Journal
EUROPEAN JOURNAL OF NANOMEDICINE
Volume 6, Issue 3, Pages 157-169Publisher
WALTER DE GRUYTER GMBH
DOI: 10.1515/ejnm-2014-0019
Keywords
mucus; nanoparticles; pulmonary barriers; respiratory epithelium; surfactant
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Funding
- Marie Curie Initial Training Network PathChooser [PITN-GA-2013-608373]
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The pulmonary route offers an exceptional, non-invasive administration site for drug delivery. The principal characteristics that make the lungs an appealing route for drug administration include a large surface for drug dispersion (approximately 100 m(2)), a low content of drug-metabolizing enzymes, and a high vascularization for systemic drug delivery. Recent advances in this field such as the development of modern inhalation devices, novel inhalation-adapted formulations, and innovative drug carriers have contributed to a significant improvement in the low level of lung aerosol deposition achieved in the past, and have allowed for an enhancement in aerosol penetration into the lungs. Less focus however has been placed on the fate of inhaled particles after they deposit onto lung surfaces. After first contact with a pulmonary surface therapeutic particles are exposed to complex microenvironments and biological barriers (both cellular and non-cellular) that may vary widely in composition depending on the region of the lung in which the particles deposit. Most of the current inhaled therapies aim to achieve deep lung deposition at the alveolar air-blood barrier. In this particular region, the epithelium is coated with the pulmonary surfactant, a thin liquid layer composed of lipids and proteins that reduces surface tension in the alveoli, but which also interacts with and may influence the fate of inhaled therapeutics within the alveolar region. In addition, alveolar macrophages efficiently engulf inhaled particulates in the 1-5 mu m size range; these therefore also pose a significant barrier to the effective delivery of therapeutic micro-and nanoparticles (NPs). Furthermore, the tightly-joined epithelium of the airways is coated with a dynamic viscous mucus layer which forms the mucociliary escalator, an efficiently coordinated piece of machinery that entraps inhaled particulates including pollutants, pathogens and, eventually, therapeutic NPs, and removes them from the lungs. A better understanding of the complex processes to which inhaled particles are subjected within distinct regions of the lungs may allow for the design of innovative therapeutics, including bio-compatible polymeric NPs, aimed to efficiently overcome the complex pulmonary barriers and thus enhance the therapeutic efficiency of NP-associated actives. The current review therefore discusses the structure of the pulmonary barriers, as well as some of most innovative strategies to overcome them in order to facilitate an enhanced delivery of inhaled therapeutics.
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