Abstract 2621: Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticles encapsulated aspirin, curcumin and free sulforaphane (ACS) combinations in BALB/c mice

Abstract

Abstract The present study aims to evaluate the preclinical systemic toxicity profile of chitosan-solid lipid nanoparticles (c-SLNs) encapsulated aspirin (ASP), curcumin (CUR), and free sulforaphane (SFN) combination (ACS) in BALB/c mice. Recently, we demonstrated pancreatic cancer chemopreventive efficacy using ACS-SLNs delivery system in the BOP carcinogen induced pancreatic cancer hamster model. In order to develop safe ACS c-SLNs for clinical applications, it is vital to investigate their toxicity. Thus, we performed acute 3-day, sub-acute 28-day and sub-chronic 90-day toxicity studies of ACS c-SLNs in the BALB/c mice model. The mice were orally gavaged once every 24h with 200 μl ACS c-SLNs at three concentrations: low dose ACS (2+4.5+0.16 mg/kg; 1/30th of high dose), medium dose ACS (20+45+1.6 mg/kg; 1/3rd of high dose) and high dose ACS (60+135+4.8 mg/kg). Total of 60 mice were used for this study (4 mice each group X 3 timepoints X 5 groups). A standard evaluation was performed, which included daily clinical signs, weekly body weight, end-of-study blood hematology, blood clinical chemistry, gross necropsy on all animals and hematoxylin and eosin-stained examination of range of tissues from each animal. The clinical chemistry tests include blood urea nitrogen (BUN) and creatine (CRE), which indicate renal toxicity. Alanine transaminase (ALT) and alkaline phosphatase (ALP) levels indicate hepatic toxicity, while glucose (GLU) and total protein are measures of healthy growth. At the end-of-study, data revealed that mean body weight gain was consistent with low-, medium- and high-ACS c-SLN dose during acute, sub-acute and sub-chronic treatment period. The blood count and blood chemistry profiles revealed lack of systemic toxicity as the numbers were within normal ranges. Extensive histopathological examination of liver, kidney, heart, brain and pancreatic tissues showed no increase in treatment-related microscopic lesions in any of the three ACS c-SLN dose groups. Collectively, these findings demonstrate that repetitive oral administration of ACS c-SLN even at high concentrations was not associated with local or systemic toxicity and did not adversely affect the blood clinical chemistry of mice. Hence, long-term ACS c-SLN oral therapy is deemed safe for prevention of pancreatic cancer. Citation Format: Arvind Thakkar, Sushma Chenreddy, Jeffrey Wang, Sunil Prabhu. Preclinical systemic toxicity evaluation of chitosan-solid lipid nanoparticles encapsulated aspirin, curcumin and free sulforaphane (ACS) combinations in BALB/c mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2621. doi:10.1158/1538-7445.AM2015-2621