Macrophage-Biomimetic Nanoparticles Ameliorate Ulcerative Colitis through Reducing Inflammatory Factors Expression

Background and Aims: Inflammatory mediator S100A9 is dramatically elevated in ulcerative colitis and correlates with disease severity. S100A9 is a potential molecule to target for the treatment of colitis, but to date, there is no effective targeting method. The aim of this study was to develop a safe and effective nano-delivery system targeting S100A9 and to evaluate its therapeutic efficacy in ulcerative colitis mouse model. Methods: We designed an oral nano-delivery system using poly (lactic acid-glycolic acid) (PLGA)-loaded S100A9 inhibitor tasquinimod to synthesize PLGA-TAS nanoparticles. TLR4-overexpressing macrophage membranes (MMs) were used to wrap the nanoparticles to make MM-PLGA-TAS, which allowed the nanoparticles to acquire the ability to specifically enrich the colitis region. Results: MM-PLGA-TAS was endocytosed by inflammatory phenotype RAW264.7 cells in vitro and can efficiently enrich in inflamed mouse colitis tissue in vivo. A chemically induced ulcerative colitis mouse model was used to evaluate the therapeutic effect of oral MM-PLGA-TAS. MM-PLGA-TAS significantly alleviated the symptoms of ulcerative colitis, and mechanically, MM-PLGA-TAS achieved immunomodulatory and suppressive effects by reducing S100a9 and other cytokines in the colitis region. Conclusion: We describe a convenient, orally targeted colitis drug delivery system that cures the disease in ulcerative colitis mice. This system substantially increases drug accumulation in inflamed colonic tissue, reduces the risk of systemic exposure, and is a promising therapeutic approach against ulcerative colitis.

[1]  Wenjie Kong,et al.  Integrated analysis of DNA methylation and gene expression profiles identified S100A9 as a potential biomarker in ulcerative colitis , 2020, Bioscience reports.

[2]  Shaobing Zhou,et al.  A Biomimetic Polymer Magnetic Nanocarrier Polarizing Tumor-Associated Macrophages for Potentiating Immunotherapy. , 2020, Small.

[3]  J. Wan,et al.  Treatment of atherosclerosis by macrophage-biomimetic nanoparticles via targeted pharmacotherapy and sequestration of proinflammatory cytokines , 2020, Nature Communications.

[4]  S. Shen,et al.  Proinflammatory S100A8 Induces PD-L1 Expression in Macrophages, Mediating Tumor Immune Escape , 2020, The Journal of Immunology.

[5]  Wentao Dai,et al.  Route to Rheumatoid Arthritis by Macrophage-Derived Microvesicle-Coated Nanoparticles. , 2018, Nano letters.

[6]  Ronnie H. Fang,et al.  Neutrophil membrane-coated nanoparticles inhibit synovial inflammation and alleviate joint damage in inflammatory arthritis , 2018, Nature Nanotechnology.

[7]  Jian Ma,et al.  S100A8/A9 in Inflammation , 2018, Front. Immunol..

[8]  D. Merlin,et al.  Nanoparticle-Based Oral Drug Delivery Systems Targeting the Colon for Treatment of Ulcerative Colitis , 2018, Inflammatory bowel diseases.

[9]  J. White,et al.  Review article: novel oral‐targeted therapies in inflammatory bowel disease , 2018, Alimentary pharmacology & therapeutics.

[10]  S. Shen,et al.  Suppression Colitis and Colitis-Associated Colon Cancer by Anti-S100a9 Antibody in Mice , 2017, Front. Immunol..

[11]  J. Clemente,et al.  Interactions Between Diet and the Intestinal Microbiota Alter Intestinal Permeability and Colitis Severity in Mice. , 2017, Gastroenterology.

[12]  M. Neurath,et al.  Current and emerging therapeutic targets for IBD , 2017, Nature Reviews Gastroenterology & Hepatology.

[13]  Gui-yuan Li,et al.  Inflammation‐induced S100A8 activates Id3 and promotes colorectal tumorigenesis , 2015, International journal of cancer.

[14]  J. Choi,et al.  Interleukin-6 Induces S100A9 Expression in Colonic Epithelial Cells through STAT3 Activation in Experimental Ulcerative Colitis , 2012, PloS one.

[15]  Wei Wang,et al.  Dynamic activation of the key pathways: linking colitis to colorectal cancer in a mouse model. , 2012, Carcinogenesis.

[16]  L. Peyrin-Biroulet,et al.  Ulcerative colitis as a progressive disease: the forgotten evidence. , 2012, Inflammatory bowel diseases.

[17]  M. Cvancarova,et al.  Work disability in inflammatory bowel disease patients 10 years after disease onset: results from the IBSEN Study , 2012, Gut.

[18]  L. Peyrin-Biroulet,et al.  Review article: remission rates achievable by current therapies for inflammatory bowel disease , 2011, Alimentary pharmacology & therapeutics.

[19]  Didier Merlin,et al.  Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines. , 2010, Nature materials.

[20]  J. Schölmerich,et al.  Increased Response and Remission Rates in Short-Duration Crohn's Disease With Subcutaneous Certolizumab Pegol: An Analysis of PRECiSE 2 Randomized Maintenance Trial Data , 2010, The American Journal of Gastroenterology.

[21]  P. Lakatos,et al.  Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. , 2008, World journal of gastroenterology.

[22]  S. Hanauer,et al.  Treatment of inflammatory bowel disease: a review of medical therapy. , 2008, World journal of gastroenterology.

[23]  W. Nacken,et al.  Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock , 2007, Nature Medicine.

[24]  W. Chazin,et al.  The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis , 2006, Arthritis research & therapy.

[25]  S. Feng,et al.  A novel controlled release formulation for the anticancer drug paclitaxel (Taxol): PLGA nanoparticles containing vitamin E TPGS. , 2003, Journal of controlled release : official journal of the Controlled Release Society.

[26]  C. Bernstein.  Treatment of IBD: Where We Are and Where We Are Going , 2015, The American Journal of Gastroenterology.