School of Therapeutic Sciences (ETDs)

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    Targeted nanosystems for tuberculosis pericarditis interventions
    (University of the Witwatersrand, Johannesburg, 2024) Ayodele, Simisola Ayobami; Kumar, Pradeep; Choonara, Yahya Essop
    Tuberculosis (TB) maintains its infamous status regarding its detrimental effect on global health, causing the highest mortality by a single infectious agent. It presents as the second most lethal infectious disease after HIV/AIDS. The presence of resistance and immune-compromising disease favors the disease in maintaining its footing in the health care burden despite various anti-TB drugs. The main factors contributing to resistance and difficulty in treating disease include prolonged treatment duration (at least 6 months) and severe toxicity, which further leads to patient non-compliance, and thus a ripple effect leading to therapeutic non-efficacy. The efficacy of new regimens demonstrates that targeting host factors concomitantly with the Mycobacterium tuberculosis (M.tb) strain is urgently required. Due to the huge expenses and time required of up to 20 years for new drug research and development, drug repurposing may be the most economical, circumspective, and conveniently faster journey to embark on. Host-directed therapy (HDT) will dampen the burden of the disease by acting as an immunomodulator, allowing it to defend the body against antibiotic-resistant pathogens whilst minimizing the possibility of developing new resistance to susceptible drugs. Repurposed drugs in TB act as host-directed therapies, acclimatizing the host immune cell to the presence of TB, improving its antimicrobial activity and time taken to get rid of the disease, whilst minimizing inflammation and tissue damage. Anti-TB drugs incorporated in nanosystems may reduce side effects by delivering the drug selectively into infection reservoirs such as macrophages, which may assist in clearing the TB bacilli faster and reducing the duration of therapy. Tuberculosis pericarditis (TBP) is a type of extrapulmonary tuberculosis caused by the retrograde lymphatic spread of the bacilli from lymph nodes. TBP is known to have a high burden in southern Africa due to the high prevalence of HIV and its contribution to TBP. Traditional anti-TB drugs have poor permeation across the pericardium, making TBP a difficult disease to treat with high mortality. Rapid HPLC methods were initially established for the detection and quantification of isoniazid and pyrazinamide at a physiological pH (pH 7.4). These methods were subsequently used for the detection and quantification of both compounds in the ex vivo pericardium studies. Although both drugs diffused across the pericardium, only isoniazid has anti-tubercular effects at physiological pH. Both drugs permeated across the pericardium at pH 7.4, but only isoniazid has anti-tubercular effects at this pH. Bedaquiline is known to shorten the duration of therapy but has limitations e.g., poor solubility and adverse effects such as prolongation of QT interval, causing careful use and close monitoring of its adverse effects and possible drug interactions. In this study, bedaquiline was incorporated into an inherently targeted nanosystem made of mannan (host-directed therapy) for improved permeation of the drug across the pericardium. The bedaquiline-loaded mannan-chitosan oligosaccharide lactate nanoparticles were prepared by a one-step ionic gelation probe sonication method. A PermeGear 7-in-line flow-through system was used for the ex vivo diffusion studies across porcine and human pericardium. The nano gel was loaded into the donor compartment. Phosphate buffer saline (pH 7.4 with 0.2% sodium lauryl sulphate) was pumped through the receptor compartments at 1.5 ml.h-1 (37 °C). Samples were collected every 2 h for 24 h and analyzed via HPLC. Bedaquiline loaded nanoparticles with particle size and potential of 192.4 nm and 40.5 mV, respectively, were synthesised. The chitosan-mannan bedaquiline loaded nanoparticles had an encapsulation efficacy of 98.7% and drug loading of 0.6%. Diffusion data of bedaquiline in the nanosystem indicated a flux of 2.889 and 2.346 μg.cm - 2. min -1 for porcine and human pericardium, respectively, as compared to 0.991 μg.cm-2.min-1 and 1.1578 μg.cm-2.min-1 for isoniazid and pyrazinamide, respectively. The permeation of the nanosystem indicated a consistent and linear diffusion pattern across both porcine and human pericardium, additionally approving the porcine pericardium as a great comparable tissue to human tissue for pericardial studies. The nanosystem, therefore, presents an exceptional direction for the treatment of tuberculosis pericarditis with prospectively minimized systemic side effects and host-directed therapy