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Document Type

Open Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Degree Program

Molecular and Cellular Biology

Year Degree Awarded

2016

Month Degree Awarded

May

First Advisor

Sallie S. Schneider

Second Advisor

Todd S. Emrick

Third Advisor

Richard B. Arenas

Fourth Advisor

Kathleen F. Arcaro

Subject Categories

Alternative and Complementary Medicine | Cancer Biology | Nanomedicine | Oncology

Abstract

Great strides have been made in cancer therapy in the past century, yet it remains one of the leading causes of death in the United States today. This work aimed to shed light on novel methods to treat a variety of aggressive and often chemo-resistant cancers both in vitro and in vivo.

The first aim of this work was to evaluate the therapeutic efficacy of poly(methacryloyloxyethyl phosphorylcholine) (polyMPC) prodrugs compared to standard chemotherapeutic agents. Conjugation of polyMPC to drugs such as doxorubicin (Dox) can result in its improved solubility, prolonged half-life and therapeutic efficacy. PolyMPC and polyMPC-Dox (at a dose less than 10mg/kg) was observed to be safe for systemic administration in a murine model. Additionally, treatment with polyMPC-Dox resulted in improved survival and reduced off target toxicities in mice with orthotopic human ovarian xenografts. Further, mesenchymal stem cells (MSCs) were observed to successfully uptake polyMPC and home to breast cancer xenografts in vivo and thus can potential serve as a vehicle to improve drug delivery.

Additional aims of this work focused on evaluating the root extract of Rhodiola crenulata (RC) plants for the treatment of aggressive cancers derived from the neural crest, including neuroblastoma and melanoma. RC was observed to reduce growth and migration of melanoma in vitro. Further, RC resulted in reduction of aggressive tumor characteristics upon topical therapy as well as the reduced establishment of metastatic foci upon enteral administration in mice with melanoma. While no difference in outcomes was observed upon RC treatment in a disseminated neuroblastoma model in vivo, RC did result in striking cytotoxic effects upon treatment of neuroblastoma cells in vitro. These cytotoxic effects of RC likely resulted from derangements altering the cell’s ability to undergo optimal cellular metabolism.

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