{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T02:55:52Z","timestamp":1784861752588,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T00:00:00Z","timestamp":1635206400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R56 AI151033-01"],"award-info":[{"award-number":["R56 AI151033-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Methicillin-resistant Staphylococcus aureus (MRSA), commonly called a superbug, is a highly alarming antibiotic-resistant population of Staphylococcus aureus (S. aureus) bacteria. Vancomycin (VAN) was first approved by the FDA in 1988, and it is still regarded as the treatment of choice for MRSA. The efficacy of VAN treatment has become less effective due to the development of VAN resistance in MRSA and the potential for nephrotoxicity. This study aims to improve the efficacy of VAN treatment by identifying the folate receptor for MRSA infected tissues and developing folate decorated lipid nanoparticles containing VAN (LVAN). In comparison to conventional VAN, LVAN showed a higher bactericidal effect and a superior ability to inhibit biofilm in MRSA with an enhanced accumulation in MRSA infected thigh tissues and a reduced accumulation in kidney. The results suggested that LVAN is a promising candidate to overcome the current limitations of bacterial resistance and adverse side effects in kidneys found in VAN.<\/jats:p>","DOI":"10.3390\/pharmaceutics13111791","type":"journal-article","created":{"date-parts":[[2021,10,26]],"date-time":"2021-10-26T23:54:33Z","timestamp":1635292473000},"page":"1791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Folate Functionalized Lipid Nanoparticles for Targeted Therapy of Methicillin-Resistant Staphylococcus aureus"],"prefix":"10.3390","volume":"13","author":[{"given":"Kushal","family":"Vanamala","sequence":"first","affiliation":[{"name":"Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ketki","family":"Bhise","sequence":"additional","affiliation":[{"name":"Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiram","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Razieh","family":"Kebriaei","sequence":"additional","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duy","family":"Luong","sequence":"additional","affiliation":[{"name":"Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4364-5875","authenticated-orcid":false,"given":"Samaresh","family":"Sau","sequence":"additional","affiliation":[{"name":"Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hosam","family":"Abdelhady","sequence":"additional","affiliation":[{"name":"Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"},{"name":"Lake Erie College of Osteopathic Medicine, Erie, PA 16509, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Rybak","sequence":"additional","affiliation":[{"name":"Anti-Infective Research Laboratory, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Andes","sequence":"additional","affiliation":[{"name":"Division of Infectious Disease, Department of Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4428-0222","authenticated-orcid":false,"given":"Arun K.","family":"Iyer","sequence":"additional","affiliation":[{"name":"Use-Inspired Biomaterials & Integrated Nano Delivery (U-BiND) Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"},{"name":"Molecular Imaging Program, Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.drudis.2020.10.011","article-title":"Novel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance","volume":"26","author":"Vanamala","year":"2021","journal-title":"Drug Discov. Today"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1128\/JCM.03221-14","article-title":"High Staphylococcus aureus colonization prevalence among patients with skin and soft tissue infections and controls in an urban emergency department","volume":"53","author":"Kumar","year":"2015","journal-title":"J. Clin. Microbiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13756-019-0550-2","article-title":"Control of MSSA and MRSA in the United States: Protocols, policies, risk adjustment and excuses","volume":"8","author":"Kavanagh","year":"2019","journal-title":"Antimicrob. Resist. Infect. Control"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1086\/422997","article-title":"Methicillin-Resistant Staphylococcus aureus (MRSA) Nares Colonization at Hospital Admission and Its Effect on Subsequent MRSA Infection","volume":"39","author":"Davis","year":"2004","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1086\/507918","article-title":"Characteristics of Patients With Healthcare-Associated Infection Due to SCC mec Type IV Methicillin-Resistant Staphylococcus aureus","volume":"27","author":"Davis","year":"2006","journal-title":"Infect. Control Hosp. Epidemiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1093\/cid\/cir034","article-title":"Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: Executive summary","volume":"52","author":"Liu","year":"2011","journal-title":"Clin. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1086\/519470","article-title":"Limitations of vancomycin in the management of resistant staphylococcal infections","volume":"45","author":"Kollef","year":"2007","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1186\/s13054-017-1801-3","article-title":"Incidence, prevalence, and management of MRSA bacteremia across patient populations-a review of recent developments in MRSA management and treatment","volume":"21","author":"Hassoun","year":"2017","journal-title":"Crit. Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1002\/phar.1423","article-title":"Vancomycin-associated nephrotoxicity in adult medicine patients: Incidence, outcomes, and risk factors","volume":"34","author":"Meaney","year":"2014","journal-title":"Pharmacotherapy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1128\/AAC.02764-13","article-title":"A novel approach utilizing biofilm time-kill curves to assess the bactericidal activity of ceftaroline combinations against biofilm- producing methicillin-resistant staphylococcus aureus","volume":"58","author":"Barber","year":"2014","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/BF01569817","article-title":"Biofilms in device-related infections","volume":"15","author":"Khardori","year":"1995","journal-title":"J. Ind. Microbiol."},{"key":"ref_12","first-page":"S19","article-title":"Antibiotics alter the gut microbiome and host health","volume":"1423","author":"Cully","year":"2019","journal-title":"Nat. Milest."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1039\/D0MD00347F","article-title":"Antibiotic administration in targeted nanoparticles protects the faecal microbiota of mice","volume":"12","author":"Borsa","year":"2021","journal-title":"RSC Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Cross, R. (2021). Without these lipid shells, there would be no mRNA vaccines for COVID-19. Chem. Eng. News, 16\u201319.","DOI":"10.47287\/cen-09908-feature1"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/j.ijpharm.2017.04.078","article-title":"Nanostructured Lipid Carriers Employing Polyphenols as Promising Anticancer Agents: Quality by Design (QbD) approach","volume":"526","author":"Bhise","year":"2017","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.4155\/tde-2017-0062","article-title":"Nanomedicine for cancer diagnosis and therapy: Advancement, success and structure-activity relationship","volume":"8","author":"Bhise","year":"2017","journal-title":"Ther. Deliv."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6745","DOI":"10.1039\/c4nr00974f","article-title":"Cancer cell-selective promoter recognition accompanies antitumor effect by glucocorticoid receptor-targeted gold nanoparticle","volume":"6","author":"Sau","year":"2014","journal-title":"Nanoscale"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.jcis.2017.01.092","article-title":"Synthesis and characterization of folate decorated albumin bio-conjugate nanoparticles loaded with a synthetic curcumin difluorinated analogue","volume":"496","author":"Gawde","year":"2017","journal-title":"J. Colloid Interface Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.jconrel.2017.03.023","article-title":"Assessment of penetration potential of pH responsive double walled biodegradable nanogels coated with eucalyptus oil for the controlled delivery of 5-fluorouracil: In vitro and ex vivo studies","volume":"253","author":"Sahu","year":"2017","journal-title":"J. Control. Release"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1016\/j.nano.2018.04.004","article-title":"CD44 directed nanomicellar payload delivery platform for selective anticancer effect and tumor specific imaging of triple negative breast cancer","volume":"14","author":"Wang","year":"2018","journal-title":"Nanomed. Nanotechnol. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bhise, K., Sau, S., Kebriaei, R., Rice, S.A., Stamper, K.C., Alsaab, H.O., Rybak, M.J., and Iyer, A.K. (2018). Combination of Vancomycin and Cefazolin Lipid Nanoparticles for Overcoming Antibiotic Resistance of MRSA. Materials, 11.","DOI":"10.3390\/ma11071245"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14700","DOI":"10.18632\/oncotarget.3739","article-title":"Assessment of folate receptor-\u03b2 expression in human neoplastic tissues","volume":"6","author":"Shen","year":"2015","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1165\/rcmb.2014-0289OC","article-title":"Molecular imaging of folate receptor \u03b2-positive macrophages during acute lung inflammation","volume":"53","author":"Han","year":"2015","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"6390","DOI":"10.1016\/j.bmc.2016.11.008","article-title":"Animal models in the pharmacokinetic\/pharmacodynamic evaluation of antimicrobial agents","volume":"24","author":"Zhao","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.coph.2017.09.004","article-title":"In vivo infection models in the pre-clinical pharmacokinetic\/pharmacodynamic evaluation of antimicrobial agents","volume":"36","author":"Andes","year":"2017","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1128\/AAC.00624-19","article-title":"In Vivo Pharmacodynamics of Omadacycline against Staphylococcus aureus in the Neutropenic Murine Thigh Infection Model","volume":"63","author":"Lepak","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9395","DOI":"10.1158\/0008-5472.CAN-09-2050","article-title":"Folate receptor \u03b2 is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory\/regulatory Macrophages","volume":"69","author":"Samaniego","year":"2009","journal-title":"Cancer Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"17282","DOI":"10.1038\/s41598-020-73687-9","article-title":"The comparative risk of acute kidney injury of vancomycin relative to other common antibiotics","volume":"10","author":"Gaggl","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2101","DOI":"10.2215\/CJN.11011016","article-title":"Vancomycin and the risk of AKI: Now clearer than mississippi mud","volume":"11","author":"Nolin","year":"2016","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1002\/cpt.726","article-title":"The Nephrotoxicity of Vancomycin","volume":"102","author":"Filippone","year":"2017","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1038\/s41467-018-04390-7","article-title":"Immunogene therapy with fusogenic nanoparticles modulates macrophage response to Staphylococcus aureus","volume":"9","author":"Kim","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.2147\/IJN.S121956","article-title":"The antimicrobial activity of nanoparticles: Present situation and prospects for the future","volume":"12","author":"Wang","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.ijheatmasstransfer.2015.04.048","article-title":"Experimental investigation on effect of ultrasonication duration on colloidal dispersion and thermophysical properties of alumina-water nanofluid","volume":"88","author":"Mahbubul","year":"2015","journal-title":"Int. J. Heat Mass Transf."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1016\/j.ijantimicag.2010.10.011","article-title":"Preparation of liposomal vancomycin and intracellular killing of meticillin-resistant Staphylococcus aureus (MRSA)","volume":"37","author":"Pumerantz","year":"2011","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S35","DOI":"10.1086\/491712","article-title":"The pharmacokinetic and pharmacodynamic properties of vancomycin","volume":"42","author":"Rybak","year":"2006","journal-title":"Clin. Infect. Dis."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/11\/1791\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:24:15Z","timestamp":1760167455000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/13\/11\/1791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,26]]},"references-count":35,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["pharmaceutics13111791"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics13111791","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,26]]}}}