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Long‐acting antituberculous therapeutic nanoparticles target macrophage endosomes
Author(s) -
Edagwa Benson J.,
Guo Dongwei,
Puligujja Pavan,
Chen Han,
McMillan JoEllyn,
Liu Xinming,
Gendelman Howard E.,
Narayanasamy Prabagaran
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-255786
Subject(s) - mycobacterium smegmatis , ethambutol , mycobacterium tuberculosis , pharmacology , chemistry , drug , antimycobacterial , pyrazinamide , isoniazid , antimicrobial , mononuclear phagocyte system , drug delivery , microbiology and biotechnology , endosome , tuberculosis , medicine , cell , biology , immunology , biochemistry , organic chemistry , pathology
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/10 6 cells in human monocyte‐derived macrophages (MDMs) for nanoparticle treatments compared with 0.1 μg/10 6 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.—Edagwa, B. J., Guo, D., Puligujja, P., Chen, H., McMillan, J., Liu, X., Gendelman, H. E., Narayanasamy, P., Long‐acting antituberculous therapeutic nanoparticles target macrophage endosomes. FASEB J. 28, 5071–5082 (2014). www.fasebj.org