{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T10:51:15Z","timestamp":1770547875359,"version":"3.49.0"},"reference-count":22,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T00:00:00Z","timestamp":1626134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Atherosclerosis involves an ongoing inflammatory response of the vascular endothelium and vessel wall of the aorta and vein. The pleiotropic effects of statins have been well described in many in vitro and in vivo studies, but these effects are difficult to achieve in clinical practice due to the low bioavailability of statins and their first-pass metabolism in the liver. The aim of this study was to test a vessel wall local drug delivery system (DDS) using PLA microstructures loaded with simvastatin. Wistar rats were fed high cholesterol chow as a model. The rat vessels were chemically injured by repeated injections of perivascular paclitaxel and 5-fluorouracil. The vessels were then cultured and treated by the injection of several concentrations of poly(L,L-lactide) microparticles loaded with the high local HMG-CoA inhibitor simvastatin (0.58 mg\/kg) concentration (SVPLA). Histopathological examinations of the harvested vessels and vital organs after 24 h, 7 days and 4 weeks were performed. Microcirculation in mice as an additional test was performed to demonstrate the safety of this approach. A single dose of SVPLA microspheres with an average diameter of 6.4 \u03bcm and a drug concentration equal to 8.1% of particles limited the inflammatory reaction of the endothelium and vessel wall and had no influence on microcirculation in vivo or in vitro. A potent pleiotropic (anti-inflammatory) effect of simvastatin after local SVPLA administration was observed. Moreover, significant concentrations of free simvastatin were observed in the vessel wall (compared to the maximum serum level). In addition, it appeared that simvastatin, once locally administered as SVPLA particles, exerted potent pleiotropic effects on chemically injured vessels and presented anti-inflammatory action. Presumably, this effect was due to the high local concentrations of simvastatin. No local or systemic side effects were observed. This approach could be useful for local simvastatin DDSs when high, local drug concentrations are difficult to obtain, or systemic side effects are present.<\/jats:p>","DOI":"10.3390\/ijms22147486","type":"journal-article","created":{"date-parts":[[2021,7,13]],"date-time":"2021-07-13T22:25:31Z","timestamp":1626215131000},"page":"7486","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Anti-Inflammatory Effect of Very High Dose Local Vessel Wall Statin Administration: Poly(L,L-Lactide) Biodegradable Microspheres with Simvastatin for Drug Delivery System (DDS)"],"prefix":"10.3390","volume":"22","author":[{"given":"Piotr","family":"Wacinski","sequence":"first","affiliation":[{"name":"Department of Cardiology, Medical University of Lublin, Jaczewskiego 8, 20-950 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariusz","family":"Gadzinowski","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, H. Sienkiewicza 112, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0449-2375","authenticated-orcid":false,"given":"Wojciech","family":"Dabrowski","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Medical University of Lublin, Jaczewskiego 8, 20-950 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justyna","family":"Szumilo","sequence":"additional","affiliation":[{"name":"Department of Pathology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakub","family":"Wacinski","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Medical University of Lublin, Jaczewskiego 8, 20-950 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Oru","sequence":"additional","affiliation":[{"name":"Fernand Vidal Hospital, Universite de M\u00e9decine Paris 7, 75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Vicaut","sequence":"additional","affiliation":[{"name":"Fernand Vidal Hospital, Universite de M\u00e9decine Paris 7, 75006 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislaw","family":"Czuczwar","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9541-6353","authenticated-orcid":false,"given":"Janusz","family":"Kocki","sequence":"additional","affiliation":[{"name":"Department of Genetics, Medical University of Lublin, Radziwillowska 18, 20-080 Lublin, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8429-9665","authenticated-orcid":false,"given":"Teresa","family":"Basinska","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, H. Sienkiewicza 112, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stanislaw","family":"Slomkowski","sequence":"additional","affiliation":[{"name":"Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, H. Sienkiewicza 112, 90-363 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1056\/NEJMra043430","article-title":"Inflammation, Atherosclerosis, and Coronary Artery Disease","volume":"352","author":"Hansson","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1111\/j.1365-2796.2008.01965.x","article-title":"The molecular mechanisms of the thrombotic complications of atherosclerosis","volume":"263","author":"Libby","year":"2008","journal-title":"J. Intern. 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