Graduation Date

Fall 12-16-2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cancer Research

First Advisor

David Oupicky

Abstract

Hydroxychloroquine (HCQ) is an established drug that has been used for the treatment of multiple diseases, including malaria, rheumatoid arthritis, and lupus erythematosus. Several recently published studies have highlighted its beneficial use in various types of cancers, and a plethora of clinical trials are currently evaluating its use in cancer therapies, wherein some of the results look promising. The preclinical studies to date suggest HCQ can work effectively in conjunction with traditional cancer treatments, as it has been shown to sensitize tumor cells to a wide range of chemotherapeutic agents. Polymeric HCQ (PCQ), a macromolecular multivalent version of HCQ, has been shown to be effective in various cancer models both in vitro and in vivo, especially as an inhibitor of cancer cell migration and experimental lung metastasis. Previous studies have shown comparisons of PCQ with HCQ in some cancer models that indicated that PCQ exhibits improvement in anti-metastatic activity over HCQ. In this current report, it is shown with detailed in vitro experimentation that low concentrations of PCQ can efficiently inhibit cancer cell migration and colony formation and translocate into the cytoplasm of pancreatic cancer cells, all the while showing low levels of cytotoxicity orders of magnitude more effectively compared to HCQ. Furthermore, shortly after the administration of PCQ in vivo, the drug shows a high level of tumor penetration and anti-metastatic activity in PDAC models, especially if administered via intraperitoneal (I.P.) injection. These studies support the idea that PCQ may be effectively used at low concentrations in the therapy of pancreatic ductal adenocarcinoma (PDAC), which is an aggressive form of cancer. In conjunction with previously published literature, these studies further undergird the potential of PCQ as a future anticancer agent.

Comments

2022 Copyright, the authors

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