Chemopreventive compound SR13668 showed promising anti-cancer activity in several in vitro and in vivo models of cancer, including breast, lung, prostate, and ovary and it was proposed that SR13668 works through the modulation of PI3K/Akt pathway. However, low oral bioavailability substantially limited its development as a chemopreventive agent. A novel nano-formulation of SR13668 encapsulated in poly(lactic-co-glycolic acid) (PLGA) was produced with the aim to enhance the oral bioavailability of SR13668 in beagle dogs. A single gavage administration of SR13668 was performed at 2.8 mg/kg as nano-formulation and also as SR13668 in 0.5 % methylcellulose in 4 male and 4 female dogs. Whole blood and plasma samples withdrawn from these animals at different time points over 24 hr period were analyzed using LC-MS/MS method to obtain the systemic drug levels and to evaluate the pharmacokinetic profile achieved. In plasma the group mean highest concentration occurred at the 4 hr time point in both males (29.6 ng/mL) and females (27.9 ng/mL) whereas in whole blood the mean group peak occurred at 4 hr in males (51.7 ng/mL) and 6 hr in females (61.9 ng/mL). The animals dosed with SR13668 in methylcellulose had all levels below limit of quantitation (1.1 ng/mL) in both plasma and whole blood for all time points. This study was the first attempt of using nano-formulation to improve oral bioavailability of the chemopreventive compound SR13668 in large animals. The systemic levels achieved were high for this poorly bioavailable compound in dogs but were not to the desired levels and further work is needed to improve bioavailability using nano-formulations. Potential improvements that are planned for the SR13668 nano-formulations include using a high through-put screening method to optimize the conditions further, use of polyethyleneglycol- poly(lactic-co-glycolic acid) (PEG-PLGA) for SR13668 encapsulation and comparison with poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEG-b-PCL) and PLGA results to possibly obtain better absorption with increased stability in the gut and also placement of negative charges on the nano-particles using poly-acrylic acid (PAA) to facilitate the particle penetrating the mucus layer to increase bioavailability.

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 2902. doi:1538-7445.AM2012-2902