Ultrashort-Course Treatment of Drug-Sensitive and Drug-Resistant Tuberculosis via Inhalation and Nanotherapeutic Delivery of Novel Drug Regimen
Abstract
Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area: Tuberculosis. Areas of Encouragement: (1) Development of novel strategies or therapeutics to treat TB. (2) Research to understand, diagnose, or treat multidrug-resistant TB or extensively drug-resistant TB. Overview: Tuberculosis (TB) infects one-third of the world’s population and causes 1.8 million deaths per year, meaning that it kills more people than any other single infectious agent. TB incidence is particularly high in the developing world, where US military personnel are often deployed, placing them at higher risk of infection. While effective antibiotics are available, treatment is prolonged, requiring 6-9 months, and is limited by serious toxicities such as liver and nerve damage and problems with treatment adherence that leads to development of drug resistance. We recently used an artificial intelligence-enabled data analysis platform to identify a combination of four drugs (Clofazimine, Bedaquiline, Pyrazinamide, Delamanid) that can achieve relapse-free cure five times faster (reduces treatment duration by 80%) than the standard regimen in the mouse pulmonary TB model. Of note, results of drug studies in the mouse TB model are highly predictive of results in humans. We believe that treatment duration can be shortened even further by adding a highly effective inhalational treatment that delivers antibiotics directly to the lungs, the primary site of TB infection, and to the specific cells in the lungs that serve as host cells for TB bacilli. TB is caused by a bacterium, Mycobacterium tuberculosis (Mtb), which grows inside host cells called macrophages. For Mtb, the macrophage is a source of nutrients for growth, a sanctuary from the host immune system, and a barrier to antibiotic therapy. However, as macrophages avidly ingest small particles, such as nanoparticles (NPs), NPs are an attractive mechanism for delivering high concentrations of antibiotics to the host cells of Mtb while minimizing exposure of other cells to the antibiotics, thus maximizing efficacy and minimizing toxicity. In previous work, we developed NPs made of porous silica (mesoporous silica nanoparticles, MSNs) in which the tubular pores of the particles are loaded with drug and the pores are closed with caps. The caps are miniature valves (nanovalves) that open and release drug cargo in response either to the low pH or the high redox potential (reducing power) inside the cell. As such, the nanovalves remain closed when outside cells but open and release drug cargo after the NPs are taken up by macrophages. The MSNs are biologically compatible, biodegradable, and highly versatile. The solid framework of MSNs allows them to be made in a variety of shapes and sizes and with pore diameters that are optimized for the size of the specific drug molecule they shall carry. The MSN interior and exterior surfaces are easily modified by attachment of specific molecules to increase their cargo-loading capacity. Critical Problem Addressed by This Study: TB treatment is burdensomely lengthy, and this prolonged treatment increases the problems of treatment non-adherence and drug toxicity; the lengthy treatment is a major burden on the healthcare resources of resource limited communities. By adding an effective inhalational therapy onto a highly effective oral drug regimen, we anticipate that the duration of treatment required to achieve relapse-free cure can be dramatically shortened from 6-9 months for drug-sensitive TB and up to 2 years for drug-resistant TB to ~1-2 weeks for both drug-sensitive and drug-resistant TB. Study Design: We shall optimize MSNs with pH- and redox-actuated nanovalves for inhalational delivery of four potent TB drugs, test them sequentially (1) under cell free conditions, to maximize drug loading and release; (2) in macrophage cell culture, to minimize toxicity and to maximize effectiveness in killing intracellular Mtb; and (3) in a mouse
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010282
Entities
People
- Marcus A Horwitz
Organizations
- United States Army
- University of California, Los Angeles