Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2017; 23(23): 4200-4210
Published online Jun 21, 2017. doi: 10.3748/wjg.v23.i23.4200
Solid lipid nanoparticles delivering anti-inflammatory drugs to treat inflammatory bowel disease: Effects in an in vivo model
Chiara Dianzani, Federica Foglietta, Benedetta Ferrara, Arianna Carolina Rosa, Elisabetta Muntoni, Paolo Gasco, Carlo Della Pepa, Roberto Canaparo, Loredana Serpe
Chiara Dianzani, Federica Foglietta, Benedetta Ferrara, Arianna Carolina Rosa, Elisabetta Muntoni, Carlo Della Pepa, Roberto Canaparo, Loredana Serpe, Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy
Paolo Gasco, Nanovector s.r.l, 10144 Torino, Italy
Author contributions: Dianzani C, Foglietta F, Ferrara B and Rosa AC performed the in vitro and in vivo experiments; Muntoni E was responsible for animal handling and performed the in vivo disease activity evaluation; Gasco P synthesized and characterized the anti-inflammatory drug nanoformulation; Della Pepa C analyzed the data and contributed to the discussion; Canaparo R analyzed the data, contributed to the discussion and reviewed the manuscript; Serpe L designed the study, analyzed the data and wrote the manuscript. All the authors have read and approved the final manuscript.
Supported by Regione Piemonte (grant “Converging Technologies”, NanoIGT) and University of Torino (grant “Ricerca Locale”, Linea A).
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of the University of Torino (Torino, Italy).
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: The technical appendix, statistical code, and dataset are available from the corresponding author at email address loredana.serpe@unito.it.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Loredana Serpe, MD, PhD, Department of Drug Science and Technology, University of Torino, Via Pietro Giuria 13, 10125 Torino, Italy. loredana.serpe@unito.it
Telephone: +39-11-6706235 Fax: +39-11-6706230
Received: February 7, 2017
Peer-review started: February 10, 2017
First decision: March 21, 2017
Revised: April 3, 2017
Accepted: May 4, 2017
Article in press: May 4, 2017
Published online: June 21, 2017
Processing time: 142 Days and 6.9 Hours
Abstract
AIM

To improve anti-inflammatory activity while reducing drug doses, we developed a nanoformulation carrying dexamethasone and butyrate.

METHODS

Dexamethasone cholesteryl butyrate-solid lipid nanoparticles (DxCb-SLN) were obtained with the warm microemulsion method. The anti-inflammatory activity of this novel nanoformulation has been investigated in vitro (cell adhesion to human vascular endothelial cells and pro-inflammatory cytokine release by lipopolysaccharide-induced polymorphonuclear cells) and in vivo (disease activity index and cytokine plasma concentrations in a dextran sulfate sodium-induced mouse colitis) models. Each drug was also administered separately to compare its effects with those induced by their co-administration in SLN at the same concentrations.

RESULTS

DxCb-SLN at the lowest concentration tested (Dx 2.5 nmol/L and Cb 0.1 μmol/L) were able to exert a more than additive effect compared to the sum of the individual effects of each drug, inducing a significant in vitro inhibition of cell adhesion and a significant decrease of pro-inflammatory cytokine (IL-1β and TNF-α) in both in vitro and in vivo models. Notably, only the DxCb nanoformulation administration was able to achieve a significant cytokine decrease compared to the cytokine plasma concentration of the untreated mice with dextran sulfate sodium-induced colitis. Specifically, DxCb-SLN induced a IL-1β plasma concentration of 61.77% ± 3.19%, whereas Dx or Cb used separately induced a concentration of 90.0% ± 2.8% and 91.40% ± 7.5%, respectively; DxCb-SLN induced a TNF-α plasma concentration of 30.8% ± 8.9%, whereas Dx or Cb used separately induced ones of 99.5% ± 4.9% and 71.1% ± 10.9%, respectively.

CONCLUSION

Our results indicate that the co-administration of dexamethasone and butyrate by nanoparticles may be beneficial for inflammatory bowel disease treatment.

Keywords: Nanoparticles; Dexamethasone; Butyrate; Inflammatory bowel disease; Drug delivery systems

Core tip: The oral treatment with dexamethasone and butyrate co-loaded into nanoparticles was effective in achieving strong anti-inflammatory effects at doses significantly lower than those required for each single drug. This nanoformulation may open a new window on the treatment of chronic inflammatory conditions such as inflammatory bowel disease, where dose- and time-dependent side effects can limit the drug’s therapeutic usefulness. Notably, dexamethasone cholesteryl butyrate-solid lipid nanoparticles significantly relieved and repaired colon inflammation in a colitis mouse model thanks to the nanoformulation, which displayed an additive synergism among the corticosteroid, dexamethasone, and the short-chain fatty acid, butyrate.