Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues☆
Introduction
Delivery technologies that improve drug pharmacokinetics and facilitate localized delivery to target tissues strongly improve the efficacy of various therapies [1], [2]. In particular, an increasing number of nanoparticle-based drug delivery systems have been approved for human use or are currently being evaluated in clinical trials [3], [4]. Nanoparticle systems can be engineered to possess a number of desirable features for therapy, including: (i) sustained and controlled release of drugs locally [5], [6], (ii) deep tissue penetration due to their nano-metric size [7], [8], [9], (iii) cellular uptake and sub-cellular trafficking [10], [11], and (iv) protection of cargo therapeutics at both the extracellular and intracellular levels [12], [13].
The development of controlled release systems for drug and gene delivery to mucosal surfaces, such as those of the lung airways, GI tract, female reproductive tract, nose and eye, is of widespread interest. However, the viscous, elastic and sticky mucus layer that lines all mucosal tissues has evolved to protect the body by rapidly trapping and removing foreign particles and hydrophobic molecules [14], [15]. The limited permeability of drug delivery particles and many hydrophobic drugs through the mucus barrier leads to their rapid clearance from the delivery site, often precluding effective drug therapies at non-toxic dosages.
In order to avoid rapid mucus clearance and/or reach the underlying epithelia, nanoparticles must quickly traverse at least the outermost layers of the mucus barrier (which are cleared most rapidly) [15], [16]. Until recently, nanoparticles were thought incapable of efficiently penetrating mucus layers [17]. The need for new strategies to increase particle transport rates is underscored by: (i) observations of the immobilization of conventional nanoparticles in mucus ex vivo [18], [19]; (ii) the very slow transport rate of herpes simplex virus (diameter ∼ 180 nm) in mucus ex vivo [19]; and (iii) animal studies showing that mucus immobilizes a range of particle types [20], [21], [22], [23].
In order to penetrate mucus, synthetic nanoparticles must avoid adhesion to mucin fibers and be small enough to avoid significant steric inhibition by the dense fiber mesh. Recently, we demonstrated that nanoparticles as large as 500 nm, if sufficiently coated with a muco-inert polymer, can rapidly traverse physiological human mucus with diffusivities as high as only 4-fold reduced compared to their rates in pure water [17]. This finding suggests that it is possible to engineer nanoparticles that overcome the mucus barrier. Combined with a suitably tailored drug release profile, these “mucus-penetrating particle” (MPP) systems offer the prospect of sustained drug delivery at mucosal surfaces and, thus, provide hope for improved efficacy and reduced side effects for a wide range of therapeutics. The generation of MPP loaded with nucleic acids may also greatly enhance the efficacy of this critical family of therapeutic agents [24], [25].
This article reviews the mechanisms by which mucus hinders or prevents particle penetration, including a discussion of previous work on nanoparticle transport in mucus both ex vivo and in vivo. Subsequently, the recent development of mucus penetrating nanoparticles is described.
Section snippets
Composition of mucus, mucus thickness, and mucus clearance times
Mucus is a viscoelastic gel layer that protects tissues that would otherwise be exposed to the external environment. Mucus is composed primarily of crosslinked and entangled mucin fibers secreted by goblet cells and submucosal glands [26], [27], [28]. Mucins are large molecules, typically 0.5–40 MDa in size [15], [16] formed by the linking of numerous mucin monomers, each about 0.3–0.5 MDa [29], [30], and are coated with a complex and highly diverse array of proteoglycans [15], [31]. At least
Typical fate of nanoparticles in mucus-covered tissues and conventional strategies for enhancing residence time
When administered to various mucosal tissues, conventional nanoparticles are likely to be trapped by mucus via steric or adhesive forces and rapidly eliminated via mucociliary clearance. In the GI tract, for example, nanoparticles delivered orally may undergo: (1) association with chyme, causing direct transit through the GI tract and fecal elimination; (2) adhesion to mucin fibers, followed by mucus clearance and fecal elimination; or (3) transport across the mucus mesh for possible entry to
Lessons from nature: Transport of viruses in mucus
To gain mechanistic insight and rationally engineer particles to cross mucus, we took an alternative approach and looked to nature for guidance. Specifically, we focused on understanding the physicochemical properties (i.e. size and surface chemistry) that govern the rapid transport of specific viruses, which have evolved over thousands of years to infect mucosal tissues.
An indirect implication of the highly immobilized nature of virus-sized polystyrene beads in mucus is that viral particles
Role of surface chemistry
Polystyrene nanoparticles as small as 59 nm, covalently modified with carboxyl groups on the surface, were found to be completely immobilized in human cervical mucus [19]. By reducing the concentrations, Dawson et al. found that some particles with surfaces modified with either carboxyl or amine groups were mobile in CF sputum, but the ensemble-averaged transport rates were still slowed at least 300-fold compared to the same particles in water [118]. Norris et al. similarly observed slow
Conclusions
The possibility of using polymer nanoparticles for controlled drug or gene delivery at mucosal sites over many hours to days is expected to lead to effective new therapeutics. However, no such product currently exists since conventional therapeutic particles cannot penetrate the human mucosal barrier, which rapidly clears trapped pathogens and particulates. The development of mucus-penetrating particles (MPP), by rendering the surfaces of particles non-mucoadhesive via lessons learned from
Acknowledgments
This work was funded in part by the NIH (R01EB003558, R21HL089816, and R21EB008515), the Cystic Fibrosis Foundation (HANES08G0) and fellowships from the NSF (Y.-Y.W.) and the Croucher Foundation (S.K.L.).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Drug and Gene Delivery to Mucosal Tissues: The Mucus Barrier”.