{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:44:02Z","timestamp":1790729042072,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,4,11]],"date-time":"2023-04-11T00:00:00Z","timestamp":1681171200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"publisher","award":["722717"],"award-info":[{"award-number":["722717"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Drug delivery to the retina is one of the major challenges in ophthalmology due to the biological barriers that protect it from harmful substances in the body. Despite the advancement in ocular therapeutics, there are many unmet needs for the treatment of retinal diseases. Ultrasound combined with microbubbles (USMB) was proposed as a minimally invasive method for improving delivery of drugs in the retina from the blood circulation. This study aimed to investigate the applicability of USMB for the delivery of model drugs (molecular weight varying from 600 Da to 20 kDa) in the retina of ex vivo porcine eyes. A clinical ultrasound system, in combination with microbubbles approved for clinical ultrasound imaging, was used for the treatment. Intracellular accumulation of model drugs was observed in the cells lining blood vessels in the retina and choroid of eyes treated with USMB but not in eyes that received ultrasound only. Specifically, 25.6 \u00b1 2.9% of cells had intracellular uptake at mechanical index (MI) 0.2 and 34.5 \u00b1 6.0% at MI 0.4. Histological examination of retinal and choroid tissues revealed that at these USMB conditions, no irreversible alterations were induced at the USMB conditions used. These results indicate that USMB can be used as a minimally invasive targeted means to induce intracellular accumulation of drugs for the treatment of retinal diseases.<\/jats:p>","DOI":"10.3390\/pharmaceutics15041220","type":"journal-article","created":{"date-parts":[[2023,4,12]],"date-time":"2023-04-12T01:35:08Z","timestamp":1681263308000},"page":"1220","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Microbubble-Assisted Ultrasound for Drug Delivery to the Retina in an Ex Vivo Eye Model"],"prefix":"10.3390","volume":"15","author":[{"given":"Charis","family":"Rousou","sequence":"first","affiliation":[{"name":"Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands"},{"name":"Imaging and Oncology Division, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicky","family":"van Kronenburg","sequence":"additional","affiliation":[{"name":"Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9065-6713","authenticated-orcid":false,"given":"Andreas F. P.","family":"Sonnen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Pathology, Division of Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrit","family":"Moonen","sequence":"additional","affiliation":[{"name":"Imaging and Oncology Division, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4296-2761","authenticated-orcid":false,"given":"Gert","family":"Storm","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands"},{"name":"Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore"},{"name":"Department of Biomaterials Science and Technology, University of Twente, 7500 AE Enschede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Mastrobattista","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Heidelberglaan 8, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5281-2949","authenticated-orcid":false,"given":"Roel","family":"Deckers","sequence":"additional","affiliation":[{"name":"Imaging and Oncology Division, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1016\/j.drudis.2019.05.035","article-title":"Challenges and opportunities for drug delivery to the posterior of the eye","volume":"24","author":"Cabrera","year":"2019","journal-title":"Drug Discov. 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