Journal of Nanoparticle Research 2: 165–171, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands. Nanoparticles as antituberculosis drugs carriers: effect on activity against Mycobacterium tuberculosis in human monocyte-derived macrophages ∗ Y.V. Anisimova, S.I. Gelperina, C.A. Peloquin and L.B. Heifets ∗∗ National Jewish Medical and Research Center, 1400 Jackson St., Denver, CO 80206, USA; ∗∗ Author for correspondence (Tel.: 303 398 1384) Received 22 December 1999; accepted in revised form 14 April 2000 Key words: tuberculosis, nanoparticles, antituberculosis drugs, Mycobacterium tuberculosis, drug delivery Abstract This is the first report evaluating the nanoparticle delivery system for three antituberculosis drugs: isoniazid, rifampin, and streptomycin. The typical particle size is 250 nm. We studied accumulation of these drugs in human monocytes as well as their antimicrobial activity against Mycobacterium tuberculosis residing in human monocyte-derived macrophages. Nanoparticle encapsulation increased the intracellular accumulation (cell-association) of all three tested drugs, but it enhanced the antimicrobial activity of isoniazid and streptomycin only. On the other hand, the activity of encapsulated rifampin against intracellular bacteria was not higher than that of the free drug. Introduction Modern regimens for tuberculosis therapy under Directly Observed Therapy (DOT) often require daily administration of the antituberculosis drugs. This alone may contribute to the patients’ poor compli- ance. A number of efforts have been made to over- come this problem. One approach is development of long-lasting antimicrobial agents (i.e., rifapentine) that can be used intermittently, twice, or even once-a- week (Keung et al., 1999). Another suggestion is to use liposome-encapsulated antimicrobial agents (i.e., amikacin) to increase accumulation of the drug in macrophages to produce a long-lasting effect (Ehlers et al., 1996). Each delivery system has certain advan- tages and disadvantages. So far, the most advanced delivery system is based on the use of liposomes. Among the disadvantages of liposomes are very limited shelf life of the drug-containing preparations (Fattal ∗ Presented at the Joint NSF–ESF Symposium on Nanopar- ticles: Technologies and Applications (Tacoma, Washington, 1999). et al., 1991), instability in vivo (Kaplun et al., 1999), difficulties in optimization of the surface structure (Kreuter, 1994), and limitation to the parenteral use only (Richards et al., 1978). Therefore, the search for new delivery systems that would address these prob- lems remains an important issue, particularly for the antimicrobial agents. Nanoparticles, a different encap- sulation system, have been introduced for adminis- tration of drugs aimed against infections other than tuberculosis, such as salmonellosis (Balland et al., 1996), fungal infections (Bajwa et al., 1987), liste- riosis (Forestier et al., 1992), leishmaniosis (Venier- Julienne et al., 1995), and AIDS (Lobenberg et al., 1996). This system has not been tested for the anti- tuberculosis drugs, and it is possible that nanoparti- cles could enhance the accumulation of these agents in macrophages, which could create a long-lasting effect. The aim of our study was to evaluate the potential use of nanoparticles for antituberculosis drugs. As a first step in this direction, we studied the accumula- tion of isoniazid (INH), rifampin (RMP), and strepto- mycin (SM) in human blood monocytes as well as the