Modeling nanoparticle delivery of TB drugs to granulomas.
Tuberculosis, which typically presents as a pulmonary disease, has a complex pathology. The primary site of infection, the Ghon focus, recruits immune cells and a granuloma forms. At earlier stages the granuloma is still vascularized, offering the best opportunity for drug treatment. In the more progressive state blood flow is reduced and a distinct caseous structure develops. Effective delivery of drugs to bacilli in the core of the granuloma becomes very difficult. It is perceivable that granuloma cores could create conditions where bacilli persist and develop resistance. In this study we analyze drug delivery to granulomas by means of a nanoparticle delivery system. The model consists of two parts; the overall distribution of the nanoparticles is described by a simple circulatory model and this result is used in the second part, focusing on transport in a capillary lined with macrophages. Nanoparticles enter the macrophages where they are metabolized and the drugs are released. The model reveals significant differences in drug concentrations between the plasma and macrophages. Based on the results of the model, strategies for improved drug delivery are proposed.
Preclinical Drug Development Platform, North-West University, Potchefstroom 2520, South Africa.
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Grobler
Department of Chemical and Biomolecular Engineering University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
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Perez Sierra
Preclinical Drug Development Platform, North-West University, Potchefstroom 2520, South Africa; Department of Chemical and Biomolecular Engineering University of Nebraska-Lincoln, Lincoln, NE 68588, USA. Electronic address: hviljoen1@unl.edu.
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Viljoen
D000465:Algorithms; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001692:Biological Transport; D016503:Drug Delivery Systems / Q000379:methods*; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology; D008962:Models, Theoretical; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D053758:Nanoparticles / Q000737:chemistry*; D012293:Rifampin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D013997:Time Factors; D014375:Tuberculoma / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology
D000995:Antitubercular Agents; D012293:Rifampin
Bioavailability; Macrophages; Metabolizing rate; Pharmacodynamics