Advisor(s)

Mansoor M. Amiji

Contributor(s)

Michael Seiden, Tara Pouyani, Ralph H. Loring, Robert Campbell

Date of Award

2008

Date Accepted

1-2008

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

Bouvé College of Health Sciences. School of Pharmacy.

Keywords

Health Sciences, Nanotechnology, Cancer

Subject Categories

Drug resistance in cancer cells, Multidrug resistance, Drug delivery systems

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

The development of multidrug resistance (MDR) to a wide variety of chemotherapeutic agents is one of the most challenging aspects of cancer therapy, and is often the cause for poor patient prognosis, since it renders the cancer un-responsive to most chemotherapeutic options. Cases of MDR in the clinic are often seen in patients that have breast or ovarian cancer, and statistics point to the fact that more than 50% of these patients will develop multidrug resistance, particularly upon relapse. Current therapeutic strategies involve the use of highly toxic doses and combinations of chemotherapeutics, although frequently unsuccessful. Strategies to circumvent one common cellular mechanism whereby MDR arises, namely P-glycoprotein efflux, are undergoing clinical trials, albeit with little success to date, due to poor target responsiveness and high systemic toxicity. As an alternate mechanism to overcome MDR, this work describes the development of a polymeric nanoparticle platform to deliver a combination therapy of the drug C6-ceramide, a synthetic analog of an endogenously occurring sphingolipid, together with the chemotherapeutic paclitaxel. This combination therapy aims to circumvent a second common cellular mechanism whereby MDR also can arise, namely the inhibition of apoptotic signaling. Drug delivery within polymeric nanoparticles furthermore enhances tumor-targeting of the therapeutic load, thereby resulting in increased therapeutic efficacy and a decrease in adverse side-effects. Moreover, evidence suggests that this nanoparticle strategy can simultaneously bypass P-glycoprotein efflux, thereby overcoming MDR by two main cellular mechanisms giving rise to the phenotype. For enhanced therapeutic efficacy, a nanoparticle system has been engineered that is composed of a blend of two polymers, a pH-responsive polymer and a slow degrading polymer, in such a way that the release of the two therapeutic agents (ceramide and paclitaxel) is precisely tuned for optimal efficacy. The studies reveal that the therapy indeed proves most efficacious against tumors bearing the MDR phenotype, as revealed in both in-vivo models of breast as well as ovarian MDR cancer. Not surprisingly, the data supports the idea that this therapy achieves success by not only by prolonging drug retention in tumor and blood and enhancing tumor drug delivery through the physical properties of nanoparticles, but more importantly by overcoming the hypothesized cellular mechanisms of MDR through the combination therapy approach. Thus, hereby a novel therapeutic strategy is presented for the treatment of MDR cancer that shows promise for clinical success.

Document Type

Dissertation

Rights Holder

Lilian Emilia van Vlerken


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