{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T16:13:58Z","timestamp":1792512838242,"version":"4.5.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,3,6]],"date-time":"2015-03-06T00:00:00Z","timestamp":1425600000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,3,6]],"date-time":"2015-03-06T00:00:00Z","timestamp":1425600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Human immunodeficiency virus (HIV) infection and <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (TB) are responsible for two of the major global human infectious diseases that result in significant morbidity, mortality and socioeconomic impact. Furthermore, severity and disease prevention of both infections is enhanced by co-infection. Parallel limitations also exist in access to effective drug therapy and the emergence of resistance. Furthermore, drug-drug interactions have proven problematic during treatment of co-incident HIV and TB infections. Thus, improvements in drug access and simplified treatment regimens are needed immediately. One of the key host cells infected by both HIV and TB is the mononuclear phagocyte (MP; monocyte, macrophage and dendritic cell). Therefore, we hypothesized that one way this can be achieved is through drug-targeting by a nanoformulated drug that ideally would be active against both HIV and TB. Accordingly, we validated macrophage targeted long acting (sustained drug release) gallium (Ga) nanoformulation against HIV-mycobacterium co-infection. The multi-targeted Ga nanoparticle agent inhibited growth of both HIV and TB in the macrophage. The Ga nanoparticles reduced the growth of mycobacterium and HIV for up to 15 days following single drug loading. These results provide a potential new approach to treat HIV-TB co-infection that could eventually lead to improved clinical outcomes.<\/jats:p>","DOI":"10.1038\/srep08824","type":"journal-article","created":{"date-parts":[[2015,3,6]],"date-time":"2015-03-06T10:01:24Z","timestamp":1425636084000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Prolonged-acting, Multi-targeting Gallium Nanoparticles Potently Inhibit Growth of Both HIV and Mycobacteria in Co-Infected Human Macrophages"],"prefix":"10.1038","volume":"5","author":[{"given":"Prabagaran","family":"Narayanasamy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara L.","family":"Switzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley E.","family":"Britigan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,6]]},"reference":[{"key":"BFsrep08824_CR1","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.chembiol.2010.01.013","volume":"17","author":"P Narayanasamy","year":"2010","unstructured":"Narayanasamy, P., Eoh, H., Brennan, P. J. & Crick, D. C. Synthesis of 4-diphosphocytidyl-2-C-methyl-D-erythritol 2-phosphate and kinetic studies of Mycobacterium tuberculosis IspF. Chemistry & biology 17, 117\u2013122 (2010).","journal-title":"Chemistry & biology"},{"key":"BFsrep08824_CR2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/S0140-6736(05)60878-1","volume":"349","author":"F Drobniewski","year":"1997","unstructured":"Drobniewski, F. Is death inevitable with multiresistant TB plus HIV infection? Lancet 349, 71\u201372 (1997).","journal-title":"Lancet"},{"key":"BFsrep08824_CR3","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1046\/j.1365-2249.2001.01481.x","volume":"123","author":"FG Imperiali","year":"2001","unstructured":"Imperiali, F. G. et al. Increased Mycobacterium tuberculosis growth in HIV-1-infected human macrophages: role of tumour necrosis factor-alpha. Clinical and experimental immunology 123, 435\u2013442 (2001).","journal-title":"Clinical and experimental immunology"},{"key":"BFsrep08824_CR4","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1517\/17425247.2011.559457","volume":"8","author":"EV Batrakova","year":"2011","unstructured":"Batrakova, E. V., Gendelman, H. E. & Kabanov, A. V. Cell-mediated drug delivery. Expert Opin Drug Deliv 8, 415\u2013433 (2011).","journal-title":"Expert Opin Drug Deliv"},{"key":"BFsrep08824_CR5","doi-asserted-by":"publisher","first-page":"379","DOI":"10.2217\/nnm.10.7","volume":"5","author":"AM Brynskikh","year":"2010","unstructured":"Brynskikh, A. M. et al. Macrophage delivery of therapeutic nanozymes in a murine model of Parkinson's disease. Nanomedicine (Lond) 5, 379\u2013396 (2010).","journal-title":"Nanomedicine (Lond)"},{"key":"BFsrep08824_CR6","doi-asserted-by":"publisher","first-page":"2827","DOI":"10.1182\/blood-2006-03-012534","volume":"108","author":"H Dou","year":"2006","unstructured":"Dou, H. et al. Development of a macrophage-based nanoparticle system for anti-retroviral drug delivery. Blood 108, 2827\u20132835 (2006).","journal-title":"Blood"},{"key":"BFsrep08824_CR7","doi-asserted-by":"publisher","first-page":"903","DOI":"10.2217\/nnm.09.71","volume":"4","author":"AS Nowacek","year":"2009","unstructured":"Nowacek, A. S. et al. NanoART synthesis, characterization, uptake, release and toxicology for human monocyte-macrophage drug delivery. Nanomedicine (Lond) 4, 903\u2013917 (2009).","journal-title":"Nanomedicine (Lond)"},{"key":"BFsrep08824_CR8","doi-asserted-by":"publisher","first-page":"6138","DOI":"10.1016\/j.bmcl.2013.09.011","volume":"23","author":"B Edagwa","year":"2013","unstructured":"Edagwa, B., Wang, Y. & Narayanasamy, P. Synthesis of azide derivative and discovery of glyoxalase pathway inhibitor against pathogenic bacteria. Bioorganic & medicinal chemistry letters 23, 6138\u20136140 (2013).","journal-title":"Bioorganic & medicinal chemistry letters"},{"key":"BFsrep08824_CR9","doi-asserted-by":"publisher","first-page":"1230","DOI":"10.1016\/j.chembiol.2009.10.014","volume":"16","author":"H Eoh","year":"2009","unstructured":"Eoh, H. et al. Expression and characterization of soluble 4-diphosphocytidyl-2-C-methyl-D-erythritol kinase from bacterial pathogens. Chemistry & biology 16, 1230\u20131239 (2009).","journal-title":"Chemistry & biology"},{"key":"BFsrep08824_CR10","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1128\/AAC.00655-09","volume":"54","author":"O Olakanmi","year":"2010","unstructured":"Olakanmi, O. et al. Gallium disrupts iron uptake by intracellular and extracellular Francisella strains and exhibits therapeutic efficacy in a murine pulmonary infection model. Antimicrobial agents and chemotherapy 54, 244\u2013253 (2010).","journal-title":"Antimicrobial agents and chemotherapy"},{"key":"BFsrep08824_CR11","doi-asserted-by":"publisher","first-page":"6074","DOI":"10.1128\/AAC.01543-13","volume":"57","author":"O Olakanmi","year":"2013","unstructured":"Olakanmi, O. et al. Gallium Nitrate Is Efficacious in Murine Models of Tuberculosis and Inhibits Key Bacterial Fe-Dependent Enzymes. Antimicrobial agents and chemotherapy 57, 6074\u20136080 (2013).","journal-title":"Antimicrobial agents and chemotherapy"},{"key":"BFsrep08824_CR12","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1128\/IAI.72.4.2022-2028.2004","volume":"72","author":"O Olakanmi","year":"2004","unstructured":"Olakanmi, O., Schlesinger, L. S., Ahmed, A. & Britigan, B. E. The nature of extracellular iron influences iron acquisition by Mycobacterium tuberculosis residing within human macrophages. Infect Immun 72, 2022\u20132028 (2004).","journal-title":"Infect Immun"},{"key":"BFsrep08824_CR13","doi-asserted-by":"publisher","first-page":"143","DOI":"10.2310\/6650.2005.00310","volume":"53","author":"O Olakanmi","year":"2005","unstructured":"Olakanmi, O., Stokes, J. B. & Britigan, B. E. Gallium-inducible transferrin-independent iron acquisition is a property of many cell types: possible role of alterations in the plasma membrane. J Investig Med 53, 143\u2013153 (2005).","journal-title":"J Investig Med"},{"key":"BFsrep08824_CR14","doi-asserted-by":"publisher","first-page":"3973","DOI":"10.1021\/jm070638m","volume":"50","author":"M Kurosu","year":"2007","unstructured":"Kurosu, M., Narayanasamy, P., Biswas, K., Dhiman, R. & Crick, D. C. Discovery of 1,4-dihydroxy-2-naphthoate [corrected] prenyltransferase inhibitors: new drug leads for multidrug-resistant gram-positive pathogens. Journal of medicinal chemistry 50, 3973\u20133975 (2007).","journal-title":"Journal of medicinal chemistry"},{"key":"BFsrep08824_CR15","doi-asserted-by":"publisher","first-page":"5071","DOI":"10.1096\/fj.14-255786","volume":"28","author":"BJ Edagwa","year":"2014","unstructured":"Edagwa, B. J. et al. Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 28, 5071\u20135082 (2014).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"BFsrep08824_CR16","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.virol.2006.08.012","volume":"358","author":"H Dou","year":"2007","unstructured":"Dou, H. et al. Laboratory investigations for the morphologic, pharmacokinetic and anti-retroviral properties of indinavir nanoparticles in human monocyte-derived macrophages. Virology 358, 148\u2013158 (2007).","journal-title":"Virology"},{"key":"BFsrep08824_CR17","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.jconrel.2010.11.019","volume":"150","author":"AS Nowacek","year":"2011","unstructured":"Nowacek, A. S. et al. Analyses of nanoformulated antiretroviral drug charge, size, shape and content for uptake, drug release and antiviral activities in human monocyte-derived macrophages. Journal of controlled release: official journal of the Controlled Release Society 150, 204\u2013211 (2011).","journal-title":"Journal of controlled release: official journal of the Controlled Release Society"},{"key":"BFsrep08824_CR18","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1016\/j.nano.2013.05.003","volume":"9","author":"P Puligujja","year":"2013","unstructured":"Puligujja, P. et al. Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections. Nanomedicine 9, 1263\u20131273 (2013).","journal-title":"Nanomedicine"},{"key":"BFsrep08824_CR19","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/j.tube.2003.08.012","volume":"84","author":"C Ratledge","year":"2004","unstructured":"Ratledge, C. Iron, mycobacteria and tuberculosis. Tuberculosis 84, 110\u2013130 (2004).","journal-title":"Tuberculosis"},{"key":"BFsrep08824_CR20","first-page":"287","volume":"38","author":"B Raghu","year":"1995","unstructured":"Raghu, B., Sarma, G. R. & Venkatesan, P. Effect of anti-tuberculosis drugs on the iron-sequestration mechanisms of mycobacteria. Indian journal of pathology & microbiology 38, 287\u2013292 (1995).","journal-title":"Indian journal of pathology & microbiology"},{"key":"BFsrep08824_CR21","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1172\/JCI112746","volume":"78","author":"CR Chitambar","year":"1986","unstructured":"Chitambar, C. R. & Seligman, P. A. Effects of different transferrin forms on transferrin receptor expression, iron uptake and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium. The Journal of clinical investigation 78, 1538\u20131546 (1986).","journal-title":"The Journal of clinical investigation"},{"key":"BFsrep08824_CR22","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1128\/IAI.68.3.1271-1275.2000","volume":"68","author":"BE Britigan","year":"2000","unstructured":"Britigan, B. E., Rasmussen, G. T., Olakanmi, O. & Cox, C. D. Iron acquisition from Pseudomonas aeruginosa siderophores by human phagocytes: an additional mechanism of host defense through iron sequestration? Infect Immun 68, 1271\u20131275 (2000).","journal-title":"Infect Immun"},{"key":"BFsrep08824_CR23","doi-asserted-by":"publisher","first-page":"5619","DOI":"10.1128\/IAI.68.10.5619-5627.2000","volume":"68","author":"O Olakanmi","year":"2000","unstructured":"Olakanmi, O., Britigan, B. E. & Schlesinger, L. S. Gallium disrupts iron metabolism of mycobacteria residing within human macrophages. Infect Immun 68, 5619\u20135627 (2000).","journal-title":"Infect Immun"},{"key":"BFsrep08824_CR24","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1002\/1097-0142(197911)44:5<1722::AID-CNCR2820440528>3.0.CO;2-C","volume":"44","author":"IH Krakoff","year":"1979","unstructured":"Krakoff, I. H., Newman, R. A. & Goldberg, R. S. Clinical toxicologic and pharmacologic studies of gallium nitrate. Cancer 44, 1722\u20131727 (1979).","journal-title":"Cancer"},{"key":"BFsrep08824_CR25","doi-asserted-by":"publisher","first-page":"2709","DOI":"10.1007\/s11095-006-9104-4","volume":"23","author":"G Dumortier","year":"2006","unstructured":"Dumortier, G., Grossiord, J. L., Agnely, F. & Chaumeil, J. C. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res 23, 2709\u20132728 (2006).","journal-title":"Pharm Res"},{"key":"BFsrep08824_CR26","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1002\/(SICI)1099-0844(199912)17:4<279::AID-CBF833>3.0.CO;2-J","volume":"17","author":"A Savarino","year":"1999","unstructured":"Savarino, A., Pescarmona, G. P. & Boelaert, J. R. Iron metabolism and HIV infection: reciprocal interactions with potentially harmful consequences? Cell biochemistry and function 17, 279\u2013287 (1999).","journal-title":"Cell biochemistry and function"},{"key":"BFsrep08824_CR27","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1038\/nrmicro1930","volume":"6","author":"H Drakesmith","year":"2008","unstructured":"Drakesmith, H. & Prentice, A. Viral infection and iron metabolism. Nature reviews. Microbiology 6, 541\u2013552 (2008).","journal-title":"Nature reviews. Microbiology"},{"key":"BFsrep08824_CR28","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1002\/j.1460-2075.1993.tb05701.x","volume":"12","author":"D Lombardi","year":"1993","unstructured":"Lombardi, D. et al. Rab9 functions in transport between late endosomes and the trans Golgi network. EMBO J 12, 677\u2013682 (1993).","journal-title":"EMBO J"},{"key":"BFsrep08824_CR29","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1083\/jcb.135.4.913","volume":"135","author":"O Ullrich","year":"1996","unstructured":"Ullrich, O., Reinsch, S., Urbe, S., Zerial, M. & Parton, R. G. Rab11 regulates recycling through the pericentriolar recycling endosome. J Cell Biol 135, 913\u2013924 (1996).","journal-title":"J Cell Biol"},{"key":"BFsrep08824_CR30","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1111\/j.1749-6632.1989.tb24036.x","volume":"557","author":"SC Clark","year":"1989","unstructured":"Clark, S. C. Interleukin-6. Multiple activities in regulation of the hematopoietic and immune systems. Annals of the New York Academy of Sciences 557, 438\u2013443 (1989).","journal-title":"Annals of the New York Academy of Sciences"},{"key":"BFsrep08824_CR31","first-page":"3393","volume":"6","author":"S Balkundi","year":"2011","unstructured":"Balkundi, S. et al. Comparative manufacture and cell-based delivery of antiretroviral nanoformulations. Int. J. Nanomed. 6, 3393\u20133404 (2011).","journal-title":"Int. J. Nanomed."},{"key":"BFsrep08824_CR32","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1021\/mp800137z","volume":"6","author":"P Xu","year":"2009","unstructured":"Xu, P. et al. Intracellular drug delivery by poly(lactic-co-glycolic acid) nanoparticles, revisited. Molecular pharmaceutics 6, 190\u2013201 (2009).","journal-title":"Molecular pharmaceutics"},{"key":"BFsrep08824_CR33","doi-asserted-by":"publisher","first-page":"128","DOI":"10.4172\/2157-7064.1000128","volume":"3","author":"R Bhandari","year":"2012","unstructured":"Bhandari, R. & Kaur, I. P. A sensitive HPLC method for determination of isoniazid in rat plasma, brain, liver and kidney. J. Chromatogr. Sep. Tech. 3, 128 (2012).","journal-title":"J. Chromatogr. Sep. Tech."},{"key":"BFsrep08824_CR34","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1016\/j.chroma.2003.12.041","volume":"1031","author":"I Calleja","year":"2004","unstructured":"Calleja, I., Blanco-Prieto, M. J., Ruz, N., Renedo, M. J. & Dios-Vieitez, M. C. High-performance liquid-chromatographic determination of rifampicin in plasma and tissues. J. Chromatogr. A 1031, 289\u2013294 (2004).","journal-title":"J. Chromatogr. A"},{"key":"BFsrep08824_CR35","doi-asserted-by":"publisher","first-page":"2827","DOI":"10.1182\/blood-2006-03-012534","volume":"108","author":"H Dou","year":"2006","unstructured":"Dou, H. et al. Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery. Blood 108, 2827-2835 (2006).","journal-title":"Blood"},{"key":"BFsrep08824_CR36","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1084\/jem.167.4.1428","volume":"167","author":"HE Gendelman","year":"1988","unstructured":"Gendelman, H. E. et al. Efficient isolation and propagation of human immunodeficiency virus on recombinant colony-stimulating factor 1-treated monocytes. J Exp Med 167, 1428\u20131441 (1988).","journal-title":"J Exp Med"},{"key":"BFsrep08824_CR37","first-page":"424","volume":"95","author":"BD Kumar","year":"1992","unstructured":"Kumar, B. D., Prasad, C. E. & Krishnaswamy, K. Detection of rifampicin-induced nephrotoxicity by N-acetyl-3-D-glucosaminidase activity. The Journal of tropical medicine and hygiene 95, 424\u2013427 (1992).","journal-title":"The Journal of tropical medicine and hygiene"},{"key":"BFsrep08824_CR38","doi-asserted-by":"publisher","first-page":"744","DOI":"10.4049\/jimmunol.1102244","volume":"189","author":"I Kadiu","year":"2012","unstructured":"Kadiu, I., Narayanasamy, P., Dash, P. K., Zhang, W. & Gendelman, H. E. Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol 189, 744\u2013754 (2012).","journal-title":"J Immunol"}],"updated-by":[{"DOI":"10.1038\/s41598-021-97514-x","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T00:00:00Z","timestamp":1630454400000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep08824","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep08824.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep08824.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T16:44:13Z","timestamp":1672937053000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep08824"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,3,6]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,8,14]]}},"alternative-id":["BFsrep08824"],"URL":"https:\/\/doi.org\/10.1038\/srep08824","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,3,6]]},"assertion":[{"value":"28 October 2014","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-021-97514-x","URL":"https:\/\/doi.org\/10.1038\/s41598-021-97514-x","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"8824"}}