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      Effect of Flow-Induced Shear Stress in Nanomaterial Uptake by Cells: Focus on Targeted Anti-Cancer Therapy

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          Abstract

          Recently, nanomedicines have gained a great deal of attention in diverse biomedical applications, including anti-cancer therapy. Being different from normal tissue, the biophysical microenvironment of tumor cells and cancer cell mechanics should be considered for the development of nanostructures as anti-cancer agents. Throughout the last decades, many efforts devoted to investigating the distinct cancer environment and understanding the interactions between tumor cells and have been applied bio-nanomaterials. This review highlights the microenvironment of cancer cells and how it is different from that of healthy tissue. We gave special emphasis to the physiological shear stresses existing in the cancerous surroundings, since these stresses have a profound effect on cancer cell/nanoparticle interaction. Finally, this study reviews relevant examples of investigations aimed at clarifying the cellular nanoparticle uptake behavior under both static and dynamic conditions.

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          Most cited references63

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          Transport of drugs from blood vessels to tumour tissue

          The effectiveness of anticancer drugs in treating a solid tumour is dependent on delivery of the drug to virtually all cancer cells in the tumour. The distribution of drug in tumour tissue depends on the plasma pharmacokinetics, the structure and function of the tumour vasculature and the transport properties of the drug as it moves through microvessel walls and in the extravascular tissue. The aim of this Review is to provide a broad, balanced perspective on the current understanding of drug transport to tumour cells and on the progress in developing methods to enhance drug delivery. First, the fundamental processes of solute transport in blood and tissue by convection and diffusion are reviewed, including the dependence of penetration distance from vessels into tissue on solute binding or uptake in tissue. The effects of the abnormal characteristics of tumour vasculature and extravascular tissue on these transport properties are then discussed. Finally, methods for overcoming limitations in drug transport and thereby achieving improved therapeutic results are surveyed.
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            Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting.

            The impact of physical and chemical modifications of nanoparticles on their biological function has been systemically investigated and exploited to improve their circulation and targeting. However, the impact of nanoparticles' flexibility (i.e., elastic modulus) on their function has been explored to a far lesser extent, and the potential benefits of tuning nanoparticle elasticity are not clear. Here, we describe a method to synthesize polyethylene glycol (PEG)-based hydrogel nanoparticles of uniform size (200 nm) with elastic moduli ranging from 0.255 to 3000 kPa. These particles are used to investigate the role of particle elasticity on key functions including blood circulation time, biodistribution, antibody-mediated targeting, endocytosis, and phagocytosis. Our results demonstrate that softer nanoparticles (10 kPa) offer enhanced circulation and subsequently enhanced targeting compared to harder nanoparticles (3000 kPa) in vivo. Furthermore, in vitro experiments show that softer nanoparticles exhibit significantly reduced cellular uptake in immune cells (J774 macrophages), endothelial cells (bEnd.3), and cancer cells (4T1). Tuning nanoparticle elasticity potentially offers a method to improve the biological fate of nanoparticles by offering enhanced circulation, reduced immune system uptake, and improved targeting.
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              Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels.

              Obstruction of critical blood vessels due to thrombosis or embolism is a leading cause of death worldwide. Here, we describe a biomimetic strategy that uses high shear stress caused by vascular narrowing as a targeting mechanism--in the same way platelets do--to deliver drugs to obstructed blood vessels. Microscale aggregates of nanoparticles were fabricated to break up into nanoscale components when exposed to abnormally high fluid shear stress. When coated with tissue plasminogen activator and administered intravenously in mice, these shear-activated nanotherapeutics induce rapid clot dissolution in a mesenteric injury model, restore normal flow dynamics, and increase survival in an otherwise fatal mouse pulmonary embolism model. This biophysical strategy for drug targeting, which lowers required doses and minimizes side effects while maximizing drug efficacy, offers a potential new approach for treatment of life-threatening diseases that result from acute vascular occlusion.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                16 July 2020
                July 2020
                : 12
                : 7
                : 1916
                Affiliations
                [1 ]Materials Science and Technology Department, College of Arts and Sciences, Qatar University, Doha 2713, Qatar; samar.h.shurbaji1993@ 123456gmail.com (S.S.); essraa_88@ 123456yahoo.com (E.A.H.)
                [2 ]College of Medicine, Department of Medical Sciences, Qatar University, Doha 2713, Qatar; guliz-y@ 123456hotmail.com
                [3 ]Biomedical Research Center, Qatar University, Doha 2713, Qatar
                [4 ]Department of Biomedical Sciences, College of Health Science-QU Health, Qatar University, Doha 2713, Qatar
                Author notes
                [* ]Correspondence: aelzatahry@ 123456qu.edu.qa (A.E.); hyalcin@ 123456qu.edu.qa (H.C.Y.); Tel.: +974-4403-6808 (A.E.); +974-4403-7719 (H.C.Y.)
                Author information
                https://orcid.org/0000-0002-7291-5723
                Article
                cancers-12-01916
                10.3390/cancers12071916
                7409087
                32708521
                307dec87-9b30-49c7-88d7-cbb3cbc29d7e
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 30 October 2019
                : 24 December 2019
                Categories
                Review

                nanomedicine,nanoparticle,targeted therapy,anti-cancer,shear stress,flow,in vitro

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