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      Polydopamine-modified dual-ligand nanoparticles as highly effective and targeted magnetic resonance/photoacoustic dual-modality thrombus imaging agents

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          Abstract

          Background

          Platelet activation and subsequent aggregation are the initial stages of thrombosis. A molecular probe that specifically targets activated platelets and remains retained under high shear stress in vivo can enhance the imaging effect to achieve early and accurate diagnosis.

          Methods and materials

          In this study, we constructed nanoparticles (NPs) using polydopamine to carry two peptides that simultaneously bind integrin αIIbβ3 and P-selectin on activated platelets to enhance the targeting of NPs to thrombus.

          Results

          The targeting specificity and binding stability of the NPs on red and white thrombi were demonstrated in vitro using a simulated circulatory device and the targeting effect of the NPs on mixed thrombus was studied by  magnetic resonance (MR)/photoacoustic (PA) dual-modality imaging in vivo. NPs that were surface modified with both peptides have higher selectivity and retention to red and white thrombi in vitro than NPs with a single or no peptide, and the targeting effect was closely related to the number and distribution of activated platelets as well as the structure and type of thrombus. The NPs also have MR/PA dual-modality imaging functionality, significantly enhancing the imaging of mixed thrombus in vivo.

          Conclusion

          These dual-targeted NPs have improved targeting specificity and binding stability to different thrombi under high shear stress and are beneficial for the early diagnosis of thrombosis.

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          Most cited references 52

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          Dopamine-melanin colloidal nanospheres: an efficient near-infrared photothermal therapeutic agent for in vivo cancer therapy.

           Yanlan Liu,  Q. Y. He,  L. Lu (2013)
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            The role of selectins in inflammation and disease.

             Klaus Ley (2003)
            Selectins are carbohydrate-binding molecules that bind to fucosylated and sialylated glycoprotein ligands, and are found on endothelial cells, leukocytes and platelets. They are involved in trafficking of cells of the innate immune system, T lymphocytes and platelets. An absence of selectins or selectin ligands has serious consequences in mice or humans, leading to recurrent bacterial infections and persistent disease. Selectins are involved in constitutive lymphocyte homing, and in chronic and acute inflammation processes, including post-ischemic inflammation in muscle, kidney and heart, skin inflammation, atherosclerosis, glomerulonephritis and lupus erythematosus. Selectin-neutralizing monoclonal antibodies, recombinant soluble P-selectin glycoprotein ligand 1 and small-molecule inhibitors of selectins have been tested in clinical trials on patients with multiple trauma, cardiac indications and pediatric asthma, respectively. Anti-selectin antibodies have also been successfully used in preclinical models to deliver imaging contrast agents and therapeutics to sites of inflammation. Further improvements in the efficiency, availability, specificity and pharmacokinetics of selectin inhibitors, and specialized application routes and schedules, hold promise for therapeutic indications.
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              Control of endothelial targeting and intracellular delivery of therapeutic enzymes by modulating the size and shape of ICAM-1-targeted carriers.

              Endocytosis in endothelial cells (ECs) is important for many biomedical applications, including drug delivery by nano- and microscale carriers. However, little is known about how carrier geometry influences endothelial drug targeting, intracellular trafficking, and effects. We studied this using prototype polymer carriers of various sizes (0.1-10 mum) and shapes (spheres versus elliptical disks). Carriers were targeted to intercellular adhesion molecule 1 (ICAM-1), a transmembrane glycoprotein that is upregulated in many pathologies and used as a target for intraendothelial drug delivery. ECs internalized anti-ICAM-coated carriers of up to several microns in size via cell adhesion molecule-mediated endocytosis. This pathway is distinct from caveolar and clathrin endocytosis that operate for submicron-size objects. Carrier geometry was found to influence endothelial targeting in the vasculature, and the rate of endocytosis and lysosomal transport within ECs. Disks had longer half-lives in circulation and higher targeting specificity in mice, whereas spheres were endocytosed more rapidly. Micron-size carriers had prolonged residency in prelysosomal compartments, beneficial for endothelial antioxidant protection by delivered catalase. Submicron carriers trafficked to lysosomes more readily, optimizing effects of acid sphingomyelinase (ASM) enzyme replacement in a model of lysosomal storage disease. Therefore, rational design of carrier geometry will help optimize endothelium-targeted therapeutics.
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                Author and article information

                Journal
                Int J Nanomedicine
                Int J Nanomedicine
                IJN
                intjnano
                International Journal of Nanomedicine
                Dove
                1176-9114
                1178-2013
                03 September 2019
                2019
                : 14
                : 7155-7171
                Affiliations
                [1 ]Department of Radiology, The Second Affiliated Hospital of Chongqing Medical University , Chongqing, People’s Republic of China
                [2 ]Chongqing Key Laboratory of Ultrasound Molecular Imaging, Department of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University , Chongqing, People’s Republic of China
                Author notes
                Correspondence: Haitao RanDepartment of Ultrasound, The Second Affiliated Hospital of Chongqing Medical University , No. 74 Linjiang Road, Yuzhong District, Chongqing400010, People’s Republic of China Email rht66@163.com
                Dajing GuoDepartment of Radiology, The Second Affiliated Hospital of Chongqing Medical University , No. 74 Linjiang Road, Yuzhong District, Chongqing400010, People’s Republic of ChinaTel +86 236 369 3537Email guodaj@hospital.cqmu.edu.cn
                Article
                216603
                10.2147/IJN.S216603
                6731970
                © 2019 Zhang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 12, Tables: 1, References: 55, Pages: 17
                Categories
                Original Research

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