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      Extracellular barriers in respiratory gene therapy

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          Abstract

          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.

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          Most cited references 113

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          Rapid transport of large polymeric nanoparticles in fresh undiluted human mucus.

          Nanoparticles larger than the reported mesh-pore size range (10-200 nm) in mucus have been thought to be much too large to undergo rapid diffusional transport through mucus barriers. However, large nanoparticles are preferred for higher drug encapsulation efficiency and the ability to provide sustained delivery of a wider array of drugs. We used high-speed multiple-particle tracking to quantify transport rates of individual polymeric particles of various sizes and surface chemistries in samples of fresh human cervicovaginal mucus. Both the mucin concentration and viscoelastic properties of these cervicovaginal samples are similar to those in many other human mucus secretions. Unexpectedly, we found that large nanoparticles, 500 and 200 nm in diameter, if coated with polyethylene glycol, diffused through mucus with an effective diffusion coefficient (D(eff)) only 4- and 6-fold lower than that for the same particles in water (at time scale tau = 1 s). In contrast, for smaller but otherwise identical 100-nm coated particles, D(eff) was 200-fold lower in mucus than in water. For uncoated particles 100-500 nm in diameter, D(eff) was 2,400- to 40,000-fold lower in mucus than in water. Much larger fractions of the 100-nm particles were immobilized or otherwise hindered by mucus than the large 200- to 500-nm particles. Thus, in contrast to the prevailing belief, these results demonstrate that large nanoparticles, if properly coated, can rapidly penetrate physiological human mucus, and they offer the prospect that large nanoparticles can be used for mucosal drug delivery.
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            Alveolar epithelial type II cell: defender of the alveolus revisited

            In 1977, Mason and Williams developed the concept of the alveolar epithelial type II (AE2) cell as a defender of the alveolus. It is well known that AE2 cells synthesise, secrete, and recycle all components of the surfactant that regulates alveolar surface tension in mammalian lungs. AE2 cells influence extracellular surfactant transformation by regulating, for example, pH and [Ca2+] of the hypophase. AE2 cells play various roles in alveolar fluid balance, coagulation/fibrinolysis, and host defence. AE2 cells proliferate, differentiate into AE1 cells, and remove apoptotic AE2 cells by phagocytosis, thus contributing to epithelial repair. AE2 cells may act as immunoregulatory cells. AE2 cells interact with resident and mobile cells, either directly by membrane contact or indirectly via cytokines/growth factors and their receptors, thus representing an integrative unit within the alveolus. Although most data support the concept, the controversy about the character of hyperplastic AE2 cells, reported to synthesise profibrotic factors, proscribes drawing a definite conclusion today.
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              Magnetofection: enhancing and targeting gene delivery by magnetic force in vitro and in vivo.

              Low efficiencies of nonviral gene vectors, the receptor-dependent host tropism of adenoviral or low titers of retroviral vectors limit their utility in gene therapy. To overcome these deficiencies, we associated gene vectors with superparamagnetic nanoparticles and targeted gene delivery by application of a magnetic field. This potentiated the efficacy of any vector up to several hundred-fold, allowed reduction of the duration of gene delivery to minutes, extended the host tropism of adenoviral vectors to nonpermissive cells and compensated for low retroviral titer. More importantly, the high transduction efficiency observed in vitro was reproduced in vivo with magnetic field-guided local transfection in the gastrointestinal tract and in blood vessels. Magnetofection provides a novel tool for high throughput gene screening in vitro and can help to overcome fundamental limitations to gene therapy in vivo.
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                Author and article information

                Contributors
                Journal
                Adv Drug Deliv Rev
                Adv. Drug Deliv. Rev
                Advanced Drug Delivery Reviews
                Elsevier Science Publishers, B.V
                0169-409X
                1872-8294
                24 December 2008
                27 February 2009
                24 December 2008
                : 61
                : 2
                : 115-127
                Affiliations
                [a ]Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmacy, Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium
                [b ]Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium
                [c ]Department of Pediatrics, Ludwig–Maximilians University, 80337 Munich, Germany
                [d ]Department of Pharmacy, Free University of Berlin, 14166 Berlin, Germany
                Author notes
                [* ]Corresponding author. Laboratory of Gene Therapy, Department of Nutrition, Genetics and Ethology, Faculty of Veterinary Medicine, Ghent University, Heidestraat 19, 9820 Merelbeke, Belgium. Tel.: +32 9 264 80; fax: +32 9 264 81 89. Niek.Sanders@ 123456UGent.be
                Article
                S0169-409X(08)00262-7
                10.1016/j.addr.2008.09.011
                7103358
                19146894
                Copyright © 2008 Elsevier B.V. All rights reserved.

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