Novel nano-drug combination therapeutic regimen demonstrates significant efficacy in the transgenic mouse model of pancreatic ductal adenocarcinoma.

Autor:	Thakkar A; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA.; Department of Pharmaceutical Sciences, College of Pharmacy, University of New England Portland, ME 04103, USA., Desai P; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA., Chenreddy S; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA., Modi J; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA., Thio A; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA., Khamas W; College of Veterinary Medicine, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA., Ann D; Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute City of Hope, Duarte, CA 91010, USA., Wang J; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA., Prabhu S; Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences 309 E. 2nd Street, Pomona, CA 91766, USA.
Jazyk:	angličtina
Zdroj:	American journal of cancer research [Am J Cancer Res] 2018 Oct 01; Vol. 8 (10), pp. 2005-2019. Date of Electronic Publication: 2018 Oct 01 (Print Publication: 2018).
Abstrakt:	The current work studied the chemopreventive efficacy of orally administered chitosan coated solid-lipid nanoparticle (c-SLN) encapsulated aspirin (ASP), curcumin (CUR) and free sulforaphane (SFN), ACS-cSLN, in the LSL-Kras G12D/ + ; Pdx-1 Cre/ + transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC). In vitro uptake study and intracellular localization of ODA-FITC labeled ASP and CUR c-SLNs were performed in Panc-1 and MIA PaCa-2 cells by fluorescence microscopy. LSL-Kras G12D/ + ; Pdx-1 Cre/ + transgenic mice (n = 30) were randomly divided into 5 groups. Treatment groups were orally gavaged with ACS c-SLNs in three doses: low (2 + 4.5 + 0.16 mg/kg), medium (20 + 45 + 1.6 mg/kg) and high (60 + 135 + 4.8 mg/kg), respectively. After 20 weeks of treatment, mice pancreas were harvested, stained with dye and scored according to various pancreatic intraepithelial neoplasms (PanIN) categories by an independent observer. In vitro , cellular uptake evaluated on Panc-1 and MIA PaCa-2 cells resulted in higher fluorescence intensities, indicating increased cellular uptake of ASP and CUR c-SLNs. For further evidence, the addition of lysoID (red fluorescence) demonstrated location and uptake of ASP and CUR c-SLNs into the lysosome. In vivo , treatment with ACS c-SLN for 20-weeks did not cause obvious adverse effects on growth and no statistically significant differences in body weight were observed between groups. However, the weight (mean ± SEM) of pancreas at the end of the study was higher in blank c-SLN group (223.6 ± 42.2 mg) compared to low (138.0 ± 26.0 mg; not significant [NS]), medium (145.0 ± 9.0 mg; NS), and high (133.8 ± 20.3 mg; NS) ACS c-SLN treated groups, demonstrating the efficacy of ACS c-SLN nanoformulations. The low, medium and high dose of ACS c-SLN combinations exhibited a reduction in tumor incidence (PanIN count) by 16.6% (P < 0.01), 66.8% (P < 0.01), and 83.4% (P < 0.01), respectively. These studies provide further proof for the use of an oral, low dose nanotechnology-based combinatorial regimen for the chemoprevention of PDAC. Competing Interests: None.
Databáze:	MEDLINE
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