Abstract
We previously reported that oral formulations containing indomethacin nanoparticles (IND-NPs) showed high bioavailability, and, consequently, improved therapeutic effects and reduced injury to the small intestine. However, the pathway for the transintestinal penetration of nanoparticles remained unclear. Thus, in this study, we investigated whether endocytosis was related to the penetration of IND-NPs (72.1 nm) using a transcell set with Caco-2 cells or rat intestine. Four inhibitors of various endocytosis pathways were used [nystatin, caveolae-dependent endocytosis (CavME); dynasore, clathrin-dependent endocytosis (CME); rottlerin, macropinocytosis; and cytochalasin D, phagocytosis inhibitor], and all energy-dependent endocytosis was inhibited at temperatures under 4 °C in this study. Although IND-NPs showed high transintestinal penetration, no particles were detected in the basolateral side. IND-NPs penetration was strongly prevented at temperatures under 4 °C. In experiments using pharmacological inhibitors, only CME inhibited penetration in the jejunum, while in the ileum, both CavME and CME significantly attenuated penetration. In conclusion, we found a novel pathway for the transintestinal penetration of drug nanoparticles. Our hypothesis was that nanoparticles would be taken up into the intestinal epithelium by endocytosis (CME in jejunum, CavME and CME in ileum), and dissolved and diffused in the intestine. Our findings are likely to be of significant use for the development of nanomedicines.
Highlights
[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl] acetic acid, indomethacin, is a non-steroidal anti-inflammatory drug (NSAID), one of the most widely prescribed groups of drugs for the treatment of inflammation and pain
The atomic force microscope (AFM) imaging showed the indomethacin after bead mill treatment to be in the nano-order (Figure 1D) with a mean particle size in the indomethacin nanoparticles (IND-NPs) of 72.1 ± 4.3 nm (Figure 1C)
In these formulations, the indomethacin consisted of two types, and it was important to investigate the ratio of solution/solid type in the IND-NPs
Summary
[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl] acetic acid, indomethacin, is a non-steroidal anti-inflammatory drug (NSAID), one of the most widely prescribed groups of drugs for the treatment of inflammation and pain. The long-term use of NSAIDs is well-known to cause severe ulceration and inflammation of the small intestine [1] Many factors, such as nitric oxide (NO), prostaglandin (PG), and intestinal bacteria, are known to be involved in the mechanisms of NSAID-induced small-intestinal injury [2,3,4,5]. These gases induce neutrophil activation and thereby COX-2 induction, as well as the production of inflammatory cytokines and mediators, which results in the onset of inflammation in the small intestine [7]. We investigated whether the uptake of IND-NPs was related to these trafficking pathways to elucidate the mechanism of transintestinal penetration in the oral administration of drug nanoparticles
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