Date of Award

5-2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Research Advisor

George C. Wood, Ph.D.

Committee

Mostafa W. Gaber, Ph.D. Ram I. Mahato, Ph.D. Bob M. Moore, Ph.D. Atul J. Shukla, Ph.D. Charles R. Yates, Ph.D.

Abstract

The objective of the study is to demonstrate alleviation of pulmonary inflammation associated with acute lung injury (ALI) using novel surface modified nanoparticles. ALI is characterized by three main pathological events: I) pulmonary edema, II) excessive pro-inflammatory cytokines and chemokines production from alveolar epithelial and endothelial cells and III) leukocyte migration from blood circulation into alveoli. Currently, there is no FDA approved pharmacological treatment available except the supportive mechanical ventilation therapy. Numerous clinical trials involving pharmacological therapies aimed at different pathological targets turned unsuccessful. National Institute of Heart Lung and Blood Institute (NHLBI) cited underappreciation of drug delivery systems as one of the attributed drawbacks.

During ALI, the αvβ6/αvβ5 integrins of alveolar epithelium and endothelium, respectively play a critical role in mediating pulmonary edema in interleukin-1b (IL-1b) stimulated ALI models. A transient blockade of both integrins by antibodies (Ab) or small Arg-Gly-Asp (RGD) peptide sequences may provide new causal therapies for pulmonary edema. A transcription factor, nuclear factor-kB (NF-kB) is associated with the regulation of a battery of genes that encode for pro-inflammatory cytokines, chemokines and cell adhesion molecules (CAMs). Glucocorticoids (GCs) exert their anti-inflammatory effects by NF-kB transcriptional interference mechanisms. Besides the above inflammatory mechanisms, leukocyte migration is another hallmark feature responsible for part of ALI pathogenesis. Leukocyte migration is dictated by sequential activation of adhesion molecules and their ligands on both leukocytes and endothelial cells (ECs). Intercellular adhesion molecule-1 (ICAM-1) located on alveolar endothelium plays a significant role in the recruitment of leukocytes into alveoli. Blockade of ICAM-1 receptors using anti-ICAM-1 antibodies may impede leukocyte migration into alveoli.

In view of high mortality associated with ALI, there is an urgent need for a drug delivery system that inhibits majority of pathological events. In drug targeting research, liposomes are considered as versatile for their ability to carry drug payloads and flexible enough to modulate their surface for targeting purposes. In the current investigation, I developed surface modified stable liposome formulation for delivery of methylprednisolone succinate (a glucocorticoid; MPS) to the lung. Liposomes were targeted to the disease sites through different routes of administration to avail the spatial expression of the receptors in response to IL-1b stimulus. MPS-LcRGD targeted to avb6 integrins of alveolar epithelium attenuated pulmonary edema. MPS-LAb were able to modulate neutrophil migration. Moreover, MPS released from targeted liposomes inhibited the expression of pro-inflammatory cytokines and chemokines. The research work demonstrated the concept of using drug encapsulated and surface modified nanoparticles for therapeutic intervention of ALI.

DOI

10.21007/etd.cghs.2009.0066

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