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Potential Active Targeting of Gatifloxacin to Macrophages by Means of Surface-Modified PLGA Microparticles Destined to Treat Tuberculosis

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Abstract

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and represents one of the leading causes of mortality worldwide due to multidrug-resistant TB (MDR-TB). In our work, a new formulation of biodegradable PLGA microparticles was developed for pulmonary administration of gatifloxacin, using a surface modifier agent to actively target alveolar macrophages thereby allowing to gain access of the drug to Mycobacterium tuberculosis. For this, rapid uptake of the particles by macrophages is beneficial. This process was evaluated with fluorescein-loaded microparticles using PLGA 502 or PLGA 502H as polymers and labrafil as surface modifier. Cell phagocytosis was studied in raw 264.7 mouse macrophage cell line after 3, 5, 24, and 48 h incubation with the microparticles. Labrafil enhanced the uptake rate of PLGA 502H microparticles by macrophages which was directly related to the modification of the polymer matrix. Gatifloxacin-loaded PLGA microparticles using PLGA 502 or PLGA 502H and labrafil were prepared. From our results, only microparticles prepared with PLGA 502H and labrafil exhibited high encapsulation efficiency (89.6 ± 0.2%), rapid phagocytosis by macrophages (3 h), and remained inside the cells for at least 48 h, thereby resulting in a suitable carrier to potentially treat MDR-TB.

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References

  1. WHO. Global tuberculosis report 2018 in http://www.who.int. 2018. Last accessed June 2018.

  2. Lin SY, Desmond EP. Molecular diagnosis of tuberculosis and drug resistance. Clin Lab Med. 2014;34:297–314. https://doi.org/10.1016/j.cll.2014.02.005.

    Article  PubMed  Google Scholar 

  3. Salamon H, Yamaguchi KD, Cirillo DM, et al. Integration of published information into a resistance-associated mutation database for Mycobacterium tuberculosis. J Infect Dis. 2015;2:50–7. https://doi.org/10.1093/infdis/jiu816.

    Article  Google Scholar 

  4. Hirota K, Terada H. Endocytosis of particles formulations by macrophages and its application to clinical treatment. INTECH, Open Access Publisher. 2012;16:13–428. https://doi.org/10.5772/45820.

    Article  CAS  Google Scholar 

  5. Patel B, Gupta N, Ahsan F. Particle engineering to enhance of lessen particle uptake by alveolar macrophages and to influence the therapeutic outcome. Eur J Pharm Biopharm. 2015;89:163–74. https://doi.org/10.1016/j.ejpb.2014.12.001.

    Article  CAS  PubMed  Google Scholar 

  6. Hirota K, Hasegawa T, Nakajima T, Makino K, Terada H. Phagostimulatory effect of uptake of PLGA microspheres loaded with rifampicin on alveolar macrophages. Colloids Surf B: Biointerfaces. 2011;87:293–8. https://doi.org/10.1016/j.colsurfb.2011.05.032.

    Article  CAS  PubMed  Google Scholar 

  7. Sharma R, Muttil P, Yadav AB, et al. Uptake of inhalable microparticles affects defense responses of macrophages infected with Mycobacterium tuberculosis H37Ra. J Antimicrob Chemother. 2007;59:499–506. https://doi.org/10.1093/jac/dkl533.

    Article  CAS  PubMed  Google Scholar 

  8. Muttil P, Kaur J, Kumar K, Yadav AB, Sharma R, Misra A. Inhalable microparticles containing large payload of anti-tuberculosis drugs. Eur J Pharm Sci. 2007;32:140–50. https://doi.org/10.1016/j.ejps.2007.06.006.

    Article  CAS  PubMed  Google Scholar 

  9. Rustomjee R, Lienhardt C, Kanyok T, et al. A phase II study of the sterilizing activities of ofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis. Int J Tuberc Lung Dis. 2008;2:128–38.

    Google Scholar 

  10. Merle CS, Sismanidis C, Sow OB, et al. A pivotal registration phase III, multicenter, randomized tuberculosis controlled trial: design issues and lesson learnt from the gatifloxacin for TB (OFLOTUB) project. Trials. 2012;18:13–61. https://doi.org/10.1186/1745-6215-13-61.

    Article  CAS  Google Scholar 

  11. Merle CS, Fielding K, Sow OB, et al. A four-month gatifloxacin containing regimen for treating tuberculosis. N Engl J Med. 2014;17:1588–98. https://doi.org/10.1056/NEJMoa1315817.

    Article  CAS  Google Scholar 

  12. Ruan Q, Liu Q, Sun F, et al. Moxifloxacin and gatifloxacin for initial therapy of tuberculosis: a meta-analysis of randomized clinical trials. Emerg Microbes Infect. 2016;24:1038–50. https://doi.org/10.1038/emi.2016.12.

    Article  CAS  Google Scholar 

  13. European Directorate for Quality in Medicines (EDQM). European Pharmacopeia 9th Edition (9.0). Preparations for inhalations: aerodynamic assessment of fine particles. Strasburg: France EDQM; 2016.

    Google Scholar 

  14. Fernandez-Carballidoa A, Pastoriza P, Barcia E, et al. PLGA/PEG-derivative polymeric matrix for drug delivery systemapplications: characterization and cell viability studies. Int J Pharm. 2008;352:50–7. https://doi.org/10.1016/j.ijpharm.2007.10.007.

    Article  CAS  Google Scholar 

  15. Puebla P, Pastoriza P, Barcia E, Fernández-Carballido A. PEG-derivative effectively modifies the characteristics of indomethacin-PLGA microspheres destined to intra-articular administration. J Microencapsul. 2005;22:793–808. https://doi.org/10.1080/02652040500273902.

    Article  CAS  PubMed  Google Scholar 

  16. Galkina E, Ley K. Immune and inflammatory mechanisms of atherosclerosis. Annu Rev Immunol. 2009;27:165–97. https://doi.org/10.1146/annurev.immunol.021908.132620.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Russel DG, Cardona PJ, Kim MJ, et al. F. Foamy macrophages and the progression of the human TB granuloma. Nat. Immunol. 2009;10:943–8. https://doi.org/10.1038/ni.1781.

    Article  CAS  Google Scholar 

  18. Pacheco P, White D, Sulchek T. Effects of microparticle size and Fc density on macrophage phagocytosis. PLoS One. 2013;8:e60989. https://doi.org/10.1371/journal.pone.0060989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chono S, Tanino T, Seki T, Morimoto K. Influence of particle size on drug delivery to rat alveolar macrophages following pulmonary administration of ciprofloxacin incorporated into liposomes. J Drug Target. 2006;14:557–66. https://doi.org/10.1080/10611860600834375.

    Article  CAS  PubMed  Google Scholar 

  20. Hirota K, Hasegawa T, Hinata H, Ito F, Inagawa H, Kochi C, et al. Optimum conditions for efficient phagocytosis of rifampicin-loaded PLGA microspheres by alveolar macrophages. J Control Release. 2007;119:69–76. https://doi.org/10.1016/j.jconrel.2007.01.013.

    Article  CAS  PubMed  Google Scholar 

  21. Simón-Yarza T, Formiga FR, Tamayo E, Pelacho B, Prosper F, Blanco-Prieto MJ. PEGylated-PLGA microparticles containing VEGF for long term drug delivery. Int J Pharm. 2012;440:13–8. https://doi.org/10.1016/j.ijpharm.2012.07.006.

    Article  CAS  PubMed  Google Scholar 

  22. Mathaes R, Winter G, Besheer A, et al. Influence of particle geometry and PEGylation on phagocytosis of particulate carriers. Int J Pharm. 2014;465:1–6. https://doi.org/10.1016/j.ijpharm.2014.02.037.

    Article  CAS  Google Scholar 

  23. Champion S, Mitragotri A. Role of target geometry in phagocytosis. Proc Natl Acad Sci. 2006;103:4930–4. https://doi.org/10.1073/pnas.0600997103.

    Article  CAS  PubMed  Google Scholar 

  24. Ahsan F, Rivas IP, Khan MA, et al. Targeting to macrophages: role of physicochemical properties of particulate carriers liposomes and microspheres on the phagocytosis by macrophages. J Control Release. 2002;79:29–40. https://doi.org/10.1016/S0168-3659(01)00549-1.

    Article  CAS  PubMed  Google Scholar 

  25. Verhoef J, Anchordoquy TJ. Questioning the use of PEGylation for drug delivery. Drug Deliv Transl Res. 2003;3:499–503.

    Article  Google Scholar 

  26. Yang C, Gao S, Dagnæs-Hansen F, Jakobsen M, Kjems J. Impact of PEG chain length on the physical properties and bioactivity of PEGylated chitosan/ siRNA nanoparticles in vitro and in vivo. ACS Appl Mater Interfaces. 2017;9:12203–16. https://doi.org/10.1021/acsami.6b16556.

    Article  CAS  PubMed  Google Scholar 

  27. Owens DE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm. 2006;307:93–102. https://doi.org/10.1016/j.ijpharm.2005.10.010.

    Article  CAS  PubMed  Google Scholar 

  28. Mosqueira C, Legrand P, Morgat J, et al. Biodistribution of long-circulating PEG-grafted nanocapsules in mice: effects of PEG chain length and density. Pharm Res. 2001;18:1411–9.

    Article  CAS  Google Scholar 

  29. Allen LA, Aderem A. Molecular definition of distinct cytoskeletal structures involved in complement and Fc receptor mediated phagocytosis in macrophages. J Exp Med. 1996;184:627–37.

    Article  CAS  Google Scholar 

  30. Greenberg S, Grinstein S. Phagocytosis and innate immunity. Curr Opin Immunol. 2002;14:136–45. https://doi.org/10.1016/S0952-7915(01)00309-0.

    Article  CAS  PubMed  Google Scholar 

  31. Telko MJ, Hickey AJ. Dry powder inhaler formulation. Respir Care. 2005;50:1209–27.

    PubMed  Google Scholar 

  32. Gardner DL, Tweedle DEF. Pathology for surgeons in training. An A-Z Revision Text. 3th ed. Boca Raton: Taylor & Francis Group; 2002. p. 32.

    Book  Google Scholar 

  33. Fernández A, Casan P. Deposition of inhaled particles in the lungs. Arch Bronconeumol. 2012;48:240–6. https://doi.org/10.1016/j.arbr.2012.02.006.

    Article  Google Scholar 

Download references

Acknowledgments

The authors wish to express their gratitude to Isabel Trabado from the Unidad de Cultivos de Células Humanas (Universidad de Alcalá, Spain) for her technical assistance.

Funding

This work was partially supported by the Complutense University of Madrid, UCM Research group 910.939.

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Authors and Affiliations

  1. Departamento de Farmacia Galénica y Tecnología Alimentaria, Facultad de Farmacia, Pl. Ramón y Cajal s/n, Universidad Complutense de Madrid, 28040, Madrid, Spain

    Patricia Marcianes, Sofia Negro, Emilia Barcia & Ana Fernández-Carballido

  2. Facultad de Farmacia, Pl. Ramón y Cajal s/n, Instituto Universitario de Farmacia Industrial, Universidad Complutense de Madrid, 28040, Madrid, Spain

    Sofia Negro, Emilia Barcia & Ana Fernández-Carballido

  3. Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad CEU-San Pablo, 28668 Boadilla del Monte, Madrid, Spain

    Consuelo Montejo

Authors
  1. Patricia Marcianes
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  2. Sofia Negro
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  3. Emilia Barcia
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  4. Consuelo Montejo
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Correspondence to Sofia Negro.

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All animal procedures were conducted according to the European Community Council Directive (010/63/UE).

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Marcianes, P., Negro, S., Barcia, E. et al. Potential Active Targeting of Gatifloxacin to Macrophages by Means of Surface-Modified PLGA Microparticles Destined to Treat Tuberculosis. AAPS PharmSciTech 21, 15 (2020). https://doi.org/10.1208/s12249-019-1552-3

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