Defense Date

3-12-2015

Availability

Worldwide Access

Submission Type

dissertation

Degree Name

PhD

Department

Pharmaceutics

School

Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences

Committee Chair

Jelena Janjic

Committee Member

Carl Anderson

Committee Member

Ira Buckner

Committee Member

Peter Wildfong

Committee Member

John Pollock

Committee Member

Lisa Rohan

Keywords

Cyclooxygenase-2, Macrophages, Near Infrared Fluorescence, Perfluorocarbon Nanoemulsions, Personalized Medicine, Theranostics

Abstract

Personalized medicine can be an approach to address the unsatisfactory treatment outcomes in inflammatory conditions such as cancer, arthritis, and cardiovascular diseases. A common feature of chronic diseases is the infiltration of pro-inflammatory macrophages at the disease loci. Infiltrating macrophages have been previously utilized for disease diagnosis. These features suggest that macrophages can be broadly applicable targets for simultaneous therapy and diagnosis. Cyclooxygenase-2 (COX-2), an enzyme involved in the biosynthesis of a lipid inflammatory mediator, prostaglandin E2 (PGE2), is over expressed in macrophages infiltrating the pathological site. Inhibition of PGE2 leads to reduced inflammation, pain and macrophage infiltration. To utilize macrophages for the purpose of simultaneous therapy and diagnosis, we proposed to integrate therapeutic and imaging capabilities on a single nanomedicine platform, referred as theranostics. A stable 19F MRI visible nanoemulsion platform was developed, incorporating celecoxib for COX-2 inhibition and near-infrared fluorescent dye(s) for fluorescence imaging. We hypothesized that inhibition of COX-2 in macrophages using a theranostic nanoemulsion will reduce the inflammation (and pain), and that this response can be visualized by monitoring changes in macrophage infiltration. In vitro characterization demonstrated that the theranostic displays excellent stability with no toxicity, and significant uptake in macrophages. Furthermore, it delivers celecoxib to macrophages and reduces PGE2 production from these cells. In vivo studies in a murine paw inflammation model showed nanoemulsion presence at the inflamed site, specifically in COX-2 expressing macrophages compared to neutrophils. Supporting our hypothesis, celecoxib delivered through a nanoemulsion demonstrated time-dependent reduction in fluorescence from the inflamed paw, indicative of reduced macrophage infiltration. In a neuropathic pain model, celecoxib delivered to macrophages led to reduced pain concomitant with reduced macrophage infiltration at the inflamed site compared to free drug control (cross reference: Kiran Vasudeva, Dissertation, 2015). In conclusion, inhibition of COX-2 in macrophages using theranostic nanoemulsions proves to be an effective and generalized strategy facilitating simultaneous therapy and diagnosis, which can be applied to many chronic diseases. The diagnostic information during therapy can be used to tailor the treatment and reduce patient variability leading to personalized medicine.

Format

PDF

Language

English

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