Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins

Kiran Sonaje, Kun Ju Lin, Michael T. Tseng, Shiaw Pyng Wey, Fang Yi Su, Er-Tuan Chuang, Chia Wei Hsu, Chiung Tong Chen, Hsing Wen Sung

Research output: Contribution to journalArticle

77 Citations (Scopus)

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 99mTc-pertechnetate ( 99mTc-LPS) and 123iodine ( 123I-insulin), respectively. The 99mTc-LPS was ingested 1 h prior to the administration of the 123I-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 123I-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.

Original languageEnglish
Pages (from-to)8712-8721
Number of pages10
JournalBiomaterials
Volume32
Issue number33
DOIs
Publication statusPublished - Nov 2011
Externally publishedYes

Fingerprint

Tight Junctions
Chitosan
Endotoxins
Nanoparticles
Lipopolysaccharides
Insulin
Mucus
Gastrointestinal Tract
Single photon emission computed tomography
Sodium Pertechnetate Tc 99m
Radioactivity
Micelles
Intestinal Mucosa
Hypoglycemic Agents
Permeation
Small Intestine
Tomography
Toxicity
Urinary Bladder
Epithelial Cells

Keywords

  • Chitosan
  • Endotoxin
  • Insulin
  • Paracellular transport
  • Tight junction

ASJC Scopus subject areas

  • Biomaterials
  • Bioengineering
  • Ceramics and Composites
  • Mechanics of Materials
  • Biophysics

Cite this

Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins. / Sonaje, Kiran; Lin, Kun Ju; Tseng, Michael T.; Wey, Shiaw Pyng; Su, Fang Yi; Chuang, Er-Tuan; Hsu, Chia Wei; Chen, Chiung Tong; Sung, Hsing Wen.

In: Biomaterials, Vol. 32, No. 33, 11.2011, p. 8712-8721.

Research output: Contribution to journalArticle

Sonaje, K, Lin, KJ, Tseng, MT, Wey, SP, Su, FY, Chuang, E-T, Hsu, CW, Chen, CT & Sung, HW 2011, 'Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins', Biomaterials, vol. 32, no. 33, pp. 8712-8721. https://doi.org/10.1016/j.biomaterials.2011.07.086
Sonaje, Kiran ; Lin, Kun Ju ; Tseng, Michael T. ; Wey, Shiaw Pyng ; Su, Fang Yi ; Chuang, Er-Tuan ; Hsu, Chia Wei ; Chen, Chiung Tong ; Sung, Hsing Wen. / Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins. In: Biomaterials. 2011 ; Vol. 32, No. 33. pp. 8712-8721.
@article{71b284006cf04c6481e939474e77da69,
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 99mTc-pertechnetate ( 99mTc-LPS) and 123iodine ( 123I-insulin), respectively. The 99mTc-LPS was ingested 1 h prior to the administration of the 123I-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 123I-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.",
keywords = "Chitosan, Endotoxin, Insulin, Paracellular transport, Tight junction",
author = "Kiran Sonaje and Lin, {Kun Ju} and Tseng, {Michael T.} and Wey, {Shiaw Pyng} and Su, {Fang Yi} and Er-Tuan Chuang and Hsu, {Chia Wei} and Chen, {Chiung Tong} and Sung, {Hsing Wen}",
year = "2011",
month = "11",
doi = "10.1016/j.biomaterials.2011.07.086",
language = "English",
volume = "32",
pages = "8712--8721",
journal = "Biomaterials",
issn = "0142-9612",
publisher = "Elsevier Science Ltd",
number = "33",

}

TY - JOUR

T1 - Effects of chitosan-nanoparticle-mediated tight junction opening on the oral absorption of endotoxins

AU - Sonaje, Kiran

AU - Lin, Kun Ju

AU - Tseng, Michael T.

AU - Wey, Shiaw Pyng

AU - Su, Fang Yi

AU - Chuang, Er-Tuan

AU - Hsu, Chia Wei

AU - Chen, Chiung Tong

AU - Sung, Hsing Wen

PY - 2011/11

Y1 - 2011/11

N2 - 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 99mTc-pertechnetate ( 99mTc-LPS) and 123iodine ( 123I-insulin), respectively. The 99mTc-LPS was ingested 1 h prior to the administration of the 123I-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 123I-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.

AB - 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 99mTc-pertechnetate ( 99mTc-LPS) and 123iodine ( 123I-insulin), respectively. The 99mTc-LPS was ingested 1 h prior to the administration of the 123I-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 123I-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.

KW - Chitosan

KW - Endotoxin

KW - Insulin

KW - Paracellular transport

KW - Tight junction

UR - http://www.scopus.com/inward/record.url?scp=80052966755&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052966755&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2011.07.086

DO - 10.1016/j.biomaterials.2011.07.086

M3 - Article

C2 - 21862121

AN - SCOPUS:80052966755

VL - 32

SP - 8712

EP - 8721

JO - Biomaterials

JF - Biomaterials

SN - 0142-9612

IS - 33

ER -