Liposomes for Treatment of Inflammatory Diseases

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Inflammation is the body’s defense mechanism to harmful stimuli such as microbial infection, allergy, stress or injury. Local or systemic inflammation is a major hallmark of several chronic diseases including asthma, obesity, diabetes, cystic fibrosis, cancer, irritable bowel syndrome and psoriasis among many others. Current treatments for the majority of these diseases do not address the underlying inflammation and in those conditions where inflammation is currently treated, there are several areas of unmet need where inflammation is not resolved with current medications or several side effects occur as a result of the treatment. Phospholipids (PLs) are amphiphilic molecules capable of forming self-assembling structures in water, making them suitable excipients in drug delivery systems such as liposomes, niosomes, solid lipid nanoparticles and phytosomes. Phosphatidylcholine (PC) is the most abundant PL and is a major component of biological membranes. The biological activity of some natural PCs and their mixtures have been demonstrated in the literature and some PCs have shown to have immunomodulatory properties in inflammatory conditions such as ulcerative colitis, arthritis and multiple organ injury. In gastrointestinal inflammation, PCs administered orally have shown local therapeutic effects; however, reduction of systemic inflammation following the ingestion of PLs has not been demonstrated. In systemic inflammation, systemic administration of naturally occurring PCs has shown anti-inflammatory properties. Natural PCs are a heterogeneous mixture of components, therefore the immunomodulatory efficacy observed in the studies cannot be attributed to one single component of the mixture. Hydrogenated natural PLs and synthetic PLs are identified in the “Inactive Ingredient Guide” by the food and drug administration (FDA). However, no study to date has investigated the therapeutic efficacy of pure synthetic PLs in form of a solution or a liposomal formulation for the treatment of inflammatory conditions. We report the first application of empty liposomes made up of synthetic PC as an anti-inflammatory treatment, in a murine model of airway inflammation and a murine model of systemic metabolic inflammation. The 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol containing liposomes (referred to as UTS-001) were prepared using the thin-film hydration method and characterized in terms of size, charge and polydispersity index. Stability studies were performed for over two months. Furthermore, UTS-001 was successfully freeze-dried using trehalose and characterized as per above for long-term storage. Asthma is a complex, chronic inflammatory respiratory disease characterized by shedding of the epithelium, airway smooth muscle hypertrophy and hyperplasia, mucus overproduction, and airway inflammation. Airway inflammation in response to environmental pollutants causes activation of epithelial cells. The release of inflammatory mediators and the influx of inflammatory cells into the airways have been attributed to the pathophysiology of asthma. In this thesis, we have demonstrated that UTS-001 was taken up by airway epithelial cells in a time-dependent manner via caveolae-mediated pathway. Furthermore, 𝘪𝘯 𝘷𝘪𝘵𝘳𝘰, in the culture of primary epithelial cells isolated from cystic fibrosis and asthmatic patients, UTS-001 treatment caused a significant reduction in interleukin-6 (IL-6) levels following stimulation with tumor necrosis factor-α (TNF-α). The immunomodulatory properties of UTS-001 were further investigated in an ovalbumin model of allergic airway inflammation. Treatment with UTS-001 resulted in reduced airway hyperresponsiveness demonstrated by improved lung function measurement and decreased eosinophil number in bronchoalveolar lavage. Obesity is commonly referred to as a systemic low-grade inflammation, exemplified by increased inflammatory macrophage number in metabolic tissues (e.g. liver and fat), as well as increased circulating inflammatory mediators. Inflammation is a well-accepted mechanism underlying weight gain, insulin resistance, hyperglycemia, and dyslipidemia in obesity. Efficacy of UTS-001 in reducing weight and systemic inflammation was investigated in a murine model of a high-fat diet. Administration of UTS-001 (along with consumption of the high-fat diet) resulted in a reduction of high-fat diet-induced inflammatory mediators such as TNF-α and peroxisome proliferator-activated receptor-gamma (PPAR-γ) in the liver. Retroperitoneal fat, liver weight and body weight were reduced significantly in obese mice following treatment with UTS-001. Macrophage numbers were reduced in fat and liver and intraperitoneal glucose tolerance test demonstrated an improved glucose tolerance following administration of UTS-001 in the high-fat diet-fed mice. Furthermore, UTS-001 caused an increase in thermogenic marker, uncoupling protein-1 (UCP-1) in the brown fat which increases non-shivering thermogenesis that enhances fat burning. Our studies demonstrated that UTS-001 has the potential to be used in the treatment of obesity and diabetes. In summary, the studies presented in this thesis demonstrate a suitable pharmaceutical formulation of UTS-001 with anti-inflammatory properties with the potential to be used as a treatment in addressing local or systemic inflammatory conditions.
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