encapsulated polyphenol formulation for prophylactic use. In Aim 1, we will determine whether oral administration of polyphenol loaded microspheres is superior to parenteral soluble material in limiting murine IBD using a prophylactic iteration of the acute DSS-induced colitis model. We will then optimize the prophylactic protocol and examine the effects of treatment on the phenotypic and functional properties of colonic LP and MLN mononuclear cells. In Aim 2, we will determine whether oral administration of polyphenol microspheres is similarly effective in the CD4+CD25- T-cell reconstituted SCID mouse model of colitis This model is also in routine operation in our laboratory. We will elucidate immunological mechanisms, as well as monitor long-term efficacy and systemic side effects. Future work will include pharmacokinetic, dose-ranging toxicology studies, as well as product development (drug product and drug substance) efforts aimed at novel pharmaceutical products. If the proposed studies are successful the hope is that the benefits of green tea, long recognized by the ancients, may at last be translated and optimized into prophylactic benefit for IBD patients.
