Drug-loaded nanoparticles targeted to the colon with polysaccharide hydrogel reduce colitis in a mouse model.
OBJECTIVE
One of the challenges to treating inflammatory bowel disease (IBD) is to target the site of inflammation. We engineered nanoparticles (NPs) to deliver an anti-inflammatory tripeptide Lys-Pro-Val (KPV) to the colon and assessed its therapeutic efficacy in a mouse model of colitis.


METHODS
NPs were synthesized by double-emulsion/solvent evaporation. KPV was loaded into the NPs during the first emulsion of the synthesis process. To target KPV to the colon, loaded NPs (NP-KPV) were encapsulated into a polysaccharide gel containing 2 polymers: alginate and chitosan. The effect of KPV-loaded NPs on inflammatory parameters was determined in vitro as well as in the dextran sodium sulfate-induced colitis mouse model.


RESULTS
NPs (400 nm) did not affect cell viability or barrier functions. A swelling degree study showed that alginate-chitosan hydrogel containing dextran-fluorescein isothiocyanate-labeled NPs collapsed in the colon. Once delivered, NPs quickly released KPV on or within the closed area of colonocytes. The inflammatory responses to lipopolysaccharide were reduced in Caco2-BBE (brush border enterocyte) cells exposed to NP-KPV compared with those exposed to NPs alone, in a dose-dependent fashion. Mice given dextran sodium sulfate (DSS) followed by NP-KPV were protected against inflammatory and histologic parameters, compared with mice given only DSS.


CONCLUSIONS
Nanoparticles are a versatile drug delivery system that can overcome physiologic barriers and target anti-inflammatory agents such as the peptide KPV to inflamed areas. By using NPs, KPV can be delivered at a concentration that is 12,000-fold lower than that of KPV in free solution, but with similar therapeutic efficacy. Administration of encapsulated drug-loaded NPs is a novel therapeutic approach for IBD.
Laroui
Hamed
H
Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia 30322, USA.
Dalmasso
Guillaume
G
Nguyen
Hang Thi Thu
HT
Yan
Yutao
Y
Sitaraman
Shanthi V
SV
Merlin
Didier
D
D000284:Administration, Oral; D000464:Alginates / Q000737:chemistry; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D048271:Chitosan / Q000737:chemistry; D003092:Colitis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004339:Drug Compounding; D005260:Female; D005765:Gastrointestinal Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D020723:Glucuronic Acid / Q000737:chemistry; D006603:Hexuronic Acids / Q000737:chemistry; D006801:Humans; D020100:Hydrogels; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry*; D012995:Solubility; D013997:Time Factors
D000464:Alginates; D000893:Anti-Inflammatory Agents; D004337:Drug Carriers; D005765:Gastrointestinal Agents; D006603:Hexuronic Acids; D020100:Hydrogels; D010446:Peptide Fragments; D011134:Polysaccharides; C043156:MSH (11-13); D020723:Glucuronic Acid; D009074:Melanocyte-Stimulating Hormones; D048271:Chitosan; D016264:Dextran Sulfate