Drug-Loaded Nanoparticles Targeted to the Colon With Polysaccharide Hydrogel Reduce Colitis in a Mouse Model

被引:202
作者
Laroui, Hamed [1 ]
Dalmasso, Guillaume [1 ]
Nguyen, Hang Thi Thu [1 ]
Yan, Yutao [1 ]
Sitaraman, Shanthi V. [1 ]
Merlin, Didier [1 ]
机构
[1] Emory Univ, Dept Med, Div Digest Dis, Atlanta, GA 30322 USA
基金
美国国家卫生研究院;
关键词
Colon Targeting; Colitis; KPV-Loaded Nanoparticle; Polysaccharide Hydrogel; INFLAMMATORY-BOWEL-DISEASE; 5-AMINOSALICYLIC ACID; ULCERATIVE-COLITIS; IN-VITRO; DELIVERY; CHITOSAN; PH; CYTOTOXICITY; CAPSULES; THERAPY;
D O I
10.1053/j.gastro.2009.11.003
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
BACKGROUND & AIMS: 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.
引用
收藏
页码:843 / U77
页数:13
相关论文
共 38 条
  • [1] Crosslinked chitosan implants as potential degradable devices for brachytherapy: In vitro and in vivo analysis
    Azab, AK
    Orkin, B
    Doviner, V
    Nissan, A
    Klein, M
    Srebnik, M
    Rubinstein, A
    [J]. JOURNAL OF CONTROLLED RELEASE, 2006, 111 (03) : 281 - 289
  • [2] Food intake, water intake, and drinking spout side preference of 28 mouse strains
    Bachmanov, AA
    Reed, DR
    Beauchamp, GD
    Tordoff, MG
    [J]. BEHAVIOR GENETICS, 2002, 32 (06) : 435 - 443
  • [3] Adverse effects of nonsteroidal anti-inflammatory drugs on the colon
    Ballinger A.
    [J]. Current Gastroenterology Reports, 2008, 10 (5) : 485 - 489
  • [4] Bioadhesive properties of poly(alkylcyanoacrylate) nanoparticles coated with polysaccharide
    Bertholon, Isabelle
    Ponchel, Gilles
    Labarre, Denis
    Couvreur, Patrick
    Vauthier, Christine
    [J]. JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY, 2006, 6 (9-10) : 3102 - 3109
  • [5] α-melanocyte-stimulating hormone and related tripeptides:: Biochemistry, antiinflammatory and protective effects in vitro and in vivo, and future perspectives for the treatment of immune-mediated inflammatory diseases
    Brzoska, Thomas
    Luger, Thomas A.
    Maaser, Christian
    Abels, Christoph
    Boehm, Markus
    [J]. ENDOCRINE REVIEWS, 2008, 29 (05) : 581 - 602
  • [6] HYALURONAN AND WOUND-HEALING - A NEW PERSPECTIVE
    BURD, DAR
    GRECO, RM
    REGAUER, S
    LONGAKER, MT
    SIEBERT, JW
    GARG, HG
    [J]. BRITISH JOURNAL OF PLASTIC SURGERY, 1991, 44 (08): : 579 - 584
  • [7] ADAM-15 inhibits wound healing in human intestinal epithelial cell monolayers
    Charrier, L
    Yan, YT
    Driss, A
    Laboisse, CL
    Sitaraman, SV
    Merlin, D
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2005, 288 (02): : G346 - G353
  • [8] THE EFFECT OF CAPSULE COMPOSITION ON THE BIOCOMPATIBILITY OF ALGINATE-POLY-L-LYSINE CAPSULES
    CLAYTON, HA
    LONDON, NJM
    COLLOBY, PS
    BELL, PRF
    JAMES, RFL
    [J]. JOURNAL OF MICROENCAPSULATION, 1991, 8 (02) : 221 - 233
  • [9] PepT1-mediated tripeptide KPV uptake reduces intestinal inflammation
    Dalmasso, Guillaume
    Charrier-Hisamuddin, Laetitia
    Nguyen, Hang Thi Thu
    Yan, Yutao
    Sitaraman, Shanthi
    Merlin, Didier
    [J]. GASTROENTEROLOGY, 2008, 134 (01) : 166 - 178
  • [10] Poly(lactide)-vitamin E derivative/montmorillonite nanoparticle formulations for the oral delivery of Docetaxel
    Feng, Si-Shen
    Mei, Lin
    Anitha, Panneerselvan
    Gan, Chee Wee
    Zhou, Wenyou
    [J]. BIOMATERIALS, 2009, 30 (19) : 3297 - 3306