Thursday, November 21, 2024
11/21/2024
The risk of developing tuberculosis (TB) is estimated to be 26 to 31 times greater in people living with Human Immunodeficiency Virus (HIV-1). The arduous treatment regimen for TB (minimum of six months on a cocktail of antibiotics with dose-limiting side-effects) has remained essentially unchanged for decades. Reducing the global TB burden has focused primarily on new antibiotics and vaccines with little focus on macrophage targeted drug delivery methods that activate the immune system to increase microbial eradication. To address this unmet need, we developed a targeted macrophage therapy with broad applications for HIV and TB. Our formulation delivers a model rifamycin drug, rifampin, loaded into β-glucan and chitosan coated poly(lactic-co-glycolic) acid (GLU-CS-PLGA) nanoparticles. Our pharmacokinetic studies found that after a single nanoparticle administration via oropharyngeal aspiration to healthy mice, rifampin was detected in the cellular fraction of the bronchoalveolar lavage up to 10 days post-dosing. Furthermore, we found a time course of release of TNFα that returns to baseline at 24 hr post administration. All nanoparticles stimulated the release of TNFα in the range of 500 to 2000 pg/ml, similar to TNFα concentrations in a TB mouse model after drug treatment. While we have demonstrated sustained delivery of rifampin to alveolar macrophage in mice using our nanoparticles, we have yet to learn how this nanoparticle functions in the setting of virulent mycobacterium tuberculosis in the lung. Furthermore, we have yet to discover how this nanoformulation affects a TB granuloma in the absence or presence of HIV viral proteins. To address this, we are taking a two-pronged approach with independent aims. Aim 1, “Determine the GLU-CS-PLGA nanoparticles in an in vitro TB granuloma model in the absence or presence of HIV proteins”, will analyze the bactericidal efficacy elicited by GLU-CS-PLGA nanoparticles in this model. We also have included an exploratory experiment to investigate the effects of HIV-1 proteins on GLU-CS-PLGA nanoparticle efficacy. Aim 2, “Determine the in vivo efficacy of GLU-CS-PLGA nanoparticles in the BALB/c TB mouse model”, will determine the bactericidal efficacy in situ in the lungs following oropharyngeal aspiration with GLU-CS-PLGA in the BALB/c TB mouse model. Therefore, this nanoplatform is broadly relevant to disorders that affect macrophage, including TB and HIV (HIV macrophage reservoirs). Determining the efficacious nature of this nanoformulation is essential to decide whether (1) we should abandon this therapeutic approach or (2) we should move forward to test it in an advanced mouse TB model that develops highly organized encapsulated necrotic lesions, i.e., granulomas, that contain large numbers of extracellular bacilli that more closely resembled human lesions and, in an HIV-TB co-infection model. This innovative proposal advances the conceptual and mechanistic knowledge of stimulation of the immune system to treat infectious diseases and this novel immune-stimulating drug delivery nanoparticle platform. By incorporating GLU onto the nanoparticle's surface, the resulting immune stimulation is independent of its therapeutic cargo.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
