title: Targeted intracellular delivery of antituberculosis drugs to Mycobacterium tuberculosis-infected macrophages via functionalized mesoporous silica nanoparticles.
abstract: Delivery of antituberculosis drugs by nanoparticles offers potential advantages over free drug, including the potential to target specifically the tissues and cells that are infected by Mycobacterium tuberculosis, thereby simultaneously increasing therapeutic efficacy and decreasing systemic toxicity, and the capacity for prolonged release of drug, thereby allowing less-frequent dosing. We have employed mesoporous silica nanoparticle (MSNP) drug delivery systems either equipped with a polyethyleneimine (PEI) coating to release rifampin or equipped with cyclodextrin-based pH-operated valves that open only at acidic pH to release isoniazid (INH) into M. tuberculosis-infected macrophages. The MSNP are internalized efficiently by human macrophages, traffic to acidified endosomes, and release high concentrations of antituberculosis drugs intracellularly. PEI-coated MSNP show much greater loading of rifampin than uncoated MSNP and much greater efficacy against M. tuberculosis-infected macrophages. MSNP were devoid of cytotoxicity at the particle doses employed for drug delivery. Similarly, we have demonstrated that the isoniazid delivered by MSNP equipped with pH-operated nanovalves kill M. tuberculosis within macrophages significantly more effectively than an equivalent amount of free drug. These data demonstrate that MSNP provide a versatile platform that can be functionalized to optimize the loading and intracellular release of specific drugs for the treatment of tuberculosis.
authors.affiliation: Division of Infectious Diseases, University of California, Los Angeles, California, USA. dclemens@mednet.ucla.edu
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Clemens
authors.forename: Bai-Yu
authors.initials: BY
authors.lastname: Lee
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.forename: Courtney R
authors.initials: CR
authors.lastname: Thomas
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferris
authors.forename: Andre E
authors.initials: AE
authors.lastname: Nel
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Horwitz
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015169:Colony Count, Microbial; D003505:Cyclodextrins / Q000737:chemistry; D004339:Drug Compounding; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007538:Isoniazid / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D050296:Microbial Viability / Q000187:drug effects; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010587:Phagocytosis / Q000502:physiology; D011094:Polyethyleneimine / Q000737:chemistry; D016062:Porosity; D012293:Rifampin / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012822:Silicon Dioxide / Q000737:chemistry*
chemical_list: D000995:Antitubercular Agents; D003505:Cyclodextrins; D012822:Silicon Dioxide; D011094:Polyethyleneimine; D007538:Isoniazid; D012293:Rifampin