title: Selective delivery of rifampicin incorporated into poly(DL-lactic-co-glycolic) acid microspheres after phagocytotic uptake by alveolar macrophages, and the killing effect against intracellular Mycobacterium bovis Calmette-Guérin.
abstract: Macrophages and their phagocytotic abilities play a dominant role for defense against infected organisms. However, Mycobacterium tuberculosis can survive in the phagosomes of macrophages. In this study, the effective delivery of a drug and the killing effect of tubercle bacilli within macrophages were investigated utilizing the phagocytotic uptake of rifampicin (RFP) that had been incorporated into poly(DL-lactic-co-glycolic) acid (PLGA) microspheres. The microspheres were composed of PLGA that had a monomer ratio (lactic acid/glycolic acid) of either 50/50 or 75/25. They had molecular weights from 5000 to 20,000, and diameters of 1.5, 3.5, 6.2 and 8.9 microm. The most significant factor for phagocytotic activity of macrophages was the diameter of the microspheres. By contrast, molecular weight and monomer ratio of PLGA did not influence phagocytosis. The amount of RFP delivered into cells was also investigated. RFP-PLGA microspheres composed of PLGA with a molecular weight of 20,000 and monomer ratio of 75/25 showed the highest amount of delivery (4 microg/1 x 10(6) cells). Fourteen days after infection, the survival rate of treated intracellular bacilli was 1% when compared with untreated cells. There was almost no killing effect of free RFP (4 or 15 microg/ml) on intracellular bacilli. In vivo efficacy of RFP-PLGA was also examined in rats infected with M. tuberculosis Kurono. Intratracheal administration of RFP-PLGA microspheres was shown to be superior to free RFP for killing of intracellular bacilli and preventing granuloma formation in some lobes. These results suggest that phagocytotic activity could be part of a new drug delivery system that selectively targeted macrophages.
authors.affiliation: Faculty of Engineering, The University of Tokushima,Tokushima-shi, Tokushima 770-8506, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshida
authors.forename: Makoto
authors.initials: M
authors.lastname: Matumoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hshizume
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Oba
authors.forename: Tatuo
authors.initials: T
authors.lastname: Tomishige
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Inagawa
authors.forename: Chie
authors.initials: C
authors.lastname: Kohchi
authors.forename: Mami
authors.initials: M
authors.lastname: Hino
authors.forename: Fuminori
authors.initials: F
authors.lastname: Ito
authors.forename: Keishiro
authors.initials: K
authors.lastname: Tomoda
authors.forename: Takehisa
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kimiko
authors.initials: K
authors.lastname: Makino
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Terada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hori
authors.forename: Gen-Ichiro
authors.initials: G
authors.lastname: Soma
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D002417:Cattle; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D016503:Drug Delivery Systems; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008863:Microspheres; D009163:Mycobacterium bovis / Q000187:drug effects* / Q000254:growth & development; D011091:Polyesters / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D012293:Rifampin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014380:Tuberculosis, Bovine / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000904:Antibiotics, Antitubercular; D011091:Polyesters; C033616:poly(lactide); D012293:Rifampin