{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:33:48Z","timestamp":1760060028392,"version":"build-2065373602"},"reference-count":32,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,8,1]],"date-time":"2025-08-01T00:00:00Z","timestamp":1754006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R21HL126250-01"],"award-info":[{"award-number":["R21HL126250-01"]}]},{"name":"Cystic Fibrosis Foundation Student Traineeship Award","award":["R21HL126250-01"],"award-info":[{"award-number":["R21HL126250-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cystic fibrosis produces viscous mucus in the lung that increases bacterial invasion, causing persistent infections and subsequent inflammation. Pseudomonas aeruginosa and Staphylococcus aureus are two of the most common infections in cystic fibrosis patients that are resistant to antibiotics. One antibiotic approved to treat these infections is levofloxacin (LVX), which functions to inhibit bacterial replication but can be further developed into tailorable particles. Nanoparticles are an emerging inhaled therapy due to enhanced targeting and delivery. The extracellular matrix (ECM) has been shown to possess pro-regenerative and non-toxic properties in vitro, making it a promising delivery agent. The combination of LVX and ECM formed into nanoparticles may overcome barriers to lung delivery to effectively treat cystic fibrosis bacterial infections. Our goal is to advance CF care by providing a combined treatment option that has the potential to address both bacterial infections and lung damage. Two hybrid formulations of a 10:1 and 1:1 ratio of LVX to ECM have shown neutral surface charges and an average size of ~525 nm and ~300 nm, respectively. The neutral charge and size of the particles may suggest their ability to attract toward and penetrate through the mucus barrier in order to target the bacteria. The NPs have also been shown to slow the drug dissolution, are non-toxic to human airway epithelial cells, and are effective in inhibiting Pseudomonas aeruginosa and Staphylococcus aureus. LVX-ECM NPs may be an effective treatment for pulmonary CF bacterial treatments.<\/jats:p>","DOI":"10.3390\/ijms26157453","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"7453","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tailored Levofloxacin Incorporated Extracellular Matrix Nanoparticles for Pulmonary Infections"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2187-0968","authenticated-orcid":false,"given":"Raahi","family":"Patel","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignacio","family":"Moyano","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1387-3009","authenticated-orcid":false,"given":"Masahiro","family":"Sakagami","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason D.","family":"Kang","sequence":"additional","affiliation":[{"name":"Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phillip B.","family":"Hylemon","sequence":"additional","affiliation":[{"name":"Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, School of Medicine, Virginia Commonwealth University, Richmond, VA 23219, USA"},{"name":"Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2437-2859","authenticated-orcid":false,"given":"Judith A.","family":"Voynow","sequence":"additional","affiliation":[{"name":"Division of Pediatric Pulmonology, Children\u2019s Hospital of Richmond at Virginia Commonwealth University, Richmond, VA 23298, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6602-6700","authenticated-orcid":false,"given":"Rebecca L.","family":"Heise","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23219, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,1]]},"reference":[{"key":"ref_1","unstructured":"Cystic Fibrosis Foundation (2023, August 13). CF Foundation Estimates Increase in CF Population. CFF. Available online: https:\/\/www.cff.org\/news\/2022-07\/cf-foundation-estimates-increase-cf-population."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1002\/ppul.24530","article-title":"Mucus, Mucins and Cystic Fibrosis","volume":"54","author":"Morrison","year":"2019","journal-title":"Pediatr. Pulmonol."},{"key":"ref_3","unstructured":"(2024, January 25). Definition of Extracellular Matrix\u2014NCI Dictionary of Cancer Terms\u2014NCI [Internet], Available online: https:\/\/www.cancer.gov\/publications\/dictionaries\/cancer-terms\/def\/extracellular-matrix."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1016\/j.jcf.2022.04.016","article-title":"Pathological remodeling of distal lung matrix in end-stage cystic fibrosis patients","volume":"21","author":"Pinezich","year":"2022","journal-title":"J. Cyst. Fibros."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1136\/thx.2006.074641","article-title":"Airway remodelling in children with cystic fibrosis","volume":"62","author":"Hilliard","year":"2007","journal-title":"Thorax"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7565","DOI":"10.1021\/acsami.1c14975","article-title":"Hybrid Lipid\/Polymer Nanoparticles to Tackle the Cystic Fibrosis Mucus Barrier in siRNA Delivery to the Lungs: Does PEGylation Make the Difference?","volume":"14","author":"Conte","year":"2022","journal-title":"ACS Appl. Mater. Interfaces"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1016\/j.biomaterials.2008.12.076","article-title":"The penetration of fresh undiluted sputum expectorated by cystic fibrosis patients by non-adhesive polymer nanoparticles","volume":"30","author":"Suk","year":"2009","journal-title":"Biomaterials"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2043","DOI":"10.1038\/mt.2016.182","article-title":"The Mucus Barrier to Inhaled Gene Therapy","volume":"24","author":"Duncan","year":"2016","journal-title":"Mol. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jconrel.2019.10.035","article-title":"Rational particle design to overcome pulmonary barriers for obstructive lung diseases therapy","volume":"314","author":"He","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.2217\/fmb-2021-0150","article-title":"Management of chronic Pseudomonas aeruginosa infection with inhaled levofloxacin in people with cystic fibrosis","volume":"16","author":"Elborn","year":"2021","journal-title":"Future Microbiol."},{"key":"ref_11","unstructured":"(2024, April 18). Drug Approval Package: Levaquin (Levofloxacin) NDA# 020634\/S04 & 0202635\/S03, Available online: https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/98\/020634s04.cfm#."},{"key":"ref_12","unstructured":"Quinsair (2024, April 18). European Medicines Agency. Available online: https:\/\/www.ema.europa.eu\/en\/medicines\/human\/EPAR\/quinsair."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1378\/chest.124.1.360","article-title":"Inhalation of a Dry Powder Tobramycin PulmoSphere Formulation in Healthy Volunteers","volume":"124","author":"Newhouse","year":"2003","journal-title":"CHEST"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1021\/acs.molpharmaceut.8b01256","article-title":"Tailored Nanocarriers for the Pulmonary Delivery of Levofloxacin against Pseudomonas aeruginosa: A Comparative Study","volume":"16","author":"Derbali","year":"2019","journal-title":"Mol. Pharm."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.smim.2017.01.002","article-title":"The host response to naturally-derived extracellular matrix biomaterials","volume":"29","author":"Morris","year":"2017","journal-title":"Semin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2331","DOI":"10.1002\/term.2768","article-title":"Electrosprayed extracellular matrix nanoparticles induce a pro-regenerative cell response","volume":"12","author":"Link","year":"2018","journal-title":"J. Tissue Eng. Regen. Med."},{"key":"ref_17","first-page":"100041","article-title":"Extracellular matrix scaffolds derived from different musculoskeletal tissues drive distinct macrophage phenotypes and direct tissue-specific cellular differentiation","volume":"12","author":"Mahon","year":"2021","journal-title":"J. Immunol. Regen. Med."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Witherel, C.E., Sao, K., Brisson, B.K., Han, B., Volk, S.W., Petrie, R.J., Han, L., and Spiller, K.L. (2021). Regulation of extracellular matrix assembly and structure by hybrid M1\/M2 macrophages. Biomaterials, 269.","DOI":"10.1016\/j.biomaterials.2021.120667"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1002\/jbm.a.35894","article-title":"Solubilized extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype","volume":"105","author":"Dziki","year":"2017","journal-title":"J. Biomed. Mater. Res. Part A"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1080\/17425247.2021.1854222","article-title":"Enhancing nanoparticle penetration through airway mucus to improve drug delivery efficacy in the lung","volume":"18","author":"Chen","year":"2021","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/j.jconrel.2020.03.032","article-title":"Peptides as surface coatings of nanoparticles that penetrate human cystic fibrosis sputum and uniformly distribute in vivo following pulmonary delivery","volume":"322","author":"Leal","year":"2020","journal-title":"J. Control. Release"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2602","DOI":"10.1007\/s11051-014-2602-0","article-title":"Sustainable strategies for nano-in-micro particle engineering for pulmonary delivery","volume":"16","author":"Silva","year":"2014","journal-title":"J. Nanopart. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.ejpb.2015.07.010","article-title":"Optimization of levofloxacin-loaded crosslinked chitosan microspheres for inhaled aerosol therapy","volume":"96","author":"Gaspar","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.colsurfb.2016.03.040","article-title":"Smart lipid nanoparticles containing levofloxacin and DNase for lung delivery. Design and characterization","volume":"143","author":"Islan","year":"2016","journal-title":"Colloids Surfaces B: Biointerfaces"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1080\/03639045.2017.1318902","article-title":"Dry powders for the inhalation of ciprofloxacin or levofloxacin combined with a mucolytic agent for cystic fibrosis patients","volume":"43","author":"Cayli","year":"2017","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wandling, E.N., Rhoads, K., Ohman, D.E., and Heise, R.L. (2023). Electrosprayed Mesenchymal Stromal Cell Extracellular Matrix Nanoparticles Accelerate Cellular Wound Healing and Reduce Gram-Negative Bacterial Growth. Pharmaceutics, 15.","DOI":"10.3390\/pharmaceutics15041277"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1093\/jac\/45.4.483","article-title":"Levofloxacin penetrates human monocytes and enhances intracellular killing of Staphylococcus aureus and Pseudomonas aeruginosa","volume":"45","author":"Smith","year":"2000","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1089\/107632702753503063","article-title":"Antimicrobial Activity Associated with Extracellular Matrices","volume":"8","author":"Sarikaya","year":"2002","journal-title":"Tissue Eng."},{"key":"ref_29","first-page":"1","article-title":"Antimicrobial Properties of Extracellular Matrix Scaffolds for Tissue Engineering","volume":"2019","year":"2019","journal-title":"BioMed Res. Int."},{"key":"ref_30","first-page":"213046","article-title":"Enhanced wound-healing capability with inherent antimicrobial activities of usnic acid incorporated poly(\u03b5-caprolactone)\/decellularized extracellular matrix nanofibrous scaffold","volume":"140","author":"Chandika","year":"2022","journal-title":"Mater. Sci. Eng. C"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Link, P.A., Pouliot, R.A., Mikhaiel, N.S., Young, B.M., and Heise, R.L. (2017). Tunable Hydrogels from Pulmonary Extracellular Matrix for 3D Cell Culture. J. Vis. Exp.","DOI":"10.3791\/55094"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s11095-019-2635-2","article-title":"In Vivo-Relevant Transwell Dish-Based Dissolution Testing for Orally Inhaled Corticosteroid Products","volume":"36","author":"Sakagami","year":"2019","journal-title":"Pharm. 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