Energy-Dependent Endocytosis is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine

Significance 

Indomethacin is a non-steroidal anti-inflammatory drug (NSAID) that is widely prescribed for the treatment of pain and inflammation. However, the prolonged use of NSAIDs inhibits the synthesis of prostaglandin, reduces mucus secretion in the small intestine, allows the invasion of intestinal bacteria, and triggers the onset of inflammation. This results in the severe injury of the small intestine. The side effects of NSAIDs may be prevented by increasing the absorption of the drug.

Recent advancements in formulation technology have enabled scientists to develop prodrugs that can be used to reduce the side effects of indomethacin. Moreover, the advent of nanotechnology has enabled researchers to develop nanoparticle drug formulations with improved cellular uptake, blood circulation times and therapeutic effectiveness.

Although previous research studies have indicated that nanoparticle formulations containing indomethacin can be used to reduce the side effects of indomethacin in rats, there is a paucity of information on the mechanism used for the transport of drug particles via the small intestine. Hence, there is a need to carry out research studies to investigate the pathway for the trans-intestinal penetration of nanoparticle formulations containing indomethacin. Recent studies have indicated that the process of energy-dependent endocytosis is associated with the transport pathways of drug nanoparticles. These pathways are mainly classified as phagocytosis, clathrin-dependent endocytosis, caveolae-dependent endocytosis, and macropinocytosis. Thus, this study aimed to investigate and explain the association between these pathways and the uptake of nanoparticle formulations containing indomethacin.

In a recent research work published in International Journal of Molecular Sciences Dr. Noriaki Nagai and colleagues at Kindai University demonstrated that energy-dependent endocytosis pathways are associated with the uptake of nanoparticle formulations containing indomethacin (IND-NPs). The authors elucidated the mechanism of the transintestinal penetration of indomethacin nanoparticles via an in vitro permeation test using human epithelial colorectal adenocarcinoma (Caco-2) cell line monolayers, and an ex vivo study using excised rat jejunum and ileum. Miyu Ishii, Yuya Fukuoka, Saori Deguchi, Hiroko Otake, Tadatoshi Tanino also contributed to the research.

The research team observed that the treatment of the cell line monolayers and rat intestine tissue with four different inhibitors caused different changes in the transintestinal penetration and accumulation of indomethacin nanoparticles. They observed that nystatin prevented the penetration and accumulation of indomethacin nanoparticles in Caco-2 cell line monolayers, as well as the jejunum of the rat intestine. Whereas, co-treatment with nystatin and dynasore strongly inhibited transintestinal penetration and accumulation of indomethacin nanoparticles in Caco-2 cell line monolayers, as well as the ileum of the rat.

The findings provide compelling evidence that indomethacin nanoparticles can be taken up into the intestinal epithelial cell by endocytosis. The authors reported that both clathrin-dependent endocytosis and caveolae-dependent endocytosis are the pathways required for the uptake of indomethacin nanoparticles in the ileum while clathrin-dependent endocytosis is the only pathway required for the uptake of indomethacin nanoparticles in the jejunum. These novel findings will advance further studies on the drug delivery pathways for oral nanomedicines.

Energy-Dependent Endocytosis Is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine - Medicine Innovates

About the author

Noriaki Nagai obtained PhD degree from Gifu Pharmaceutical University at 2009. Currently, he is a principal scientist in Laboratory of Advanced Design for Pharmaceuticals, Faculty of Pharmacy, Kindai University (Osaka, Japan). His main areas of interests are design of novel solid nanomedicine, and nano drug delivery systems with enhanced performance. He has approximately 120 publications in discipline-specific high impact factor journals and several presentations in local and international conferences. He also has won several awards locally and internationally for excellence in research.

Reference

Ishii, M., Fukuoka, Y., Deguchi, S., Otake, H., Tanino, T. and Nagai, N. Energy-Dependent Endocytosis Is Involved in the Absorption of Indomethacin Nanoparticles in the Small Intestine, International Journal of Molecular Sciences 20, 476 (2019).

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