Abstract 5246: Pharmacokinetic evaluation of novel nano-formulations of aspirin, curcumin and sulforaphane for pancreatic cancer chemoprevention

Abstract

Abstract The objective of this study was to evaluate the pharmacokinetics of orally administered chitosan - coated solid lipid nanoparticles (c-SLN) formulations encapsulating aspirin (ASP) and curcumin (CUR) with free-sulforaphane (SFN) (ACS), in rats. Twenty five rats were divided into 5 groups at random (n = 5), and received three different dosing levels of ACS c-SLN formulations by oral gavage (low: 2 ASP+4.5 CUR+0.16 SFN mg/kg; medium: 20 ASP+45 CUR+1.6 SFN mg/kg; high: 60 ASP+ 135 CUR+ 4.8 SFN mg/kg), and a high dose of unmodified ACS regimen. Blood samples were drawn at 0, 0.5, 1, 2, 6, 24, and 48 h. The concentrations of ASP, CUR and SFN and their major metabolites such as salicylic acid (SA) and tetrahydrocurcumin (THC) in plasma were measured using an LC/MS/MS method. Briefly, the analytes in rat plasma were extracted by a protein precipitation method using acetonitrile containing 0.1% formic acid. SA and ASP were detected in negative ion mode with m/z transition of 136.9 to 93.0 and 179.0 to 137.2 respectively, while CUR, THC, and SFN were detected in positive ion mode with m/z transition of 369.1 to 177.1, 373.1 to 137.2, and 178.1 to 91.1, respectively. The chromatographic separation was carried out using a mobile phase of acetonitrile and formic acid (0.1% v/v) containing 2 mM amino acetate with a flow rate of 0.3 ml/min. The analyses were linear over 0.005 to 2.5, 0.05 to 25, 0.01 to 5, 0.01 to 5, and 0.002 to 1 μg/ml for SA, ASP, CUR, THC, and SFN, respectively. Preliminary results indicated that there was an 18% increase in the area under curve (AUC) of SA (85 mg.hr/L), ASP (3.4 mg.hr/L), and SFN (2.08 mg.hr/L) of c-SLN formulation when compared to the SA (70 mg.hr/L) and ASP (2.8 mg.hr/L) from unmodified high dose ACS combination. No substantial plasma concentrations of CUR and THC were detected due to the extensive metabolism during absorption. The Cmax of SA (11.0 μg/ml), ASP (0.2 μg/ml), and SFN (0.39 μg/ml) were significantly higher indicating the ability of enhancement of drug absorption by the nano-formulation, while the tmax values of SA (2.54 h), ASP (4.5 h), and SFN (1.5h) were longer compared to unmodified SA (1.25 h) and ASP (2.25 h), demonstrating a sustained release of the drug. The elimination t1/2 values were increased in the c-SLN formulation which suggested a slow release of free compounds in the systemic circulation. The results demonstrate that ACS c-SLN could increase drug exposure following oral administration by enhancing the absorption and sustained release of the drugs. Data obtained from this study provides insights to the clinical development of ACS regimen for pancreatic cancer chemoprevention. Citation Format: Arvind Thakkar, Sushma Chenreddy, Zhijun Wang, Jalpa Modi, Jeffrey Wang, Sunil Prabhu. Pharmacokinetic evaluation of novel nano-formulations of aspirin, curcumin and sulforaphane for pancreatic cancer chemoprevention. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5246.