Defense Date

2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Matthew C.T. Hartman

Abstract

Cancer is responsible for about 25% of deaths in developed countries and for 15% of all deaths worldwide. Cancer is a devastating disease and while there have been great advances in the development of anticancer drugs, off-target toxicity is a major limitation with conventional cancer chemotherapy. The consequence of this form of treatment results in the killing of healthy and rapidly-growing non-cancerous cells including cells in the bone marrow; hair follicles; and cells in the mouth, digestive tract, and reproductive system. In addition to these general effects, certain anticancer drugs can have other associated toxicities. For instance, the anticancer drug doxorubicin (Dox), which my research has focused around, has dose-limiting cardiotoxicity. For these reasons, there has been much research focused on improving the selectivity of anticancer drugs in order to lower their toxicity to normal cells and decrease associated side effects. To circumvent the problem of non-selectivity, many methods have been developed to target cancer cells regionally at the site of the tumor. One such method is photodynamic therapy (PDT) which relies on a photosensitizer that is activated using light directed towards the tumor. Once activated, the photosensitizer creates singlet oxygen, which is cytotoxic to the illuminated tumor cells. PDT has shown profound effects in the treatment of many cancers including head and neck, lung, bladder, prostate, and esophagus. As PDT continues to be streamlined, it has the potential to serve as a standalone modality in the treatment and management of cancer at different stages. However, there are many inadequacies in the use of PDT. The fundamental problem lies in the inability of PDT to treat solid, bulky tumors or deep-seated tumors. This is partly due to the fact that current PS used cannot effectively kill cancer cells because with increasing tissue thickness the number of hypoxic cells increases. We have designed a new light based drug delivery which will allow for drugs to be released on the surface of the tumor, allowing the drug to freely diffuse through the tumor without the need of O2 and also, due to the manner our drug is attached, a more potent form the pre-attached drug is released. In this methodology, drug delivery will only be specific to an area of interest and the potential for side effects emerging from chemotherapy should be limited. Here we have shown, for the first time the generation of highly potent drug in a light dependent manner via a photocaging molecule and the commonly used chemotherapy agent Dox. We designed our photocage to generate a latent reactive form of Dox after illumination with UV light. This intermediate reacts in an intramolecular fashion to generate a highly potent form of the drug compared to its previous unattached form. Because of its high potency we have named the cleaved drug Super-Dox. Once the synthesis of the photocleavable drug conjugate was complete and we confirmed the photorelease of Super-Dox, via photolytic assay, and confirmed our drug conjugate is 80% cleaved from its photocage after 30 minutes of irritation with UV light. Next, we performed cell viability assays using MCF7 breast cancer cells to determine the efficiency of our drug conjugate to induce cell death. Our drug conjugate was able to induce significant cell death in the presence of light when compared to the dark. When compared to Dox, our cleaved drug conjugate is 26 folds more potent with light illumination an when compared to toxicity in the dark our drug conjugate was 374 fold less potent when conjugated to the photocage. However, our drug conjugate was not completely benign in the dark due to cell permeability, evidenced by confocal microscopy, we have worked equip our linker with sulfated cell impermeable group that will lower its background toxicity in the dark and allow us to achieve even higher enhancements in activity with light. This type of innovation creates a new avenue into cancer treatment which can limit adverse side effects and improve overall treatment.

Rights

© Patrick S. Dupart

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

12-12-2018

Available for download on Thursday, December 14, 2023

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