Elsevier

Biomaterials

Volume 34, Issue 33, November 2013, Pages 8393-8400
Biomaterials

Suppression of NSAID-induced small intestinal inflammation by orally administered redox nanoparticles

https://doi.org/10.1016/j.biomaterials.2013.06.032Get rights and content

Abstract

Patients regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (IND) have a risk of small intestinal injuries. In this study, we have developed an oral nanotherapeutics by using a redox nanoparticle (RNPO), which is prepared by self-assembly of an amphiphilic block copolymer that possesses nitroxide radicals as side chains of hydrophobic segment via ether linkage, to reduce inflammation in mice with IND-induced small intestinal injury. The localization and accumulation of RNPO in the small intestine were determined using fluorescent-labeled RNPO and electron spin resonance. After oral administration, the accumulation of RNPO in both the jejunum and ileum tissues was about 40 times higher than those of low-molecular-weight nitroxide radical compounds, and RNPO was not absorbed into the bloodstream via the mesentery, thereby avoiding the adverse effects of nitroxide radicals in the entire body. RNPO remarkably suppressed inflammatory mediators such as myeloperoxidase, superoxide anion, and malondialdehyde in the small intestines of IND-treated mice. Compared to low-molecular-weight nitroxide radical compounds, RNPO also significantly increased the survival rate of mice treated daily with IND. On the basis of these results, RNPO is promising as a nanotherapeutics for treatment of inflammation in the small intestine of patients receiving NSAIDs.

Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin (IND) are the most commonly prescribed drugs for their antipyretic, analgesic, and anti-inflammatory effects. The total consumption of NSAIDs is increasing in accordance with the increase in the incidence of orthopedic and cardiovascular diseases [1], [2], [3]. However, it has been reported that the use of NSAIDs causes severe adverse effects including ulcers, erosions, bleeding, perforation, and strictures in the gastrointestinal (GI) tract such as stomach and small intestine [4], [5], [6], [7], [8], [9]. The absolute number of patients with serious NSAIDs-induced GI complications is increasing due to the expansion of long-term NSAIDs treatment. Though the etiology and pathogenesis of NSAIDs-induced inflammation are not well understood [10], several studies have reported that overproduction of reactive oxygen species (ROS) and an imbalance of important antioxidants exist in the intestine of patients receiving repeated doses of NSAIDs, leading to oxidative damage [8], [11], [12], [13], [14]. Self-sustaining cycles of oxidant production may amplify inflammation and mucosal injury. Thus far, it has been reported that antioxidant compounds and free radical scavengers heal NSAIDs-induced inflammation [15], [16]. However, orally administered low-molecular-weight (LMW) compounds are not sufficiently effective due to their non-specific distribution to the entire body, metabolism in the GI tract, low retention in the lesion area, and undesired adverse effects.

To address these issues, we have developed a newly designed oral nanotherapeutic using redox nanoparticles (RNPO) with ROS scavenging potential of nitroxide radicals for treatment of inflammation in the GI tract. RNPO is a core-shell-type polymeric micelle with approximately 40 nm in diameter, prepared by the self-assembly of methoxy-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-1-oxyl)oxymethylstyrene] (MeO-PEG-b-PMOT), which is an amphiphilic block copolymer possessing nitroxide radicals as side chains of hydrophobic segment via ether linkages (Fig. 1a). Thus far, we have found that orally administered RNPO specifically accumulates in the colonic mucosa and effectively suppresses inflammation in mice with colitis [17]. In addition, we have previously confirmed that, as RNPO is not absorbed into the bloodstream via the mesentery, it does not cause the adverse effects of nitroxide radicals in the entire body [17].

The objective of this work was to confirm the protective effect of RNPO on IND-induced small intestinal inflammation in mice. The accumulation tendency of orally administered RNPO and the suppression of ROS and inflammation in the small intestine by RNPO were investigated in detail (Fig. 1b).

Section snippets

Preparation of RNPO

RNPO was prepared by the self-assembly of an amphiphilic block copolymer (MeO-PEG-b-PMOT) composed of the hydrophilic PEG segment and the hydrophobic poly(4-methylstyrene) segment possessing nitroxide radicals as side chains via ether linkages, according to our previous study [18]. Briefly, poly(ethylene glycol)-b-poly(chloromethylstyrene) (MeO-PEG-b-PCMS) was synthesized by the radical telomerization of chloromethylstyrene using MeO-PEG-SH (Mn = 5000; NOF corporation, Tokyo, Japan) as a

The specific accumulation of RNPO in small intestine

The accumulation of nanoparticles in the small intestine is one of the most important features for effective nanotherapeutics against small intestinal injury. We have previously confirmed that a fairly large amount of RNPO (ca. 15% of injected dose) accumulated in the colonic mucosa by oral administration. In order to confirm the effect of RNPO on NSAID-induced injury, we examined the localization of RNPO in the small intestine using fluorescent rhodamine-labeled RNPO. When LMW rhodamine was

Conclusions

This study demonstrates the protective effect of orally administered RNPO on IND-induced small intestinal inflammation in mice. Compared to LMW nitroxide radical compounds, RNPO showed remarkable accumulation and long retention in the jejunum and ileum, especially in the mucosa layer, resulting in effective scavenging of ROS and suppression of inflammation in the small intestines of IND-treated mice. On the basis of these results, we believe that the oral administration of RNPO, prior to the

Acknowledgment

A portion of this work was supported by a Grant-in-Aid for Scientific Research A (No. 21240050) and the World Premier International Research Center Initiative (WPI Initiative) on Materials Nanoarchitronics of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.

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