TY - JOUR
T1 - Long-acting antituberculous therapeutic nanoparticles target macrophage endosomes
AU - Edagwa, Benson J.
AU - Guo, Dongwei
AU - Puligujja, Pavan
AU - Chen, Han
AU - McMillan, Jo Ellyn
AU - Liu, Xinming
AU - Gendelman, Howard E.
AU - Narayanasamy, Prabagaran
N1 - Publisher Copyright:
© The Author(s).
PY - 2014/12/1
Y1 - 2014/12/1
N2 - 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.
AB - 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.
KW - Immunoisolation
KW - MDM
KW - Mycobacterium smegmatis
KW - Mycobacterium tuberculosis
KW - Subcellular trafficking
UR - http://www.scopus.com/inward/record.url?scp=84919784607&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84919784607&partnerID=8YFLogxK
U2 - 10.1096/fj.14-255786
DO - 10.1096/fj.14-255786
M3 - Article
C2 - 25122556
AN - SCOPUS:84919784607
SN - 0892-6638
VL - 28
SP - 5071
EP - 5082
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -