Targeted drug delivery to intestinal macrophages by bioactive nanovesicles released from grapefruit.
The gut mucosal immune system is considered to play an important role in counteracting potential adverse effects of food-derived antigens including nanovesicles. Whether nanovesicles naturally released from edible fruit work in a coordinated manner with gut immune cells to maintain the gut in a noninflammatory status is not known. Here, as proof of concept, we demonstrate that grapefruit-derived nanovesicles (GDNs) are selectively taken up by intestinal macrophages and ameliorate dextran sulfate sodium (DSS)-induced mouse colitis. These effects were mediated by upregulating the expression of heme oxygenase-1 (HO-1) and inhibiting the production of IL-1β and TNF-α in intestinal macrophages. The inherent biocompatibility and biodegradability, stability at wide ranges of pH values, and targeting of intestinal macrophages led us to further develop a novel GDN-based oral delivery system. Incorporating methotrexate (MTX), an anti-inflammatory drug, into GDNs and delivering the MTX-GDNs to mice significantly lowered the MTX toxicity when compared with free MTX, and remarkably increased its therapeutic effects in DSS-induced mouse colitis. These findings demonstrate that GDNs can serve as immune modulators in the intestine, maintain intestinal macrophage homeostasis, and can be developed for oral delivery of small molecule drugs to attenuate inflammatory responses in human disease.
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA. Electronic address: B0wang06@louisville.edu.
Baomei
B
Wang
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Xiaoying
X
Zhuang
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Zhong-Bin
ZB
Deng
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Hong
H
Jiang
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Jingyao
J
Mu
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Qilong
Q
Wang
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Xiaoyu
X
Xiang
Department of Diagnostic Radiology, University of Louisville, Louisville, Kentucky, USA; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, USA.
Haixun
H
Guo
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Lifeng
L
Zhang
Department of Medicine, University of Louisville, Louisville, Kentucky, USA.
Gerald
G
Dryden
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Jun
J
Yan
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA.
Donald
D
Miller
James Brown Cancer Center, University of Louisville, Louisville, Kentucky, USA; Department of Microbiology & Immunology, University of Louisville, Louisville, Kentucky, USA; Louisville Veterans Administration Medical Center, Louisville, Kentucky, USA. Electronic address: H0Zhan17@louisville.edu.
Huang-Ge
HG
Zhang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D032083:Citrus paradisi / Q000737:chemistry*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy*; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology; D053583:Interleukin-1beta / Q000276:immunology; D007413:Intestinal Mucosa / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D049329:Nanostructures / Q000008:administration & dosage*; D010936:Plant Extracts / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D051547:Heme Oxygenase-1; D008727:Methotrexate