title: Thioridazine in PLGA nanoparticles reduces toxicity and improves rifampicin therapy against mycobacterial infection in zebrafish.
abstract: Encapsulating antibiotics such as rifampicin in biodegradable nanoparticles provides several advantages compared to free drug administration, including reduced dosing due to localized targeting and sustained release. Consequently, these characteristics reduce systemic drug toxicity. However, new nanoformulations need to be tested in complex biological systems to fully characterize their potential for improved drug therapy. Tuberculosis, caused by infection with the bacterium Mycobacterium tuberculosis, requires lengthy and expensive treatment, and incomplete therapy contributes to an increasing incidence of drug resistance. Recent evidence suggests that standard therapy may be improved by combining antibiotics with bacterial efflux pump inhibitors, such as thioridazine. However, this drug is difficult to use clinically due to its toxicity. Here, we encapsulated thioridazine in poly(lactic-co-glycolic) acid nanoparticles and tested them alone and in combination with rifampicin nanoparticles, or free rifampicin in macrophages and in a zebrafish model of tuberculosis. Whereas free thioridazine was highly toxic in both cells and zebrafish embryos, after encapsulation in nanoparticles no toxicity was detected. When combined with rifampicin nanoparticles, the nanoparticles loaded with thioridazine gave a modest increase in killing of both Mycobacterium bovis BCG and M. tuberculosis in macrophages. In the zebrafish, the thioridazine nanoparticles showed a significant therapeutic effect in combination with rifampicin by enhancing embryo survival and reducing mycobacterial infection. Our results show that the zebrafish embryo is a highly sensitive indicator of drug toxicity and that thioridazine nanoparticle therapy can improve the antibacterial effect of rifampicin in vivo.
authors.affiliation: a Department of Biosciences , University of Oslo , Oslo , Norway .
authors.forename: Carina Beatrice
authors.initials: CB
authors.lastname: Vibe
authors.affiliation: a Department of Biosciences , University of Oslo , Oslo , Norway .
authors.forename: Federico
authors.initials: F
authors.lastname: Fenaroli
authors.affiliation: b Centro De Patogénese Molecular-URIA/Instituto De Medicina Molecular, Instituto De Investigação Do Medicamento, iMed-ULisboa, Faculdade De Farmácia Da Universidade De Lisboa , Lisbon , Portugal .
authors.forename: David
authors.initials: D
authors.lastname: Pires
authors.affiliation: c Department of Chemistry , University of Oslo , Oslo , Norway , and.
authors.forename: Steven Ray
authors.initials: SR
authors.lastname: Wilson
authors.affiliation: d Department of Molecular Biology of the Cell Cycle , Institute of Molecular Biology, Bulgarian Academy of Sciences , Sofia , Bulgaria.
authors.forename: Vanya
authors.initials: V
authors.lastname: Bogoeva
authors.affiliation: a Department of Biosciences , University of Oslo , Oslo , Norway .
authors.forename: Raja
authors.initials: R
authors.lastname: Kalluru
authors.affiliation: a Department of Biosciences , University of Oslo , Oslo , Norway .
authors.forename: Martin
authors.initials: M
authors.lastname: Speth
authors.affiliation: b Centro De Patogénese Molecular-URIA/Instituto De Medicina Molecular, Instituto De Investigação Do Medicamento, iMed-ULisboa, Faculdade De Farmácia Da Universidade De Lisboa , Lisbon , Portugal .
authors.forename: Elsa
authors.initials: E
authors.lastname: Anes
authors.affiliation: a Department of Biosciences , University of Oslo , Oslo , Norway .
authors.forename: Gareth
authors.initials: G
authors.lastname: Griffiths
authors.affiliation: a Department of Biosciences , University of Oslo , Oslo , Norway .
authors.forename: Jon
authors.initials: J
authors.lastname: Hildahl
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008297:Male; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry*; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012293:Rifampin / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D013881:Thioridazine / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology; D015027:Zebrafish / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D013881:Thioridazine; D012293:Rifampin
keywords: Efflux pumps; efflux pump inhibitor; in vivo; tuberculosis