title: Antitubercular Nanocarrier Combination Therapy: Formulation Strategies and in Vitro Efficacy for Rifampicin and SQ641.
abstract: Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome the problems associated with dosing frequency, patient compliance, and drug resistance. To reduce side effects associated with systemic drug distribution and improve drug concentration at the target site, stable therapeutic nanocarriers (NCs) were prepared and evaluated for efficacy in vitro in Mycobacterium tuberculosis-infected macrophages. Rifampicin (RIF), a current, broad-spectrum antibiotic used in TB therapy, was conjugated by degradable ester bonds to form hydrophobic prodrugs. NCs encapsulating various ratios of nonconjugated RIF and the prodrugs showed the potential ability to rapidly deliver and knockdown intracellular M. tuberculosis by nonconjugated RIF and to obtain sustained release of RIF by hydrolysis of the RIF prodrug. NCs of the novel antibiotic SQ641 and a combination NC with cyclosporine A were formed by flash nanoprecipitation. Delivery of SQ641 in NC form resulted in significantly improved activity compared to that of the free drug against intracellular M. tuberculosis. A NC formulation with a three-compound combination of SQ641, cyclosporine A, and vitamin E inhibited intracellular replication of M. tuberculosis significantly better than SQ641 alone or isoniazid, a current first-line anti-TB drug.
authors: †Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, United States.
authors: Suzanne M
authors: SM
authors: D'Addio
authors: ‡Sequella Inc., Rockville, Maryland 77845, United States.
authors: Venkata M
authors: VM
authors: Reddy
authors: †Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, United States.
authors: Ying
authors: Y
authors: Liu
authors: §Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey 08854, United States.
authors: Patrick J
authors: PJ
authors: Sinko
authors: ‡Sequella Inc., Rockville, Maryland 77845, United States.
authors: Leo
authors: L
authors: Einck
authors: †Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey 08544, United States.
authors: Robert K
authors: RK
authors: Prud'homme
mesh_terms: D000995:Antitubercular Agents / Q000494:pharmacology*; D016572:Cyclosporine / Q000737:chemistry; D007538:Isoniazid / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry*; D012293:Rifampin / Q000737:chemistry / Q000494:pharmacology*; D014810:Vitamin E / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D014810:Vitamin E; D016572:Cyclosporine; D007538:Isoniazid; D012293:Rifampin
keywords: SQ641; block copolymer; flash nanoprecipitation; isoniazid; nanocarrier; nanoparticle; prodrug; rifampicin; tuberculosis