Graduate Thesis Or Dissertation
 

Nanotheraputic Platforms to address Chemotherapeutic Challenges in Breast and Ovarian Cancer Treatment

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/t435gm37w

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  • Utilizing nanocarrier based drug delivery for improving the magnitude of efficacy of chemotherapeutic agents in many diseases has acquired more attention in research applications. It has shown promising results in both preclinical and clinical trials. The Food and Drug Administration (FDA) has approved many of these polymeric carriers, and tens of them are in clinical trials. Thousands of compounds in the Compound Screening Libraries have shown efficacy in vitro, but due to their solubility or stability limitations, many of them are unable to demonstrate efficacy in vivo. For example, in oncology, many small molecules have numerous applications in the field but have a weak solubility profile. Several of these drugs fail to achieve favorable outcomes due to toxicity issues or development of resistance to these agents, which leads to a worsening progression of the disease. Herein we utilize nanocarrier based drug delivery strategies to overcome these issues, improving health outcomes and mitigating the toxicity of these agents. In the majority of cases, these chemotherapeutic agents have adverse effects that threaten the lives of patients more than the symptoms of the disease. For example, treatment with Adriamycin causes cardiomyopathy in patients. In the last two decades, researchers have shown that targeting the tumor environment and the tumor blood supply improved treatment in many patients. In many solid tumors, malignant cells occupied a smaller percentage of the tumor mass compared to microenvironment niches, such as collagen and fibroblasts. Since many of these cells can mutate, grow back, and develop resistance to these chemotherapeutic agents, a better treatment methodology has to be developed. The first strategy we performed in this work is utilizing combinatorial treatment to target malignancies. mammalian target of rapamycin (mTOR) inhibitors and taxanes were loaded in copolymer micelles, and screening was completed to determine the optimal dosage regimen to normalize blood vessels and help the immune populations to clear up malignant cells. Copolymer micelles were made of methoxy poly(ethylene glycol)-b-poly(D,L- lactide), an FDA approved, biocompatible, and amphiphilic block copolymer. This nanocarrier was developed to deliver docetaxel and everolimus with tailored dosage regimens at and below their maximum tolerated dose. Treatments allow for tumor growth control and normalization of angiogenesis in the tumor niche. The immune-modulatory effect in the tumor bed was investigated to determine if these agents have a direct effect on the immune populations or an indirect effect where the immune system is induced through immunogenic cell death. A second nanostructure was prepared with Pluronic micelles using poloxamer 407 copolymers (ethylene oxide and propylene oxide blocks). The goal is to encapsulate polyphenols for chemosensitization and mitigation of Adriamycin induced cardiotoxicity at selected ratios. We aim for a better quality of life for the patients who are fighting chronic diseases such as cancer. Using polymeric micelles is a successful approach that helps with increasing the solubility of poorly water-soluble agents in an aqueous medium, resulting in minimization of side effects related to solvents used in solubilizing hydrophobic chemotherapeutic agents. In cancer therapy, combinatorial treatment has a superior effect compared to using a singular agent. Controlling the pharmacokinetic profile of any chemotherapeutic drug that allows for more freedom in tailored dosing is one of the advantages of optimizing these cargos. In this work, we successfully utilized two different drug-loaded copolymer micelles to treat ovarian and triple-negative breast cancer. These strategies allow for the development of optimal treatment regimens using docetaxel and everolimus in triple-negative breast cancer and Adriamycin in combination with polyphenols in ovarian cancer.
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  • Pending Publication
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  • 2020-03-18 to 2022-04-19

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