title: Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins.
abstract: Recently, we reported a pH-responsive nanoparticle (NP) system shelled with chitosan (CS), which could effectively increase the oral absorption of insulin and produce a hypoglycemic effect, presumably due to the CS-mediated tight junction (TJ) opening. It has been often questioned whether CS can also enhance the absorption of endotoxins present in the small intestine. To address this concern, we studied the effect of CS NPs on the absorption of lipopolysaccharide (LPS), the most commonly found toxin in the gastrointestinal tract. To follow their biodistribution by the single-photon emission computed tomography/computed tomography, LPS and insulin were labeled with (99m)Tc-pertechnetate ((99m)Tc-LPS) and (123)iodine ((123)I-insulin), respectively. The (99m)Tc-LPS was ingested 1 h prior to the administration of the (123)I-insulin-loaded NPs to mimic the physiological conditions. The confocal and TEM micrographs show that the orally administered CS NPs were able to adhere and infiltrate through the mucus layer, approach the epithelial cells and mediate to open their TJs. The radioactivity associated with LPS was mainly restricted to the gastrointestinal tract, whereas (123)I-insulin started to appear in the urinary bladder at 3 h post administration. This observation indicates that the insulin-loaded in CS NPs can traverse across the intestinal epithelium and enter the systemic circulation, whereas LPS was unable to do so, probably because of the charge repulsion between the anionic LPS in the form of micelles and the negatively charged mucus layer. Our in vivo toxicity study further confirms that the enhancement of paracellular permeation by CS NPs did not promote the absorption of LPS. These results suggest that CS NPs can be used as a safe carrier for oral delivery of protein drugs.
authors.affiliation: Department of Chemical Engineering, National Tsing Hua University, Hsinchu 30013, Taiwan, ROC.
authors.forename: Kiran
authors.initials: K
authors.lastname: Sonaje
authors.forename: Kun-Ju
authors.initials: KJ
authors.lastname: Lin
authors.forename: Michael T
authors.initials: MT
authors.lastname: Tseng
authors.forename: Shiaw-Pyng
authors.initials: SP
authors.lastname: Wey
authors.forename: Fang-Yi
authors.initials: FY
authors.lastname: Su
authors.forename: Er-Yuan
authors.initials: EY
authors.lastname: Chuang
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Hsu
authors.forename: Chiung-Tong
authors.initials: CT
authors.lastname: Chen
authors.forename: Hsing-Wen
authors.initials: HW
authors.lastname: Sung
mesh_terms: D000284:Administration, Oral; D000818:Animals; D048271:Chitosan; D004731:Endotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D008823:Micelles; D053758:Nanoparticles; D051381:Rats; D017208:Rats, Wistar; D019108:Tight Junctions; D014018:Tissue Distribution
chemical_list: D004731:Endotoxins; D008823:Micelles; D048271:Chitosan