Oral drug delivery with polymeric nanoparticles: The gastrointestinal mucus barriers

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Abstract

Oral delivery is the most common method for drug administration. However, poor solubility, stability, and bioavailability of many drugs make achieving therapeutic levels via the gastrointestinal (GI) tract challenging. Drug delivery must overcome numerous hurdles, including the acidic gastric environment and the continuous secretion of mucus that protects the GI tract. Nanoparticle drug carriers that can shield drugs from degradation and deliver them to intended sites within the GI tract may enable more efficient and sustained drug delivery. However, the rapid secretion and shedding of GI tract mucus can significantly limit the effectiveness of nanoparticle drug delivery systems. Many types of nanoparticles are efficiently trapped in and rapidly removed by mucus, making controlled release in the GI tract difficult. This review addresses the protective barrier properties of mucus secretions, how mucus affects the fate of orally administered nanoparticles, and recent developments in nanoparticles engineered to penetrate the mucus barrier.

Introduction

Oral delivery is the most widely used and most readily accepted form of drug administration. The human intestinal epithelium is highly absorptive and is composed of villi that increase the total absorptive surface area in the gastrointestinal (GI) tract to 300–400 m2 [1]. Enterocytes (absorptive) and goblet cells (mucus secreting) cover the villi, which are interspersed with Follicle Associated Epithelium (FAE). These lymphoid regions, Peyer's patches, are covered with M cells specialized for antigen sampling. M cells are significant for drug delivery, since they are relatively less protected by mucus [2] and have a high transcytotic capacity [3].

Despite these potential advantages, oral formulations face several common problems, particularly for peptides and proteins: (i) poor stability in the gastric environment, (ii) low solubility and/or bioavailability and (iii) the mucus barrier can prevent drug penetration and subsequent absorption. To overcome these limitations, nanoparticle formulations are being developed that encapsulate and protect drugs and release them in a temporally or spatially controlled manner. The nanoparticle surface can also be modified to enhance or reduce bioadhesion to target specific cells.

The mucus layers that protect epithelial surfaces have been highlighted as significant barriers to nanoparticle penetration [[4], [5], [6], [7], [8], [9], [10]]. Mucus has evolved to protect exposed epithelial surfaces by efficiently trapping pathogens and foreign particulates and rapidly clearing them. Mucus is continuously secreted both to remove pathogens and to lubricate the epithelium as material passes through, decreasing the residence time of nanoparticles that fail to penetrate the loosely adherent layer of GI mucus. This article reviews the properties and function of mucus in the GI tract, including how the barrier properties and composition change with GI diseases; these changes can affect the fate of nanoparticle-based drug delivery systems aimed at providing improved drug pharmacokinetics and/or targeting. Strategies for improving drug delivery to the GI tract by using mucoadhesive nanoparticles, and by disrupting the mucus barrier, are also discussed. Lastly, the recent development of mucus penetrating particles and their potential for further improving drug delivery to the GI tract is discussed.

Section snippets

Mucus composition, thickness, and pH in the GI tract

Mucus is a complex hydrogel composed of proteins, carbohydrates, lipids, salts, antibodies, bacteria, and cellular debris. The main protein component of mucus is mucins, which can be either secreted or cell-bound. In total, there are at least twenty proteins encoded in the MUC gene family [5], of which, MUC2, MUC5AC, and MUC6 are the secreted mucin types found throughout the GI tract [11]. Secreted mucin monomers link together via disulfide bonds to form large molecules, 0.5–40 MDa in size [12].

Mucoadhesive nanoparticle systems

Most orally administered particles are not retained and undergo direct transit through the GI tract [36], [37]. Mucoadhesion has been commonly employed in attempting to improve the residence time of particles in the GI tract. Non-specific mucoadhesion of microparticles in the GI tract is a well-known phenomenon; in 1962, Florey observed in cats that particles of India ink become coated with intestinal mucus such that they do not come into contact with the intestinal epithelium [38]. Gruber et

Disrupting the mucus barrier

An alternative approach to studies employing nanoparticles designed to be mucoadhesive is to develop methods that enhance nanoparticle-based drug delivery by disrupting barrier properties of the mucus lining. Although Peyer's patches are reported to be less protected by the mucus barrier than the rest of the GI tract, this lymphoid tissue only accounts for 1% of the total surface area [42]. The mucus barrier thus limits delivery to the non-lymphoid tissue, as well as potentially binding and

Alterations to the mucus barrier in disease states

Another important consideration for oral drug delivery is that the barrier properties of mucus are altered in disease states. Despite the highly protective properties of GI mucus, breaches do occur. On a daily basis, the GI tract is confronted with the formidable task of allowing transfer and uptake of nutrients and fluids, while being confronted with potentially harmful substances and pathogenic bacteria. It is remarkable that the GI tract is able to maintain a healthy homeostasis, considering

Animal models

In general, in vivo studies investigating oral delivery of nanoparticles have mainly focused on therapeutic effects or pharmacokinetics, as opposed to understanding the fate of the particles and how the results might translate in humans. Thus, it is worth briefly discussing the relevance of commonly used animal models. Rats and mice are most commonly used, but these rodents do not produce as much mucin as humans, possibly reducing the barrier properties to drug delivery and nanoparticle

Conclusions

Oral delivery is the most commonly used and readily accepted form of drug administration. Many small molecule drugs are successfully administered via the oral route, due to the high absorptive capacity of the GI tract. However, many drugs are not suitable for oral administration due to poor solubility, stability, and/or bioavailability. Encapsulating these drugs in nanoparticles can overcome these limitations, as well as allowing the potential for targeted, sustained delivery in the GI tract.

Acknowledgments

This work was supported in part by the NIH (5R01HD062844, 5R33AI079740, 5R21AI094519) (J.H. and R.C), the Cystic Fibrosis Foundation (HANES07XX0) (J.H.), and fellowships from the National Science Foundation and the Howard Hughes Medical Institute (L.M.E). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The mucus penetrating particle technology described in this publication is being developed by

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    This review is part of the Advanced Drug Delivery Reviews theme issue on “Advances in Oral Drug Delivery: Improved Bioavailability of Poorly Absorbed Drugs by Tissue and Cellular Optimization”.

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