Abstract 5438: Oral administration of naturally occurring chitosan based nanoformulated green tea polyphenol EGCG effectively inhibits prostate cancer cell growth in a xenograft model

Abstract

Abstract Prevention of cancer by natural agents is often restricted by the lack of delivery of desired levels in target tissue thus limiting their bioavailability and clinical outcome. Hence, newer approaches are required to improve bioavailability and to decrease toxicity of natural agents to accomplish maximum response. Among all natural agents, green tea has shown promise in preclinical, epidemiological and initial clinical studies, especially for prostate cancer (PCa). Much of the effects of green tea are considered to be exerted by its major polyphenol (-) epigallocatechin-3-gallate (EGCG). We reported significant dose-advantage of polylactic acid-polyethylene glycol (PLA-PEG) encapsulated EGCG (nanoEGCG) over non-encapsulated EGCG (Cancer Res. 2009; 69: 1712-1716), for PCa in cell-culture and xenograft model. However, PLA-PEG is unstable in acidic environment and is therefore not recommended for oral consumption, a desired route for chemopreventive agents. We developed a formulation of nanoEGCG suitable for oral delivery employing a naturally occurring polymer chitosan, which here is referred to as Chit-nanoEGCG. This Chit-nanoEGCG when administered to mice resulted in a steady and sustained release of EGCG in the plasma of mice at 1 and 8 hours post-treatment. The effect of Oral Chit-nanoEGCG was then determined on the growth of tumors in athymic nude mice implanted with CWR22Rν1 cells. Treatment with Chit-nanoEGCG (3 and 6 mg/kg body wt.) resulted in significant inhibition of tumor growth. At these doses, non-encapsulated EGCG was totally ineffective. In control group, the average tumor volume of 1,200 mm3 was reached in 32 days after tumor cell inoculation. At this time point, the average tumor volume was 514, 310 and 216 in non-encapsulated EGCG, Chit-nanoEGCG (3mg/kg body wt.) and Chit-nanoEGCG (6mg/kg body wt.) treated groups, respectively. The average tumor volume of 1,200 mm3 was achieved on 46, 53 and 60 days after tumor cell inoculation in these three groups, respectively. There was significant inhibition of secreted prostate specific antigen (PSA) levels by 13-36%, 26-54% and 57-72% in EGCG, Chit-nanoEGCG (3mg/kg body wt.) and Chit-nanoEGCG (6mg/kg body wt.) treated groups, respectively as compared to the control group. In tumor tissues of mice treated with both doses of Chit-nanoEGCG as compared to group treated with EGCG and controls, there was significant (i) reduction in Ki-67 and proliferating cell nuclear antigen (PCNA) (ii) induction of poly (ADP-ribose) polymerases (PARP) cleavage, (iii) activation of caspases and, (iv) increase in the protein expression of Bax and decrease in Bcl2. Through this study, we propose a novel preventive and therapeutic modality using EGCG that addresses issues related to bioavailability, that is a major reason for its limited success in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5438. doi:1538-7445.AM2012-5438