الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
The substantial burden of fungal diseases has been estimated as 1,500,000 worldwide deaths every year. Pulmonary Aspergillosis (PA) is a life-threatening fungal infection.
The prevalence of this disease has dramatically increased with the growing numbers of patients with impaired immune state, chronic lung diseases, autoimmune and inflammatory conditions.
Triazoles are the mainstay of therapy for treatment and prophylaxis. Lately, increased azole resistance has become a significant challenge in effective management of aspergillosis.
Consequently, second generation triazoles, e.g., voriconazole (VRZ), were synthesized to overcome this resistance. VRZ is a broad spectrum antifungal agent that possesses an increased activity against resistant Aspergillus species. Unfortunately, the broader spectrum of activity often comes at the expenses of increased pharmacokinetic variability, adverse effects and toxicity.
Hence, local administration of VRZ can be a successful way to reduce the dose, decrease the adverse effects and systemic toxicity, and maximize the treatment impact by targeting the drug directly toward the lungs.
Fabrication of lipid nano-particles (LNPs) loaded with VRZ can help in achieving high local lung concentration coupled with low systemic concentration, controlled release patterns and enhanced antifungal activity with the lowest possible doses. Nano-scale delivery systems should prevent rapid drug clearance, increase intrapulmonary deposition, provide remarkable uptake by the fungus and reduce the risk of developing resistance.
to be of better tolerability in the airways since phospholipids are considered as the major components of lung surfactants. DPPC; which is the most abundant endogenous pulmonary surfactant, is recognized by the FDA as GRAS excipients for pulmonary delivery.
It helps in retaining normal airway patency, escape lung clearance mechanism and enhance aerosolization parameters. from these perspectives, we believed that development of locally-acting VRZ-LNPs would be an interesting alternative to the currently available VRZ systemic dosage forms.
Moreover, DPPC integration into the developed nanoparticles can be a successful platform for efficient yet biocompatible pulmonary drug delivery systems.Accordingly, we aimed to investigate DPPC potential to produce modified VRZ-LNPs for local targeting of PA in order to maximize the treatment impact, improve survival and limit the extent of disease invasiveness.
The work in the current thesis was divided into three chapters