Design, Synthesis and Biological Evaluation of Novel Tumor-targeting Taxane-based Drug Delivery Systems

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Authors
Das, Manisha
Issue Date
1-Aug-10
Type
Dissertation
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en_US
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Abstract
Cancer continues to be a leading cause of death in the U.S. after heart disease and has become the leading cause of death for people younger than 85. Cancer chemotherapy relies on the hypothesis that rapidly proliferating cancer cells will be the more likely target of cytotoxic agents. However, cytotoxic agents have very little or no specificity towards cancer cells leading to systemic toxicity causing severe undesirable side effects. A tumor-targeting drug delivery system (DDS) that can distinguish between normal and cancer cells by utilizing their physiological and/or morphological differences is amongst the most promising protocols. Tumor cells overexpress many receptors and biomarkers which can be targeted to deliver chemotherapeutic agents specifically inside the cancer cells. Generally, a tumor-targeting DDS consists of a tumor-targeting moiety (TTM) connected to a cytotoxic agent directly or through a suitable linker.A novel tumor-targeting DDS using folic acid as the TTM conjugated to a potent novel second-generation taxoid via a novel mechanism-based self-immolative linker has been successfully developed. In vitro internalization studies using confocal fluorescence microscopy (CFM) and flow cytometry as well as cytotoxicity assays against several folate receptor positive and negative cancer cell lines exhibited excellent specificity. Immunofluorescent assays demonstrated the release of the potent taxane and its binding to microtubules. Another DDS using functionalized single-walled carbon-nanotubes (f-SWNT) as the drug delivery vehicle and biotin as the TTM was successfully developed to study dual therapy effects of thermal ablation and cytotoxicity. The intrinsic property of SWNT to absorb light at near-IR range and thermally ablate cells was successfully utilized in these studies. CFM studies demonstrated specific internalization and thermal ablation of biotin-receptor positive cancer cells.The stability of disulfide linkers while in circulation and the effective disulfide bond cleavage to liberate the potent drug after the prodrug reaches the targeted tumor site is crucial in the design of successful linkers. A novel series of disulfide linkers have been designed and synthesized to study substituent effects and other key factors in their stability. The blood plasma stability of several DDS with biotin as TTM has also been determined.
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The Graduate School, Stony Brook University: Stony Brook, NY.
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