Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes

Benson J. Edagwa, Dongwei Guo, Pavan Puligujja, Han Chen, Jo Ellyn McMillan, Xinming Liu, Howard E. Gendelman, Prabagaran Narayanasamy

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Eradication of Mycobacterium tuberculosis (MTB) infection requires daily administration of combinations of rifampin (RIF), isoniazid [isonicotinylhydrazine (INH)], pyrazinamide, and ethambutol, among other drug therapies. To facilitate and optimize MTB therapeutic selections, a mononuclear phagocyte (MP; monocyte, macrophage, and dendritic cell)-targeted drug delivery strategy was developed. Long-acting nanoformulations of RIF and an INH derivative, pentenyl-INH (INHP), were prepared, and their physicochemical properties were evaluated. This included the evaluation of MP particle uptake and retention, cell viability, and antimicrobial efficacy. Drug levels reached 6 μg/106 cells in human monocyte-derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/106 cells for native drugs. High RIF and INHP levels were retained in MDM for >15 d following nanoparticle loading. Rapid loss of native drugs was observed in cells and culture fluids within 24 h. Antimicrobial activities were determined against Mycobacterium smegmatis (M. smegmatis). Coadministration of nanoformulated RIF and INHP provided a 6-fold increase in therapeutic efficacy compared with equivalent concentrations of native drugs. Notably, nanoformulated RIF and INHP were found to be localized in recycling and late MDM endosomal compartments. These were the same compartments that contained the pathogen. Our results demonstrate the potential of antimicrobial nanomedicines to simplify MTB drug regimens.

Original languageEnglish (US)
Pages (from-to)5071-5082
Number of pages12
JournalFASEB Journal
Volume28
Issue number12
DOIs
StatePublished - Dec 1 2014

Keywords

  • Immunoisolation
  • MDM
  • Mycobacterium smegmatis
  • Mycobacterium tuberculosis
  • Subcellular trafficking

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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