Author: Ruchit Trivedi

Publisher:

Published: 2014

Total Pages: 239

ISBN-13:

Drug delivery to the lungs is difficult to achieve and conventional approaches like intravenous and oral administration of drugs do not effectively deliver drugs to the lungs. The inhalation route of administration provides a way to deliver the drugs locally, thereby increasing their efficacy. However, there are several problems associated with inhalation delivery like rapid clearance from the lung, uptake by non-relevant cell types within the lung, leading to side effects, and difficulty of formulation. Apart from these routes and their difficulties, optimization of drug delivery is required for different type of drugs like proteins, siRNAs, and small molecules. Hence, efficient drug delivery to the lung is an unmet need for the treatment of lung diseases. The objective of this research was to design and implement novel targeted drug delivery strategies to deliver proteins, siRNAs, and small molecules (pirfenidone) for the treatment of lung diseases. We evaluated efficacy of a fusion protein of tumstatin in vitro in proliferation, invasion, and tube formation assays, and in vivo in a xenograft model of lung cancer upon intravenous administration and comparedit with its parent molecule tumstatin. We found that transferrin-tumstatin was superior to tumstatin in all the assays. siRNA delivery to the lung is challenging, and to achieve effective delivery of siRNA to the lungs, we prepared novel targeted nanoparticles encapsulating CXCL1 siRNA. CXCL1 siRNA was used as a model siRNA to treat acute lung injury in mice which reflects human acute respiratory distress syndrome (ARDS). We evaluated the biodistribution and efficacy of these nanoparticles in a bleomycin induced ARDS mouse model. We found that functionalized nanoparticles were superior in targeting the lungs as well as more efficacious in treating ARDS when compared to non-functionalized nanoparticles and naked siRNA. For small molecule delivery, we developed an inhalation route of administration. For inhaled drugs, it is essential to target them to relevant cells. First, we determined the optimum size of nanoparticles to target various cells within the lung and then used optimally sized nanoparticles to treat a mouse model of idiopathic pulmonary fibrosis (IPF) using pirfenidone as a model small molecule. We found that 200 nm nanoparticles were superior at targeting epithelial cells compared to 20 nm and 2000 nm nanoparticles. Nanoparticles sized approximately 200 nm loaded with pirfenidone were more effective in retaining the drug within the lung up to 1 week compared to pirfenidone solution and they were more efficacious in treating pulmonary fibrosis in a mouse model compared to pirfenidone solution.