Abstract:
:Although nitric oxide (NO) is a bactericidal component of the macrophage's innate response to intracellular infections such as tuberculosis (TB), prolonged inhalation of NO gas has little benefit in chemotherapy of TB. The impact of controlled release of NO through intracellular delivery of NO donors to macrophages infected in vitro with Mycobacterium tuberculosis (Mtb) was investigated. Inhalable microparticles (MP) were prepared by spray-drying. Isosorbide mononitrate (ISMN), sodium nitroprusside (SNP), and diethylenetriamine nitric oxide adduct (DETA/NO) were incorporated in poly(lactic-co-glycolic acid) (PLGA) with encapsulation efficiencies of >90% to obtain MP yields of ∼70%. The mass median aerodynamic diameter (MMAD) of the MP was 2.2-2.4 μm within geometric standard deviations (GSD) of ≤0.1 μm. MP were phagocytosed by THP-1 derived macrophages in culture and significantly (P < 0.05) sustained NO secretion into culture supernatant from 6 to 72 h in comparison to equivalent amounts of drugs in solution. Significantly (P < 0.05) higher dose-dependent killing of intracellular Mtb by MP compared to equivalent amounts of drugs in solution was observed on estimation of colony forming units (CFU) surviving 24 h after exposure to drugs or MP. The cytotoxicity of MP toward macrophages was lower than that of dissolved drugs. It was concluded that inhalable MP can target NO donors to the macrophage, control NO release in the macrophage cytosol, and reduce Mtb CFU by up to 3-log in 24 h, at doses that are much lower than those required for cardiovascular effects.
journal_name
Mol Pharmjournal_title
Molecular pharmaceuticsauthors
Verma RK,Singh AK,Mohan M,Agrawal AK,Verma PR,Gupta A,Misra Adoi
10.1021/mp300269gsubject
Has Abstractpub_date
2012-11-05 00:00:00pages
3183-9issue
11eissn
1543-8384issn
1543-8392journal_volume
9pub_type
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