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      Endocytic Uptake, Transport and Macromolecular Interactions of Anionic PAMAM Dendrimers within Lung Tissue

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          Abstract

          Purpose

          Polyamidoamine (PAMAM) dendrimers are a promising class of nanocarrier with applications in both small and large molecule drug delivery. Here we report a comprehensive evaluation of the uptake and transport pathways that contribute to the lung disposition of dendrimers.

          Methods

          Anionic PAMAM dendrimers and control dextran probes were applied to an isolated perfused rat lung (IPRL) model and lung epithelial monolayers. Endocytosis pathways were examined in primary alveolar epithelial cultures by confocal microscopy. Molecular interactions of dendrimers with protein and lipid lung fluid components were studied using small angle neutron scattering (SANS).

          Results

          Dendrimers were absorbed across the intact lung via a passive, size-dependent transport pathway at rates slower than dextrans of similar molecular sizes. SANS investigations of concentration-dependent PAMAM transport in the IPRL confirmed no aggregation of PAMAMs with either albumin or dipalmitoylphosphatidylcholine lung lining fluid components. Distinct endocytic compartments were identified within primary alveolar epithelial cells and their functionality in the rapid uptake of fluorescent dendrimers and model macromolecular probes was confirmed by co-localisation studies.

          Conclusions

          PAMAM dendrimers display favourable lung biocompatibility but modest lung to blood absorption kinetics. These data support the investigation of dendrimer-based carriers for controlled-release drug delivery to the deep lung.

          Electronic supplementary material

          The online version of this article (doi:10.1007/s11095-017-2190-7) contains supplementary material, which is available to authorized users.

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          Most cited references 50

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          Is Open Access

          Endocytosis and exocytosis of nanoparticles in mammalian cells

           Nuri Oh,  Ji-Ho Park (2014)
          Engineered nanoparticles that can be injected into the human body hold tremendous potential to detect and treat complex diseases. Understanding of the endocytosis and exocytosis mechanisms of nanoparticles is essential for safe and efficient therapeutic application. In particular, exocytosis is of significance in the removal of nanoparticles with drugs and contrast agents from the body, while endocytosis is of great importance for the targeting of nanoparticles in disease sites. Here, we review the recent research on the endocytosis and exocytosis of functionalized nanoparticles based on various sizes, shapes, and surface chemistries. We believe that this review contributes to the design of safe nanoparticles that can efficiently enter and leave human cells and tissues.
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            Inhaling medicines: delivering drugs to the body through the lungs.

            Remarkably, with the exception of anaesthetic gases, the ancient human practice of inhaling substances into the lungs for systemic effect has only just begun to be adopted by modern medicine. Treatment of asthma by inhaled drugs began in earnest in the 1950s, and now such 'topical' or targeted treatment with inhaled drugs is considered for treating many other lung diseases. More recently, major advances have led to increasing interest in systemic delivery of drugs by inhalation. Small molecules can be delivered with very rapid action, low metabolism and high bioavailability; and macromolecules can be delivered without injections, as highlighted by the recent approval of the first inhaled insulin product. Here, we review these advances, and discuss aspects of lung physiology and formulation composition that influence the systemic delivery of inhaled therapeutics.
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              Caveolin-stabilized membrane domains as multifunctional transport and sorting devices in endocytic membrane traffic.

              Endocytosis comprises several routes of internalization. An outstanding question is whether the caveolar and endosomal pathways intersect. Following transport of the caveolar protein Caveolin-1 and two cargo complexes, Simian Virus 40 and Cholera toxin, in live cells, we uncovered a Rab5-dependent pathway in which caveolar vesicles are targeted to early endosomes and form distinct and stable membrane domains. In endosomes, the low pH selectively allowed the toxin to diffuse out of the caveolar domains into the surrounding membrane, while the virus remained trapped. Thus, we conclude that, unlike cyclic assembly and disassembly of coat proteins in vesicular transport, oligomeric complexes of caveolin-1 confer permanent structural stability to caveolar vesicles that transiently interact with endosomes to form subdomains and release cargo selectively by compartment-specific cues.
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                Author and article information

                Contributors
                Christopher.J.Morris@uea.ac.uk
                gumbleton@cf.ac.uk
                Journal
                Pharm Res
                Pharm. Res
                Pharmaceutical Research
                Springer US (New York )
                0724-8741
                1573-904X
                14 June 2017
                14 June 2017
                2017
                : 34
                : 12
                : 2517-2531
                Affiliations
                [1 ]ISNI 0000 0001 1092 7967, GRID grid.8273.e, School of Pharmacy, , University of East Anglia, ; Norwich Research Park, NR4 7TJ UK
                [2 ]Cardiff School of Pharmacy & Pharmaceutical Sciences, Redwood Building, Cardiff, CF10 3NB UK
                [3 ]ISNI 0000 0001 0806 5472, GRID grid.36316.31, Department of Pharmaceutical, Chemical and Environmental Science, , University of Greenwich, ; Medway Campus, Kent, ME4 4TB UK
                Article
                2190
                10.1007/s11095-017-2190-7
                5736778
                28616685
                © The Author(s) 2017

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000266, Engineering and Physical Sciences Research Council;
                Award ID: EP/C013220/1
                Categories
                Research Paper
                Custom metadata
                © Springer Science+Business Media, LLC, part of Springer Nature 2017

                Pharmacology & Pharmaceutical medicine

                dendrimer, endocytosis, lung, polymer, scattering, transport, uptake

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