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Advanced Drug Delivery Reviews (v.61, #2)
Drug and gene delivery to mucosal tissues: the mucus barrier
by Justin Hanes (Theme Editor); Jo Demeester (Theme Editor) (pp. 73-74).
Barrier properties of mucus by Richard A. Cone (pp. 75-85).
Mucus is tenacious. It sticks to most particles, preventing their penetration to the epithelial surface. Multiple low-affinity hydrophobic interactions play a major role in these adhesive interactions. Mucus gel is also shear-thinning, making it an excellent lubricant that ensures an unstirred layer of mucus remains adherent to the epithelial surface. Thus nanoparticles (NP) must diffuse readily through the unstirred adherent layer if they are to contact epithelial cells efficiently. This article reviews some of the physiological and biochemical properties that form the mucus barrier. Capsid viruses can diffuse through mucus as rapidly as through water and thereby penetrate to the epithelium even though they have to diffuse ‘upstream’ through mucus that is being continuously secreted. These viruses are smaller than the mucus mesh spacing, and have surfaces that do not stick to mucus. They form a useful model for developing NP for mucosal drug delivery.
Keywords: Mucus; Virus; Mucin
Micro- and macrorheology of mucus by Samuel K. Lai; Ying-Ying Wang; Denis Wirtz; Justin Hanes (pp. 86-100).
Mucus is a complex biological material that lubricates and protects the human lungs, gastrointestinal (GI) tract, vagina, eyes, and other moist mucosal surfaces. Mucus serves as a physical barrier against foreign particles, including toxins, pathogens, and environmental ultrafine particles, while allowing rapid passage of selected gases, ions, nutrients, and many proteins. Its selective barrier properties are precisely regulated at the biochemical level across vastly different length scales. At the macroscale, mucus behaves as a non-Newtonian gel, distinguished from classical solids and liquids by its response to shear rate and shear stress, while, at the nanoscale, it behaves as a low viscosity fluid. Advances in the rheological characterization of mucus from the macroscopic to nanoscopic levels have contributed critical understanding to mucus physiology, disease pathology, and the development of drug delivery systems designed for use at mucosal surfaces. This article reviews the biochemistry that governs mucus rheology, the macro- and microrheology of human and laboratory animal mucus, rheological techniques applied to mucus, and the importance of an improved understanding of the physical properties of mucus to advancing the field of drug and gene delivery.
Keywords: human mucus; animal mucus; mucus barrier; viscosity; elasticity; macrorheology; particle tracking microrheology
Mathematical modeling of molecular diffusion through mucus by Yen Cu; W. Mark Saltzman (pp. 101-114).
The rate of molecular transport through the mucus gel can be an important determinant of efficacy for therapeutic agents delivered by oral, intranasal, intravaginal/rectal, and intraocular routes. Transport through mucus can be described by mathematical models based on principles of physical chemistry and known characteristics of the mucus gel, its constituents, and of the drug itself. In this paper, we review mathematical models of molecular diffusion in mucus, as well as the techniques commonly used to measure diffusion of solutes in the mucus gel, mucus gel mimics, and mucosal epithelia.
Keywords: Mass transport; Diffusion in gel; Imaging; Mucosa; Drug delivery; Particles
Extracellular barriers in respiratory gene therapy by Niek Sanders; Carsten Rudolph; Kevin Braeckmans; Stefaan C. De Smedt; Joseph Demeester (pp. 115-127).
Respiratory gene therapy has been considered for the treatment of a broad range of pulmonary disorders. However, respiratory secretions form an important barrier towards the pulmonary delivery of therapeutic nucleic acids. In this review we will start with a brief description of the biophysical properties of respiratory mucus and alveolar fluid. This must allow the reader to gain insights into the mechanisms by which respiratory secretions may impede the gene transfer efficiency of nucleic acid containing nanoparticles (NANs). Subsequently, we will summarize the efforts that have been done to understand the barrier properties of respiratory mucus and alveolar fluid towards the respiratory delivery of therapeutic nucleic acids. Finally, new and current strategies that can overcome the inhibitory effects of respiratory secretions are discussed.
Keywords: Respiratory gene therapy; NANs; Nucleic acid containing nanoparticles; Mucus Alveolar fluid
Gene transfer to the lung: Lessons learned from more than 2 decades of CF gene therapy by Uta Griesenbach; Eric W.F.W. Alton (pp. 128-139).
Gene therapy is currently being developed for a wide range of acute and chronic lung diseases. The target cells, and to a degree the extra and intra-cellular barriers, are disease-specific and over the past decade the gene therapy community has recognized that no one vector is good for all applications, but that the gene transfer agent (GTA) has to be carefully matched to the specific disease target. Gene therapy is particularly attractive for diseases that currently do not have satisfactory treatment options and probably easier for monogenic disorders than for complex diseases. Cystic fibrosis (CF) fulfils these criteria and is, therefore, a good candidate for gene therapy-based treatment. This review will focus on CF as an example for lung gene therapy, but lessons learned may be applicable to other target diseases.
Keywords: Cystic fibrosis; Gene transfer; Viral vectors; Non-viral vectors; Barriers to gene transfer; Clinical trials
Nanoparticles for nasal vaccination by Noemi Csaba; Marcos Garcia-Fuentes; Maria Jose Alonso (pp. 140-157).
The great interest in mucosal vaccine delivery arises from the fact that mucosal surfaces represent the major site of entry for many pathogens. Among other mucosal sites, nasal delivery is especially attractive for immunization, as the nasal epithelium is characterized by relatively high permeability, low enzymatic activity and by the presence of an important number of immunocompetent cells. In addition to these advantageous characteristics, the nasal route could offer simplified and more cost-effective protocols for vaccination with improved patient compliance.The use of nanocarriers provides a suitable way for the nasal delivery of antigenic molecules. Besides improved protection and facilitated transport of the antigen, nanoparticulate delivery systems could also provide more effective antigen recognition by immune cells. These represent key factors in the optimal processing and presentation of the antigen, and therefore in the subsequent development of a suitable immune response. In this sense, the design of optimized vaccine nanocarriers offers a promising way for nasal mucosal vaccination.
Keywords: Mucosal immunity; Nasal administration; Antigen delivery; Transmucosal transport; Bioadhesion; Nanoparticles
Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues by Samuel K. Lai; Ying-Ying Wang; Justin Hanes (pp. 158-171).
Mucus is a viscoelastic and adhesive gel that protects the lung airways, gastrointestinal (GI) tract, vagina, eye and other mucosal surfaces. Most foreign particulates, including conventional particle-based drug delivery systems, are efficiently trapped in human mucus layers by steric obstruction and/or adhesion. Trapped particles are typically removed from the mucosal tissue within seconds to a few hours depending on anatomical location, thereby strongly limiting the duration of sustained drug delivery locally. A number of debilitating diseases could be treated more effectively and with fewer side effects if drugs and genes could be more efficiently delivered to the underlying mucosal tissues in a controlled manner. This review first describes the tenacious mucus barrier properties that have precluded the efficient penetration of therapeutic particles. It then reviews the design and development of new mucus-penetrating particles that may avoid rapid mucus clearance mechanisms, and thereby provide targeted or sustained drug delivery for localized therapies in mucosal tissues.
Keywords: Mucus; Mucus barrier properties; Mucus-penetrating particles; Therapeutic particles
Lessons from nature: “Pathogen-Mimetic” systems for mucosal Nano-medicines by Randall J. Mrsny (pp. 172-192).
Mucosal surfaces establish an interface with external environments that provide a protective barrier with the capacity to selectively absorb and secrete materials important for homeostasis of the organism. In man, mucosal surfaces such as those in the gastrointestinal tract, respiratory tree and genitourinary system also represent significant barrier to the successful administration of certain pharmaceutical agents and the delivery of newly designed nano-scale therapeutic systems. This review examines morphological, physiological and biochemical aspects of these mucosal barriers and presents currently understood mechanisms used by a variety of virulence factors used by pathogenic bacteria to overcome various aspects of these mucosal barriers. Such information emphasizes the impediments that biologically active materials must overcome for absorption across these mucosal surfaces and provides a template for strategies to overcome these barriers for the successful delivery of nano-scale bioactive materials, also known as nano-medicines.
Keywords: Bacterial toxin; Transcytosis; Protein therapeutics; Delivery