{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:48:50Z","timestamp":1760150930302,"version":"build-2065373602"},"reference-count":70,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,28]],"date-time":"2022-01-28T00:00:00Z","timestamp":1643328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100011748","name":"Phospholipid Research Center","doi-asserted-by":"publisher","award":["KKO-2017-057\/1-1"],"award-info":[{"award-number":["KKO-2017-057\/1-1"]}],"id":[{"id":"10.13039\/501100011748","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Dutch Research Council","doi-asserted-by":"publisher","award":["17543"],"award-info":[{"award-number":["17543"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Thorax Center of Erasmus University Medical Center in Rotterdam","award":["not applicable"],"award-info":[{"award-number":["not applicable"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Phospholipid-coated targeted microbubbles are used for ultrasound molecular imaging and locally enhanced drug delivery, with the binding efficacy being an important trait. The use of organic solvent in microbubble production makes the difference between a heterogeneous or homogeneous ligand distribution. This study demonstrates the effect of ligand distribution on the binding efficacy of phospholipid-coated \u03b1\u03bd\u03b23-targeted microbubbles in vitro using a monolayer of human umbilical-vein endothelial cells and in vivo using chicken embryos. Microbubbles with a homogeneous ligand distribution had a higher binding efficacy than those with a heterogeneous ligand distribution both in vitro and in vivo. In vitro, 1.55\u00d7 more microbubbles with a homogeneous ligand distribution bound under static conditions, while this was 1.49\u00d7 more under flow with 1.25 dyn\/cm2, 1.56\u00d7 more under flow with 2.22 dyn\/cm2, and 1.25\u00d7 more in vivo. The in vitro dissociation rate of bound microbubbles with homogeneous ligand distribution was lower at low shear stresses (1\u20135 dyn\/cm2). The internalized depth of bound microbubbles was influenced by microbubble size, not by ligand distribution. In conclusion, for optimal binding the use of organic solvent in targeted microbubble production is preferable over directly dispersing phospholipids in aqueous medium.<\/jats:p>","DOI":"10.3390\/pharmaceutics14020311","type":"journal-article","created":{"date-parts":[[2022,1,29]],"date-time":"2022-01-29T05:26:17Z","timestamp":1643433977000},"page":"311","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Theranostic Microbubbles with Homogeneous Ligand Distribution for Higher Binding Efficacy"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7604-3013","authenticated-orcid":false,"given":"Simone A. G.","family":"Langeveld","sequence":"first","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9492-6706","authenticated-orcid":false,"given":"Bram","family":"Meijlink","sequence":"additional","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"In\u00e9s","family":"Beekers","sequence":"additional","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"},{"name":"Department of Health, ORTEC B.V., 2719 EA Zoetermeer, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Olthof","sequence":"additional","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonius F. W.","family":"van der Steen","sequence":"additional","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8902-0099","authenticated-orcid":false,"given":"Nico","family":"de Jong","sequence":"additional","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"},{"name":"Imaging Physics, Delft University of Technology, 2628 CJ Delft, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0607-4989","authenticated-orcid":false,"given":"Klazina","family":"Kooiman","sequence":"additional","affiliation":[{"name":"Thorax Center, Biomedical Engineering, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,28]]},"reference":[{"key":"ref_1","unstructured":"Krause, W. (2002). Ultrasound Contrast Agents: Development of the Field and Current Status. Contrast Agents II: Optical, Ultrasound, X-ray and Radiopharmaceutical Imaging, Springer."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1007\/s00261-018-1516-1","article-title":"Imaging with ultrasound contrast agents: Current status and future","volume":"43","author":"Chong","year":"2018","journal-title":"Abdom. Radiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2118","DOI":"10.2174\/138161212800099955","article-title":"How do microbubbles and ultrasound interact? Basic physical, dynamic and engineering principles","volume":"18","author":"Azmin","year":"2012","journal-title":"Curr. Pharm. Des."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jconrel.2006.02.007","article-title":"Vibrating microbubbles poking individual cells: Drug transfer into cells via sonoporation","volume":"112","author":"Kooiman","year":"2006","journal-title":"J. Control Release"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.jconrel.2020.03.038","article-title":"Opening of endothelial cell\u2013cell contacts due to sonoporation","volume":"322","author":"Beekers","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Fekri, F., Delos Santos, R.C., Karshafian, R., and Antonescu, C.N. (2016). Ultrasound Microbubble Treatment Enhances Clathrin-Mediated Endocytosis and Fluid-Phase Uptake through Distinct Mechanisms. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156754"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1166\/jbn.2018.2594","article-title":"Ultrasound-Triggered Drug Delivery for Breast Tumor Therapy Through iRGD-Targeted Paclitaxel-Loaded Liposome-Microbubble Complexes","volume":"14","author":"Zhang","year":"2018","journal-title":"J. Biomed. Nanotechnol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2651","DOI":"10.1016\/j.ultrasmedbio.2017.06.029","article-title":"Ultrasound Improves the Delivery and Therapeutic Effect of Nanoparticle-Stabilized Microbubbles in Breast Cancer Xenografts","volume":"43","author":"Snipstad","year":"2017","journal-title":"Ultrasound Med. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.jconrel.2016.10.007","article-title":"A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer","volume":"243","author":"Dimcevski","year":"2016","journal-title":"J. Control. Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1148\/radiol.2202001804","article-title":"Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits","volume":"220","author":"Hynynen","year":"2001","journal-title":"Radiology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabj4011","DOI":"10.1126\/scitranslmed.abj4011","article-title":"MR-guided focused ultrasound enhances delivery of trastuzumab to Her2-positive brain metastases","volume":"13","author":"Meng","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7780","DOI":"10.1021\/la301368v","article-title":"Protein Adsorption at the Electrified Air\u2013Water Interface: Implications on Foam Stability","volume":"28","author":"Engelhardt","year":"2012","journal-title":"Langmuir"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1039\/C9SM01516G","article-title":"Kinetics of albumin microbubble dissolution in aqueous media","volume":"16","author":"Khan","year":"2020","journal-title":"Soft Matter"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1063\/1.1643544","article-title":"Optical observation of lipid- and polymer-shelled ultrasound microbubble contrast agents","volume":"84","author":"Bloch","year":"2004","journal-title":"Appl. Phys. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1161\/hc4201.097061","article-title":"Ultrasound Assessment of Inflammation and Renal Tissue Injury With Microbubbles Targeted to P-Selectin","volume":"104","author":"Lindner","year":"2001","journal-title":"Circulation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/BF02594596","article-title":"Targeting and ultrasound imaging of microbubble-based contrast agents","volume":"8","author":"Klibanov","year":"1999","journal-title":"Magma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5126","DOI":"10.7150\/thno.27221","article-title":"Ultrasound molecular imaging as a non-invasive companion diagnostic for netrin-1 interference therapy in breast cancer","volume":"8","author":"Wischhusen","year":"2018","journal-title":"Theranostics"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1574","DOI":"10.1158\/1078-0432.CCR-17-2057","article-title":"Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma","volume":"24","author":"Wang","year":"2018","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1200\/JCO.2016.70.8594","article-title":"Ultrasound Molecular Imaging With BR55 in Patients with Breast and Ovarian Lesions: First-in-Human Results","volume":"35","author":"Willmann","year":"2017","journal-title":"J. Clin. Oncol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"121154","DOI":"10.1016\/j.ijpharm.2021.121154","article-title":"Vancomycin-decorated microbubbles as a theranostic agent for Staphylococcus aureus biofilms","volume":"609","author":"Kouijzer","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"726","DOI":"10.7150\/thno.14514","article-title":"Thrombus-Targeted Theranostic Microbubbles: A New Technology towards Concurrent Rapid Ultrasound Diagnosis and Bleeding-free Fibrinolytic Treatment of Thrombosis","volume":"6","author":"Wang","year":"2016","journal-title":"Theranostics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.7150\/thno.4410","article-title":"Theranostic oxygen delivery using ultrasound and microbubbles","volume":"2","author":"Kwan","year":"2012","journal-title":"Theranostics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.cbpa.2021.04.013","article-title":"Phospholipid-coated targeted microbubbles for ultrasound molecular imaging and therapy","volume":"63","author":"Langeveld","year":"2021","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1097\/RLI.0000000000000362","article-title":"First-in-Human Ultrasound Molecular Imaging With a VEGFR2-Specific Ultrasound Molecular Contrast Agent (BR55) in Prostate Cancer: A Safety and Feasibility Pilot Study","volume":"52","author":"Smeenge","year":"2017","journal-title":"Investig. Radiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.jacc.2018.06.044","article-title":"Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries","volume":"72","author":"Moccetti","year":"2018","journal-title":"J. Am. Coll Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"899","DOI":"10.3389\/fphar.2019.00899","article-title":"In Vivo Ultrasound Molecular Imaging of SDF-1 Expression in a Swine Model of Acute Myocardial Infarction","volume":"10","author":"Wang","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"311","DOI":"10.7785\/tcrt.2012.500321","article-title":"A comparative evaluation of ultrasound molecular imaging, perfusion imaging, and volume measurements in evaluating response to therapy in patient-derived xenografts","volume":"12","author":"Streeter","year":"2013","journal-title":"Technol. Cancer Res. Treat."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s11307-018-1274-z","article-title":"Pharmacokinetic Modeling of Targeted Ultrasound Contrast Agents for Quantitative Assessment of Anti-Angiogenic Therapy: A Longitudinal Case-Control Study in Colon Cancer","volume":"21","author":"Turco","year":"2019","journal-title":"Mol. Imaging Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"7308","DOI":"10.1038\/s41598-020-64433-2","article-title":"Ultrasound Molecular Imaging of Renal Cell Carcinoma: VEGFR targeted therapy monitored with VEGFR1 and FSHR targeted microbubbles","volume":"10","author":"Ingels","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/j.ultrasmedbio.2019.11.007","article-title":"Seeing the Invisible-Ultrasound Molecular Imaging","volume":"46","author":"Kosareva","year":"2020","journal-title":"Ultrasound Med. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Steinl, D.C., Xu, L., Ochoa-Espinosa, A., Punjabi, M., and Kaufmann, B.A. (2019). Non-invasive contrast enhanced ultrasound molecular imaging of inflammation in autoimmune myocarditis for prediction of left ventricular fibrosis and remodeling. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0224377"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2493","DOI":"10.1016\/j.ultrasmedbio.2019.05.026","article-title":"Validation of Normalized Singular Spectrum Area as a Classifier for Molecularly Targeted Microbubble Adherence","volume":"45","author":"Herbst","year":"2019","journal-title":"Ultrasound Med. Biol"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.jcyt.2018.05.006","article-title":"StemBell therapy stabilizes atherosclerotic plaques after myocardial infarction","volume":"20","author":"Woudstra","year":"2018","journal-title":"Cytotherapy"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3221","DOI":"10.1021\/acs.langmuir.9b03912","article-title":"Ligand Distribution and Lipid Phase Behavior in Phospholipid-Coated Microbubbles and Monolayers","volume":"36","author":"Langeveld","year":"2020","journal-title":"Langmuir"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"101415","DOI":"10.1016\/j.mcp.2019.06.005","article-title":"Ultrasound-mediated destruction of vascular endothelial growth factor (VEGF) targeted and paclitaxel loaded microbubbles for inhibition of human breast cancer cell MCF-7 proliferation","volume":"46","author":"Su","year":"2019","journal-title":"Mol. Cell Probes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"127534","DOI":"10.1016\/j.bmcl.2020.127534","article-title":"Inhibitory effect of 5-FU loaded ultrasound microbubbles on tumor growth and angiogenesis","volume":"30","author":"He","year":"2020","journal-title":"Bioorganic. Med. Chem. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/s12195-019-00597-w","article-title":"Tissue Targeting and Ultrasound-Targeted Microbubble Destruction Delivery of Plasmid DNA and Transfection In Vitro","volume":"13","author":"Wang","year":"2020","journal-title":"Cell Mol. Bioeng."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12674","DOI":"10.1073\/pnas.1914906117","article-title":"Low-frequency ultrasound-mediated cytokine transfection enhances T cell recruitment at local and distant tumor sites","volume":"117","author":"Ilovitsh","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1097\/01.rli.0000115926.96796.75","article-title":"Detection of Individual Microbubbles of Ultrasound Contrast Agents","volume":"39","author":"Klibanov","year":"2004","journal-title":"Investig. Radiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1109\/TUFFC.2014.006440","article-title":"Targeted microbubble mediated sonoporation of endothelial cells in vivo","volume":"61","author":"Skachkov","year":"2014","journal-title":"IEEE Trans. Ultrason. Ferroelectr. Freq. Control"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.jconrel.2011.04.008","article-title":"Sonoporation of endothelial cells by vibrating targeted microbubbles","volume":"154","author":"Kooiman","year":"2011","journal-title":"J. Control. Release"},{"key":"ref_42","first-page":"e62076","article-title":"The Preparation of Chicken Ex Ovo Embryos and Chorioallantoic Membrane Vessels as In Vivo Model for Contrast-Enhanced Ultrasound Imaging and Microbubble-Mediated Drug Delivery Studies","volume":"168","author":"Meijlink","year":"2021","journal-title":"JoVE"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2575","DOI":"10.1016\/j.ultrasmedbio.2019.06.004","article-title":"Combined Confocal Microscope and Brandaris 128 Ultra-High-Speed Camera","volume":"45","author":"Beekers","year":"2019","journal-title":"Ultrasound Med. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.jcis.2008.09.066","article-title":"Microbubble size isolation by differential centrifugation","volume":"329","author":"Feshitan","year":"2009","journal-title":"J. Colloid Interface Sci."},{"key":"ref_45","first-page":"9","article-title":"Vascular Wall Shear Stress: Basic Principles and Methods","volume":"46","author":"Papaioannou","year":"2005","journal-title":"Hell. J. Cardiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1126\/science.7512751","article-title":"Requirement of Vascular Integrin \u03b1v\u03b23 for Angiogenesis","volume":"264","year":"1994","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1868","DOI":"10.1136\/heartjnl-2019-315103","article-title":"In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis","volume":"105","author":"Jenkins","year":"2019","journal-title":"Heart"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"120896","DOI":"10.1016\/j.biomaterials.2021.120896","article-title":"Molecular magnetic resonance imaging of Alpha-v-Beta-3 integrin expression in tumors with ultrasound microbubbles","volume":"275","author":"Pathak","year":"2021","journal-title":"Biomaterials"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"114rv113","DOI":"10.1126\/scitranslmed.3003149","article-title":"Forty-Year Journey of Angiogenesis Translational Research","volume":"3","author":"Cao","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s10237-012-0385-8","article-title":"Effect of the glycocalyx layer on transmission of interstitial flow shear stress to embedded cells","volume":"12","author":"Tarbell","year":"2013","journal-title":"Biomech. Model. Mechanobiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1016\/j.jbiomech.2006.06.023","article-title":"Effects of extracellular fiber architecture on cell membrane shear stress in a 3D fibrous matrix","volume":"40","author":"Pedersen","year":"2007","journal-title":"J. Biomech."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.jbiomech.2010.09.003","article-title":"Effects of shear stress cultivation on cell membrane disruption and intracellular calcium concentration in sonoporation of endothelial cells","volume":"44","author":"Park","year":"2011","journal-title":"J. Biomech."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1073\/pnas.98.3.1042","article-title":"Integrin-mediated mechanotransduction requires its dynamic interaction with specific extracellular matrix (ECM) ligands","volume":"98","author":"Jalali","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1093\/emboj\/20.17.4639","article-title":"Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment","volume":"20","author":"Tzima","year":"2001","journal-title":"EMBO J."},{"key":"ref_55","first-page":"3","article-title":"Effect of Pulse Shaping on Subharmonic Aided Pressure Estimation In Vitro and In Vivo","volume":"36","author":"Gupta","year":"2017","journal-title":"J. Ultrasound Med. Off. J. Am. Inst. Ultrasound Med."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Lum, J.S., Stobbe, D.M., Borden, M.A., and Murray, T.W. (2018). Photoacoustic technique to measure temperature effects on microbubble viscoelastic properties. Appl. Phys. Lett., 112.","DOI":"10.1063\/1.5005548"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.ultrasmedbio.2017.09.021","article-title":"Effect of Temperature on the Size Distribution, Shell Properties, and Stability of Definity(R)","volume":"44","author":"Shekhar","year":"2018","journal-title":"Ultrasound Med. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.ultras.2016.04.013","article-title":"Influence of temperature, needle gauge and injection rate on the size distribution, concentration and acoustic responses of ultrasound contrast agents at high frequency","volume":"70","author":"Sun","year":"2016","journal-title":"Ultrasonics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/j.ultrasmedbio.2010.03.003","article-title":"Temperature dependent behavior of ultrasound contrast agents","volume":"36","author":"Mulvana","year":"2010","journal-title":"Ultrasound Med. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e127","DOI":"10.1016\/j.ultras.2006.06.031","article-title":"Thermal response of contrast agent microbubbles: Preliminary results from physico-chemical and US-imaging characterization","volume":"44","author":"Guiot","year":"2006","journal-title":"Ultrasonics"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3109\/02652048.2011.638993","article-title":"Development and evaluation of lipid microbubbles targeted to alpha(v)beta(3)-integrin via biotin-avidin bridge","volume":"29","author":"Wang","year":"2012","journal-title":"J. Microencapsul."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.jconrel.2004.03.002","article-title":"Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow","volume":"96","author":"Takalkar","year":"2004","journal-title":"J. Control. Release"},{"key":"ref_63","first-page":"2043","article-title":"Adhesion of bio-functionalized ultrasound microbubbles to endothelial cells by targeting to vascular cell adhesion molecule-1 under shear flow","volume":"6","author":"Yang","year":"2011","journal-title":"Int. J. Nanomed."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1114\/1.1513565","article-title":"Modulating targeted adhesion of an ultrasound contrast agent to dysfunctional endothelium","volume":"30","author":"Weller","year":"2002","journal-title":"Ann. Biomed. Eng."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1002\/bit.22857","article-title":"Optimization of Ultrasound Contrast Agents with Computational Models to Improve Selection of Ligands and Binding Strength","volume":"107","author":"Maul","year":"2010","journal-title":"Biotechnol. Bioeng."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1392","DOI":"10.1016\/j.biomaterials.2009.11.007","article-title":"Potential role of size and hemodynamics in the efficacy of vascular-targeted spherical drug carriers","volume":"31","author":"Charoenphol","year":"2010","journal-title":"Biomaterials"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1016\/S0301-5629(99)00062-9","article-title":"Acoustic radiation force in vivo: A mechanism to assist targeting of microbubbles","volume":"25","author":"Dayton","year":"1999","journal-title":"Ultrasound Med. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1549-8719.2011.00152.x","article-title":"Use of intravital microscopy to study the microvascular behavior of microbubble-based ultrasound contrast agents","volume":"19","author":"Schneider","year":"2012","journal-title":"Microcirculation"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2440","DOI":"10.1016\/j.biomaterials.2009.01.019","article-title":"The association of silicon microparticles with endothelial cells in drug delivery to the vasculature","volume":"30","author":"Serda","year":"2009","journal-title":"Biomaterials"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1161\/01.CIR.102.5.531","article-title":"Noninvasive Imaging of Inflammation by Ultrasound Detection of Phagocytosed Microbubbles","volume":"102","author":"Lindner","year":"2000","journal-title":"Circulation"}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/2\/311\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:09:39Z","timestamp":1760134179000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/2\/311"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,28]]},"references-count":70,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["pharmaceutics14020311"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14020311","relation":{},"ISSN":["1999-4923"],"issn-type":[{"type":"electronic","value":"1999-4923"}],"subject":[],"published":{"date-parts":[[2022,1,28]]}}}