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
Permanent URL
Recommended Citation
Jabr-Milane, Lara Scheherazade, "Tumor hypoxia, the Warburg Effect, and multidrug resistance: modulation of hypoxia induced MDR using EGFR-targeted polymer blend nanocarriers for combination paclitaxel/lonidamine therapy" (2010). Pharmaceutical Science Dissertations. Paper 8. http://hdl.handle.net/2047/d20000642
Click button above to open, or right-click to save.