Abstract 3725: Pre-clinical evaluation of prostate specific membrane antigen (PSMA) nanobioconjugate encapsulating green tea polyphenol EGCG for prostate cancer

Abstract

Abstract For prostate cancer green tea constituent (-)-epigallocatechin-3-gallate (EGCG) has shown promise in preclinical, geographical and epidemiological studies and more importantly in many clinical trials. However, concerns related to stability, poor intestinal absorption and extensive systemic and enteric metabolism have hampered its use in the clinic. We introduced the idea of nanotechnology to enhance the outcome of chemoprevention with EGCG and coined the term ‘Nanochemoprevention' and later reported the efficacy of chitosan nanoparticles encapsulating EGCG for PCa prevention and therapy. Here, we evaluated an aptamer conjugated prostate targeting nanobioconjugate encapsulating EGCG in two relevant pre-clinical mouse models of human PCa. We developed chitosan nanobioconjugates encapsulating EGCG, surface functionalized with the A10 2′-fluoropyrimidine RNA aptamers that recognize the extracellular domain of the prostate specific membrane antigen (PSMA), henceforth called chit-EGCG-Apt. Mice implanted with androgen sensitive CWR22Rν1 cells and treated with Chit-EGCG-Apt showed significant inhibition in tumor growth that was also associated with decreased serum PSA levels as compared to native EGCG. Tumor tissues from mice treated with Chit-EGCG-Apt exhibited significant (i) induction of PARP cleavage, (ii) increase in the protein expression of Bax with concomitant decrease in Bcl-2, (iii) activation of caspases and (iv) reduction in Ki-67 and PCNA. We further observed inhibition of markers of angiogenesis, invasion and metastasis in tumor tissues in these mice. We next evaluated the efficacy of Chit-EGCG-Apt in the prostate specific Pten knockout mouse model that recapitulates disease progression as seen in humans. Longitudinal MRI analysis suggested significant inhibition of PCa development and tumor growth in these mice. We observed a significant inhibition in tumor growth as evaluated by genitourinary and prostate tissue weight. We further observed a significant decrease in serum IGF-I levels with concomitant increase in serum IGFBP-3 levels in these mice. We analyzed tumor tissues isolated from the mice and observed significant (i) induction of apoptosis, (ii) modulation of Pten/PI3K/Akt, MAPK pathway, IGF-1 signaling and iii) inhibition of markers associated with angiogenesis, invasion and metastasis. These data support our hypothesis that target-specific nanobioconjugates enhance efficacy through boosting bioavailability, thus leading to a significant potential for possible clinical outcome. Targeted nano-encapsulation approach could be viewed as “precision chemoprevention” for PCa patients that are considered low-risk and put on active surveillance. Citation Format: Imtiaz A. Siddiqui, Vaqar M. Adhami, Islam Rady, Hasan Mukhtar. Pre-clinical evaluation of prostate specific membrane antigen (PSMA) nanobioconjugate encapsulating green tea polyphenol EGCG for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3725.