title: pH-Responsive Isoniazid-Loaded Nanoparticles Markedly Improve Tuberculosis Treatment in Mice.
abstract: Tuberculosis is a major global health problem for which improved therapeutics are needed to shorten the course of treatment and combat emergence of drug resistance. Mycobacterium tuberculosis, the etiologic agent of tuberculosis, is an intracellular pathogen of mononuclear phagocytes. As such, it is an ideal pathogen for nanotherapeutics because macrophages avidly ingest nanoparticles even without specific targeting molecules. Hence, a nanoparticle drug delivery system has the potential to target and deliver high concentrations of drug directly into M. tuberculosis-infected cells-greatly enhancing efficacy while avoiding off-target toxicities. Stimulus-responsive mesoporous silica nanoparticles of two different sizes, 100 and 50 nm, are developed as carriers for the major anti-tuberculosis drug isoniazid in a prodrug configuration. The drug is captured by the aldehyde-functionalized nanoparticle via hydrazone bond formation and coated with poly(ethylene imine)-poly(ethylene glycol) (PEI-PEG). The drug is released from the nanoparticles in response to acidic pH at levels that naturally occur within acidified endolysosomes. It is demonstrated that isoniazid-loaded PEI-PEG-coated nanoparticles are avidly ingested by M. tuberculosis-infected human macrophages and kill the intracellular bacteria in a dose-dependent manner. It is further demonstrated in a mouse model of pulmonary tuberculosis that the nanoparticles are well tolerated and much more efficacious than an equivalent amount of free drug.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, 3013 Young Dr. East, CA, 90095-1569, USA.
authors.forename: Angela A
authors.initials: AA
authors.lastname: Hwang
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, CHS 37-121, 10833 Le Conte Ave., CA, 90095-1688, USA.
authors.forename: Bai-Yu
authors.initials: BY
authors.lastname: Lee
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, CHS 37-121, 10833 Le Conte Ave., CA, 90095-1688, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Clemens
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, CHS 37-121, 10833 Le Conte Ave., CA, 90095-1688, USA.
authors.forename: Barbara Jane
authors.initials: BJ
authors.lastname: Dillon
authors.affiliation: Department of Chemistry and Biochemistry, University of California, Los Angeles, 3013 Young Dr. East, CA, 90095-1569, USA.|California NanoSystems Institute, University of California, Los Angeles, CA, 90095-8352, USA.
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.affiliation: Division of Infectious Diseases, Department of Medicine, University of California, Los Angeles, CHS 37-121, 10833 Le Conte Ave., CA, 90095-1688, USA.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007538:Isoniazid / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D008807:Mice, Inbred BALB C; D050296:Microbial Viability / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D016062:Porosity; D011355:Prodrugs / Q000627:therapeutic use; D012822:Silicon Dioxide / Q000737:chemistry; D013056:Spectrophotometry, Ultraviolet; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000447:Aldehydes; D011355:Prodrugs; D011092:Polyethylene Glycols; D012822:Silicon Dioxide; D011094:Polyethyleneimine; D007538:Isoniazid
keywords: drug delivery; mesoporous silica; mesoporous silica nanoparticles; multifunctional nanoparticles; tuberculosis