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Development and Optimization of Polymeric Carriers for Lymphatic Imaging and Drug Delivery
Bagby, Taryn Rochelle
Bagby, Taryn Rochelle
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Abstract
Many cancers, including melanoma and breast cancer, metastasize via the lymphatic system, a mono-directional network of vessels and nodes that parallels the circulatory system. Accurate determination of the lymph nodes involved in the early lymphatic spread of the primary tumor is paramount for survival of the patient. Melanoma and breast cancer, when detected early offer promising 5-year survival rates of more than 90%; however, once the metastases have spread beyond the lymph node basin draining the primary tumor, the typical first metastatic site, to successive lymph nodes or organs, the 5-year survival dramatically drops to less than 20%. However, conventional systemic chemotherapy offers limited penetration into the lymphatic to treat lymphatic metastases, and often the dose limiting toxicities associated with systemic chemotherapy limit the dose to below that needed for effective treatment. Therefore, there is a great need to develop localized treatment and imaging agents for the delivery and identification of the tumor lymphatics and metastases, which can offer enhanced detection and improved efficacy and reduced toxicity over systemic therapy. Specific targeting of the lymphatics is possible by utilizing the natural structure of the lymphatic capillaries by tailoring the size and charge of the carriers to 10 to 100 nm in diameter and modifying the surface charge to be neutral to anionic in nature. Herein this dissertation focuses on the development and optimization of two different polymeric platforms for enhanced lymphatic uptake by tailoring the size and degree of anionic charge, utilizing hyaluronan and star polymers, respectively, as intralymphatic delivery platforms for the use in imaging and treatment of lymphatically metastatic cancers, such as melanoma and breast cancer. Further, the development of a geldanamycin-polymer conjugate utilizing the optimized star polymer and evaluation of its efficacy in three orthotopic tumor models for melanoma and breast cancer will also be discussed.
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Date
2011-12-31
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University of Kansas
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Keywords
Pharmaceutical sciences, Breast cancer, Drug delivery, Imaging, Lymphatic, Melanoma, Star polymer