Advisor(s)

Mansoor M. Amiji

Contributor(s)

Ralph H. Loring, Akio Ohta, Samuel Gatley, Zhenfeng Duan

Date of Award

2010

Date Accepted

6-2010

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

Bouvé College of Health Sciences. Department of Pharmaceutical Sciences.

Keywords

Cancer, Hypoxia, Warburg Effect, Nanomedicine

Subject Categories

Cancer therapy, Drug resistance in cancer cells, Anoxemia, Lonidamine, Nanoparticles, Paclitaxel

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

Multi-drug resistant (MDR) cancer is a significant clinical obstacle and is often implicated in cases of recurrent, non-responsive disease. The biological focus of this work is to explore the relationship between the hypoxic microenvironment of a tumor, the development of MDR, and the energetic profile characteristic of the Warburg effect (aerobic glycolysis). The therapeutic aim of this research is to develop an EGFR-targeted nanocarrier system for combination (paclitaxel/lonidamine) therapy for the treatment of MDR cancer. The stability of the nanocarrier formulation was validated in vitro and the system was characterized for drug release kinetics, size, surface modification, and EGFR-targeting ability. An orthotopic animal model of hypoxic, MDR breast cancer was developed for the pre-clinical evaluation of this system. The EGFR-targeted nanoparticles loaded with lonidamine and paclitaxel demonstrated superior pharmacokinetic parameters relative to non-targeted nanoparticles and drug solution. Combination therapy with lonidamine and paclitaxel, in solution and EGFR-targeted nanoparticle form, was more effective at suppressing tumor growth than single agent treatment. However, combination therapy with EGFR-targeted nanoparticles was less toxic than treatment with drug solution. Combination therapy did change the MDR and hypoxic character of the tumors as demonstrated by a decrease in marker proteins. This EGFR-targeted combination nanocarrier therapy has the potential to make the successful treatment of MDR a clinical reality.

Document Type

Dissertation

Rights Holder

Lara Scheherazade Jabr-Milane

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