{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T22:48:03Z","timestamp":1773269283993,"version":"3.50.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Pulmonary arterial hypertension (PAH) remains a challenge to tackle despite various available medications. Metformin, although promising, has major adverse effects; the use of an appropriate drug delivery method may improve its efficacy and safety. The aim of this study was to develop a novel treatment for PAH using metformin. We developed a novel approach of using low-dose metformin encapsulated in pulmonary artery-targeted nanocapsules to alleviate PAH while avoiding adverse effects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Metformin-loaded lung-targeted nanocapsules (MET nanocapsules) were created using a specific lipid composition, including cationic lipids. Their uptake and effects on cell viability were assessed in human pulmonary arterial smooth muscle cells (hPASMCs) from healthy individuals and patients with PAH. Their therapeutic effects were assessed in a PAH rat model. The safety of MET nanocapsules was confirmed using rat serum biochemical tests.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We successfully prepared MET nanocapsules and demonstrated their effectiveness in inhibiting PASMC proliferation. In PAH model rats, MET nanocapsule treatment led to improved hemodynamics, right ventricular hypertrophy, and pulmonary arterial medial thickening. The nanocapsules effectively accumulated in the lungs of PAH model rats.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Intravenous administration of MET nanocapsules is a safe and innovative therapeutic approach for PAH. This method could improve PAH treatment outcomes while minimizing adverse effects, with potential applications in other types of pulmonary hypertension.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1577570","type":"journal-article","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T07:30:00Z","timestamp":1745998200000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Pulmonary artery-targeted low-dose metformin-loaded nanocapsules safely improve pulmonary arterial hypertension in rats"],"prefix":"10.3389","volume":"16","author":[{"given":"Ayako","family":"Chida-Nagai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Masaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Sato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatsuya","family":"Kato","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emi","family":"Takakuwa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Matsuno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Manabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsuhito","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"175579","DOI":"10.1016\/j.ejphar.2023.175579","article-title":"AMPK activation by metformin protects against pulmonary hypertension in rats and relaxes isolated human pulmonary artery","volume":"946","author":"Abdelazeem","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"2747","DOI":"10.1161\/circulationaha.109.927681","article-title":"Formation of plexiform lesions in experimental severe pulmonary arterial hypertension","volume":"121","author":"Abe","year":"2010","journal-title":"Circulation"},{"key":"B3","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1016\/s0022-2836(64)80115-7","article-title":"Negative staining of phospholipids and their structural modification by surface-active agents as observed in the electron microscope","volume":"8","author":"Bangham","year":"1964","journal-title":"J. Mol. Biol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.nantod.2014.04.008","article-title":"Challenges associated with penetration of nanoparticles across cell and tissue barriers: a review of current status and future prospects","volume":"9","author":"Barua","year":"2014","journal-title":"Nano Today"},{"key":"B5","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1164\/rccm.202009-3698OC","article-title":"Association between initial treatment strategy and long-term survival in pulmonary arterial hypertension","volume":"204","author":"Boucly","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e018349","DOI":"10.1161\/jaha.120.018349","article-title":"Mechanistic phase II clinical trial of metformin in pulmonary arterial hypertension","volume":"9","author":"Brittain","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"B7","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41565-020-0669-6","article-title":"Selective organ targeting (SORT) nanoparticles for tissue-specific mRNA delivery and CRISPR-Cas gene editing","volume":"15","author":"Cheng","year":"2020","journal-title":"Nat. Nanotechnol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"e0211450","DOI":"10.1371\/journal.pone.0211450","article-title":"Role of BRCA1-associated protein (BRAP) variant in childhood pulmonary arterial hypertension","volume":"14","author":"Chida-Nagai","year":"2019","journal-title":"PLoS One"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1834","DOI":"10.1172\/jci117169","article-title":"Protection of rabbit lungs from endotoxin injury by in vivo hyperexpression of the prostaglandin G\/H synthase gene","volume":"93","author":"Conary","year":"1994","journal-title":"J. Clin. Invest"},{"key":"B10","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1161\/hypertensionaha.116.07353","article-title":"Metformin reverses development of pulmonary hypertension via aromatase inhibition","volume":"68","author":"Dean","year":"2016","journal-title":"Hypertension"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1043","DOI":"10.1378\/chest.15-0300","article-title":"Five-Year outcomes of patients enrolled in the REVEAL Registry","volume":"148","author":"Farber","year":"2015","journal-title":"Chest"},{"key":"B12","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1038\/s41574-019-0242-2","article-title":"Understanding the glucoregulatory mechanisms of metformin in type 2 diabetes mellitus","volume":"15","author":"Foretz","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"170003","DOI":"10.1183\/16000617.0003-2017","article-title":"Pulmonary hypertensive vasculopathy in parenchymal lung diseases and\/or hypoxia: number 1 in the series \u201cpathology for the clinician\u201d edited by peter dorfm\u00fcller and alberto cavazza","volume":"26","author":"Ghigna","year":"2017","journal-title":"Eur. Respir. Rev."},{"key":"B14","doi-asserted-by":"publisher","first-page":"3618","DOI":"10.1093\/eurheartj\/ehac237","article-title":"2022 ESC\/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension","volume":"43","author":"Humbert","year":"2022","journal-title":"Eur. Heart J."},{"key":"B30","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1161\/circulationaha.117.033113","article-title":"Selenoprotein P Promotes the Development of Pulmonary Arterial Hypertension: Possible Novel Therapeutic Target","volume":"138","author":"Kikuchi","year":"2018","journal-title":"Circulation"},{"key":"B15","doi-asserted-by":"publisher","first-page":"7534","DOI":"10.1021\/nn401317t","article-title":"Lipid envelope-type nanoparticle incorporating a multifunctional peptide for systemic siRNA delivery to the pulmonary endothelium","volume":"7","author":"Kusumoto","year":"2013","journal-title":"ACS Nano"},{"key":"B16","doi-asserted-by":"publisher","first-page":"191","DOI":"10.3389\/fendo.2020.00191","article-title":"Metformin and its benefits for various diseases","volume":"11","author":"Lv","year":"2020","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"B17","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1089\/oli.1.1999.9.71","article-title":"Cationic lipids employed for antisense oligodeoxynucleotide transport may inhibit vascular cell adhesion molecule-1 expression in human endothelial cells: a word of caution","volume":"9","author":"Maus","year":"1999","journal-title":"Antisense Nucleic Acid. Drug Dev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"41","DOI":"10.2174\/1567201819666220324093821","article-title":"Liposome nanoparticles as a novel drug delivery system for therapeutic and diagnostic applications","volume":"20","author":"Meng","year":"2022","journal-title":"Curr. Drug Deliv."},{"key":"B19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1146\/annurev-med-062613-093128","article-title":"Metformin in cancer treatment and prevention","volume":"66","author":"Morales","year":"2015","journal-title":"Annu. Rev. Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"5034","DOI":"10.1038\/s41467-022-32568-7","article-title":"AMPK deficiency in smooth muscles causes persistent pulmonary hypertension of the new-born and premature death","volume":"13","author":"Moral-Sanz","year":"2022","journal-title":"Nat. Commun."},{"key":"B21","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1161\/circresaha.115.308178","article-title":"Protective roles of endothelial AMP-activated protein kinase against hypoxia-induced pulmonary hypertension in mice","volume":"119","author":"Omura","year":"2016","journal-title":"Circ. Res."},{"key":"B22","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1161\/atvbaha.121.317168","article-title":"Caspase-8 promotes pulmonary hypertension by activating macrophage-associated inflammation and IL-1\u03b2 (interleukin 1\u03b2) production","volume":"42","author":"Rong","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1183\/09031936.00174908","article-title":"Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension","volume":"34","author":"Selimovic","year":"2009","journal-title":"Eur. Respir. J."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1161\/circulationaha.120.048191","article-title":"MDM2-Mediated ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension","volume":"142","author":"Shen","year":"2020","journal-title":"Circulation"},{"key":"B25","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1186\/s12931-022-02001-0","article-title":"Evaluation for clinical benefit of metformin in patients with idiopathic pulmonary fibrosis and type 2 diabetes mellitus: a national claims-based cohort analysis","volume":"23","author":"Teague","year":"2022","journal-title":"Respir. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"948101","DOI":"10.3389\/fphar.2022.948101","article-title":"Effectiveness and mechanism of metformin in animal models of pulmonary fibrosis: a preclinical systematic review and meta-analysis","volume":"13","author":"Wu","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.lfs.2018.07.018","article-title":"Activation of AMPK prevents monocrotaline-induced pulmonary arterial hypertension by suppression of NF-\u03baB-mediated autophagy activation","volume":"208","author":"Zhai","year":"2018","journal-title":"Life Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/978-1-4939-6591-5_2","article-title":"Thin-film hydration followed by extrusion method for liposome preparation","volume":"1522","author":"Zhang","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"348","DOI":"10.5414\/cp202686","article-title":"Hemodialysis-refractory metformin-associated lactate acidosis with hypoglycemia, hypothermia, and bradycardia in a diabetic patient with belated diagnosis and chronic kidney disease","volume":"55","author":"Zibar","year":"2017","journal-title":"Int. J. Clin. Pharmacol. Ther."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1577570\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T07:30:00Z","timestamp":1745998200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1577570\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,30]]},"references-count":30,"alternative-id":["10.3389\/fphar.2025.1577570"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1577570","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,30]]},"article-number":"1577570"}}