Exogenous Surfactant as a Delivery Vehicle for Intrapulmonary Therapeutics
Abstract
As an organ system, the lung has unique advantages and disadvantages for direct drug delivery. Its contact with the external environment allows for the airways to be easily accessible to intrapulmonary delivery. However, its complex structure, which divides into more narrow airways with each branch, can make direct delivery to the remote alveoli challenging. The objective of this thesis was to overcome this issue by using exogenous surfactant, a lipoprotein complex used to treat neonatal respiratory distress syndrome, as a carrier for pulmonary therapeutics. It was hypothesized that therapeutics administered with a surfactant vehicle would display enhanced delivery to the deeper regions of the lung. Acute respiratory distress syndrome and bacterial pneumonia were selected as prototypical examples of pulmonary conditions in which surfactant-drug combinations may be beneficial. Consequently, the pharmaceuticals utilized were those with antibacterial or anti-inflammatory activities.
To test this hypothesis, the wet bridge transfer system was developed in Chapter 2 as a novel in vitro screening tool for surfactant-based therapeutics. Several antibiotic and anti-inflammatory medications combined with a commercially available exogenous surfactant were screened based on 1) surfactant spreading and 2) the biological efficacy of the transported drug at a remote site. In Chapter 3 this platform, in combination with other in vitro techniques, were utilized to gain the mechanistic insight required for optimizing surfactant vehicle prior to animal studies. Specifically, through these experiments a synthetic surfactant was designed, such that, the antibacterial activity of cathelicidins, a family of potent antimicrobial peptides, was retained when transported to a remote site. Finally, Chapter 4 used a rat model of lung inflammation, to assess the efficacy of this delivery approach for a mainstay anti-inflammatory. Surfactant based delivery was found to downregulate of a wide variety of inflammatory markers across both sexes.
To conclude, surfactant-based delivery of antimicrobial and anti-inflammatory therapeutics was found to enhance drug delivery and efficacy at remote sites in vitro as well as in vivo. Based on these findings, it is also suggested that future research expand on the optimization process of this thesis for other surfactant-drug preparations and assess those combinations in clinically relevant animal models.