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      Rapid transport of deformation-tuned nanoparticles across biological hydrogels and cellular barriers

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          Abstract

          To optimally penetrate biological hydrogels such as mucus and the tumor interstitial matrix, nanoparticles (NPs) require physicochemical properties that would typically preclude cellular uptake, resulting in inefficient drug delivery. Here, we demonstrate that (poly(lactic-co-glycolic acid) (PLGA) core)-(lipid shell) NPs with moderate rigidity display enhanced diffusivity through mucus compared with some synthetic mucus penetration particles (MPPs), achieving a mucosal and tumor penetrating capability superior to that of both their soft and hard counterparts. Orally administered semi-elastic NPs efficiently overcome multiple intestinal barriers, and result in increased bioavailability of doxorubicin (Dox) (up to 8 fold) compared to Dox solution. Molecular dynamics simulations and super-resolution microscopy reveal that the semi-elastic NPs deform into ellipsoids, which enables rotation-facilitated penetration. In contrast, rigid NPs cannot deform, and overly soft NPs are impeded by interactions with the hydrogel network. Modifying particle rigidity may improve the efficacy of NP-based drugs, and can be applicable to other barriers.

          Abstract

          Penetration of the mucus and tumor interstitial matrix is an important consideration for drug delivery devices. Here, the authors report on a study into the optimization of rigidity for the transport of nanoparticles through biological hydrogels using core-shell polymer-lipid nanoparticles.

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          Most cited references 38

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          Nanoparticle-mediated cellular response is size-dependent.

          Nanostructures of different sizes, shapes and material properties have many applications in biomedical imaging, clinical diagnostics and therapeutics. In spite of what has been achieved so far, a complete understanding of how cells interact with nanostructures of well-defined sizes, at the molecular level, remains poorly understood. Here we show that gold and silver nanoparticles coated with antibodies can regulate the process of membrane receptor internalization. The binding and activation of membrane receptors and subsequent protein expression strongly depend on nanoparticle size. Although all nanoparticles within the 2-100 nm size range were found to alter signalling processes essential for basic cell functions (including cell death), 40- and 50-nm nanoparticles demonstrated the greatest effect. These results show that nanoparticles should no longer be viewed as simple carriers for biomedical applications, but can also play an active role in mediating biological effects. The findings presented here may assist in the design of nanoscale delivery and therapeutic systems and provide insights into nanotoxicity.
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            Bio-inspired, bioengineered and biomimetic drug delivery carriers.

            Synthetic carriers such as polymer and lipid particles often struggle to meet clinical expectations. Natural particulates - that range from pathogens to mammalian cells - are therefore worth examining in more depth, as they are highly optimized for their specific functions in vivo and possess features that are often desired in drug delivery carriers. With a better understanding of these biological systems, in conjunction with the availability of advanced biotechnology tools that are useful for re-engineering the various natural systems, researchers have started to exploit natural particulates for multiple applications in the delivery of proteins, small interfering RNA and other therapeutic agents. Here, we review the natural drug delivery carriers that have provided the basis and inspiration for new drug delivery systems.
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              Oral drug delivery with polymeric nanoparticles: the gastrointestinal mucus barriers.

              Oral delivery is the most common method for drug administration. However, poor solubility, stability, and bioavailability of many drugs make achieving therapeutic levels via the gastrointestinal (GI) tract challenging. Drug delivery must overcome numerous hurdles, including the acidic gastric environment and the continuous secretion of mucus that protects the GI tract. Nanoparticle drug carriers that can shield drugs from degradation and deliver them to intended sites within the GI tract may enable more efficient and sustained drug delivery. However, the rapid secretion and shedding of GI tract mucus can significantly limit the effectiveness of nanoparticle drug delivery systems. Many types of nanoparticles are efficiently trapped in and rapidly removed by mucus, making controlled release in the GI tract difficult. This review addresses the protective barrier properties of mucus secretions, how mucus affects the fate of orally administered nanoparticles, and recent developments in nanoparticles engineered to penetrate the mucus barrier. Copyright © 2011 Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                ygan@simm.ac.cn
                shixh@nanoctr.cn
                huajian_Gao@brown.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                4 July 2018
                4 July 2018
                2018
                : 9
                Affiliations
                [1 ]ISNI 0000000119573309, GRID grid.9227.e, Shanghai Institute of Materia Medica, , Chinese Academy of Sciences, ; 201203 Shanghai, China
                [2 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; NO.19A Yuquan Road, 100049 Beijing, China
                [3 ]ISNI 0000 0000 8645 4345, GRID grid.412561.5, School of Pharmacy, , Shenyang Pharmaceutical University, ; 110016 Shenyang, China
                [4 ]ISNI 0000000119573309, GRID grid.9227.e, CAS Key Laboratory for Nanosystem and Hierarchy Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, , Chinese Academy of Sciences, ; 100190 Beijing, China
                [5 ]ISNI 0000000119573309, GRID grid.9227.e, LNM, Institute of Mechanics, , Chinese Academy of Sciences, ; 100190 Beijing, China
                [6 ]ISNI 0000 0004 1936 9094, GRID grid.40263.33, School of Engineering, , Brown University, ; Providence, RI 02912 USA
                Article
                5061
                10.1038/s41467-018-05061-3
                6031689
                29973592
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);
                Award ID: 81373356
                Award ID: 81573378
                Award ID: 81773651
                Award ID: 11422215
                Award ID: 11272327
                Award Recipient :
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