Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Supervisor

Veldhuizen, Ruud AW.

2nd Supervisor

Yamashita, Cory.

Co-Supervisor

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.

Summary for Lay Audience

The branching structure of the lung makes direct drug delivery to its more remote regions challenging. The objective of this thesis was to overcome this delivery issue by using exogenous surfactant as a carrier for drugs targeting the lung. It was hypothesized that drugs administered with a surfactant would show enhanced delivery to the more remote regions of the lung. Although many lung conditions could benefit from this approach, this thesis focused on: acute respiratory distress syndrome (Lung Inflammation) and bacterial pneumonia (Lung Infection). Consequently, the drugs explored were those with the ability to kill bacteria and downregulate inflammation.

To test this hypothesis, the wet bridge transfer system was developed in Chapter 2 as a new screening tool for surfactant-drug mixtures. It was used to screen several antibiotic and anti-inflammatory medications that were combined with an exogenous surfactant, based on 1) surfactant spreading as well as 2) drug efficacy at a remote site. In Chapter 3, this platform was combined with other techniques to design a better surfactant vehicle for antibacterial peptides, known as cathelicidins. Finally, Chapter 4 used an animal model of lung inflammation to assess the effectiveness an anti-inflammatory medication delivered by a surfactant vehicle.

Together, the findings of this thesis support surfactant as a drug delivery vehicle for anti-bacterial and anti-inflammatory medications. It is also recommended that future research use the methods outlined in this thesis to design and evaluate surfactant vehicles for other types of medication.

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