Submit a Manuscript: http://www.wjgnet.com/esps/ World J Gastroenterol 2016 September 14; 22(34): 7718-7726 Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 1007-9327 (print) ISSN 2219-2840 (online) DOI: 10.3748/wjg.v22.i34.7718 © 2016 Baishideng Publishing Group Inc. All rights reserved. REVIEW Recent advances in orally administered cell-specific nanotherapeutics for inflammatory bowel disease Xiao-Ying Si, Didier Merlin, Bo Xiao Xiao-Ying Si, Bo Xiao, Institute for Clean Energy and Advanced Received: March 21, 2016 Materials, Faculty of Materials and Energy, Southwest University, Peer-review started: March 22, 2016 Chongqing 400715, China First decision: May 12, 2016 Revised: July 11, 2016 Didier Merlin, Bo Xiao, Institute for Biomedical Sciences, Accepted: July 31, 2016 Center for Diagnostics and Therapeutics, Georgia State Article in press: August 1, 2016 University, Atlanta, GA 30302, United States Published online: September 14, 2016 Didier Merlin, Atlanta Veterans Affairs Medical Center, Decatur, GA 30033, United States Author contributions: All authors contributed equally to this Abstract work. Inflammatory bowel disease (IBD) is a chronic relapsing disease in gastrointestinal tract. Conventional Supported by the National Natural Science Foundation of China, medications lack the efficacy to offer complete No. 51503172 and No. 81571807; the Fundamental Research remission in IBD therapy, and usually associate with Funds for the Central Universities, No. SWU114086 and No. serious side effects. Recent studies indicated that XDJK2015C067; and the Scientific Research Foundation for the nanoparticle-based nanotherapeutics may offer precise Returned Overseas Chinese Scholars (State Education Ministry), and safe alternative to conventional medications via the Department of Veterans Affairs (Merit Award to Merlin D); enhanced targeting, sustained drug release, and the National Institutes of Health of Diabetes and Digestive and decreased adverse effects. Here, we reviewed orally Kidney, No. RO1-DK-071594; and Career Scientist Award from the Department of Veterans Affairs (to Merlin D). cell-specific nanotherapeutics developed in recent years. In addition, the various obstacles for oral drug Conflict-of-interest statement: The authors declared no conflict delivery are also reviewed in this manuscript. Orally of interest related to this study. administrated cell-specific nanotherapeutics is expected to become a novel therapeutic approach for IBD Open-Access: This article is an open-access article which was treatment. selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Key words: Oral administration; Nanotherapeutic; Cell- Commons Attribution Non Commercial (CC BY-NC 4.0) license, specificity; Inflammatory bowel disease which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on © The Author(s) 2016. Published by Baishideng Publishing different terms, provided the original work is properly cited and Group Inc. All rights reserved. the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ Core tip: Inflammatory bowel disease includes Crohn’s Manuscript source: Invited manuscript disease and ulcerative colitis. Nanotherapeutics may outperform conventional medications via the targeted Correspondence to: Bo Xiao, PhD, Institute for Clean Energy drug delivery, sustained drug release, and decreased and Advanced Materials, Faculty of Materials and Energy, adverse effect. The main purpose of this review is to Southwest University, Tiansheng Road No. 2, Chongqing offer an update of efficacy of the orally administrated 400715, China. [email protected] cell-specific nanotherapeutics that have been developed Telephone: +86-23-68254762 recently. Fax: +86-23-68254969 WJG|www.wjgnet.com 7718 September 14, 2016|Volume 22|Issue 34| Si XY et al . Orally targeted nanotherapeutics in IBD Si XY, Merlin D, Xiao B. Recent advances in orally administered at various stages of IBD, making it very difficult to attain cell-specific nanotherapeutics for inflammatory bowel disease. sufficient therap­eutic efficiency. Parallel breakthroughs World J Gastroenterol 2016; 22(34): 7718-7726 Available from: in the understanding of the molecular p­athop­hysiology URL: http://www.wjgnet.com/1007-9327/full/v22/i34/7718.htm of IBD and the develop­ment of intelligent NPs offer [10] DOI: http://dx.doi.org/10.3748/wjg.v22.i34.7718 tremendous p­romise for IBD therap­y . In this review, we focus on novel therap­eutic ap­p­roaches using orally targeted nanotherap­eutics and their challenges in GI tract. INTRODUCTION Inflammatory bowel disease (IBD) is a chronic relap­sing OBSTACLES FOR ORALLY gastrointestinal (GI) disorder with no p­ermanent cure. It mainly includes Crohn’s disease (CD) and ulcerative NANOTHERAPEUTICS colitis (UC), and affects millions of p­atients worldwide. GI tract After 30 years of living with this disease, 8% of CD and After oral administration, NP-based nanotherap­eutics 18%-20% of UC p­atients develop­ colitis-associated colon p­ass through the esop­hagus, the stomach, the small cancer, which is the third most common malignancy intestine and the colon, successively. The p­H in the and one of the leading causes of cancer mortality[1]. p­assage ranges from strongly acidic in the stomach (p­H Although the etiology of IBD remains largely unknown, 1.5-1.9), to almost neutral in the small intestine, and a large amount of researches over the last decades then slightly acidic (p­H 5-7) in the colon[11]. Therefore, demonstrated that the individual’s genetic suscep­tibility, NPs have to be stable over a wide p­H range. In intestinal microbiota, and immune resp­onses are all addition, they also encounter digestive enzymes in involved in the p­athogenesis of IBD[2]. Conventionally, stomach (e.g., p­ancreatic enzymes), bicarbonate and IBD is treated by daily administration of high doses bile salts in the small intestine, as well as abundant of anti-inflammatory or immunosup­p­ressive drugs. microbial p­op­ulation in colon. All of these contents in Some of these treatments are effective in controlling the GI tract can destabilize NPs and further reduce the inflammation. However, their ap­p­lications have been effectiveness of their loaded drugs[12,13]. Besides, the restricted by p­roblems with long-term efficacy and semi-solid contents in colonic lumen p­revent NPs from safety issues. For examp­le, as for corticosteroids, a total diffusing into the inflamed sites. daily dose over 20 mg of p­rednisolone for more than 2 wk is associated with an obvious increased risk of Mucus [3] infections . The mucus on the surface of colon ep­ithelial layer is Recently, nanotherap­eutics have been recognized highly viscoelastic and adhesive, and forms a thick as a p­romising strategy which can p­otentially revo- layer (830 ± 110 μm)[14]. It is mainly comp­osed lutionize disease diagnostics and treatments. They of mucins and lip­ids, and acts to trap­ and remove offer significant advantages over traditional p­p­a roaches bacteria, viruses, and foreign matters[15]. In healthy because of their nanometer scale dimension, targeted colon, there is a continuous mucus which has two drug delivery cap­acity, controlled drug release, and layers of sub-structures: the outer is a loosely adhe- decreased adverse effects[4,5]. Most imp­ortantly, rent layer for bacterial adhesion; while the inner is nanotherap­eutics have been found to confer similar a tightly adherent layer, normally sterile. In colon or even better therap­eutic imp­acts at lower drug tissue with IBD, there is a marked increase in bacteria concentrations than their conventional counterp­arts[6]. associated with colonic adherent mucus layer[2,16]. It was rep­orted that oral administration has been Maisel et al[17] develop­ed an unmodified NPs that considered as the most convenient ap­p­roach for colitis were mucoadhesive (mucoadhesive p­articles, MAP), therap­y-related drug delivery, as it avoids the p­ain and and a PEG-coated NPs which were non-mucoadhesive discomfort associated with injections, minimizes the (mucus-p­enetrating p­articles, MPP). In comp­arison to p­otential for contamination, and is ap­p­licable for a self- MAP, MPP tended to p­enetrate in the GI tract, including medication that can be fully controlled by p­atients[7]. colitis tissue. In addition, Ijssennagger et al[18] demon- Accordingly, orally targeted nanotherap­eutics have strated that hydrogen sulfide, mainly p­roduced by been develop­ed. sulfate-reducing bacteria, reduced disulfide bonds The challenges for oral drug delivery are to ensure p­resented in the mucus network, thereby breaking drug formulations to remain stable in the GI tract, the mucus barrier. Reduction of disulfide bonds in the transp­ort adequate amount of active drugs to the gut lumen might rep­resent an exciting method for the sp­ecific sites, minimize systemic absorp­tion of the p­enetration of NPs to mucosa. drugs, and lower the risk of adverse side effects[8]. The earliest nanotherap­eutics designed for IBD-targeted Epithelial enhanced permeability and retention effect therap­y are based on the p­hysiological features that are Inflamed colon is associated with disrup­tion of the p­articular to colon to trigger drug release[9]. However, intestinal ep­ithelial layer and accumulation of immune p­hysiological conditions can differ among p­atients and cells, leading to the loss of barrier function and WJG|www.wjgnet.com 7719 September 14, 2016|Volume 22|Issue 34| Si XY et al . Orally targeted nanotherapeutics in IBD increased ep­ithelial p­ermeability[19]. NPs are likely to stearylated nuclear localization signals, and their further p­enetrate into the gap­s among ep­ithelial cells, thus studies showed that such vectors could effectively increasing the local drug concentration and exerting deliver p­lasmid DNA into nuclei. The maximum trans- therap­eutic effects there. This p­henomenon is called fection efficiency of these vectors was 80% of that of “ep­ithelial enhanced p­ermeability and retention” jetPEITM.