Dissertations, Theses, and Capstone Projects

Date of Degree

2-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Maria Contel

Advisor

Jason S. Lewis

Committee Members

Mara Schvarzstein

Moira Sauane

Mariana Torrente

Subject Categories

Biology | Cancer Biology | Pharmaceutics and Drug Design

Keywords

cancer, breast cancer, drug development

Abstract

The overexpression of HER2 accounts for 20-30% of breast cancer tumors and not only serves as a marker for poor predictive clinical outcomes but also as a target for treatment. Antibody-drug conjugates (ADCs) combine the selectivity of monoclonal antibodies (mAbs) with the efficacy of chemotherapeutic drugs to provide targeted treatment without toxicity to normal tissue. Most of the ADCs currently in the clinic for cancer chemotherapy are based on complex organic molecules. In contrast, the conjugation of metallodrugs to mAbs has been overlooked when there is enormous potential in this area with the resurgence of metal-based drugs as prospective cancer chemotherapeutics. In this study, we have evaluated the efficacy of gold(I)- based cytotoxic payloads in ADCs based on the HER2 targeted mAb, Trastuzumab, Pertuzumab and THIOMAB®. The ADCs were selective and highly efficacious towards HER2-positive breast cancer cells. We then assessed the anti-tumor efficacy of a selected gold-based ADC in a HER2- positive tumor-bearing mouse model and found the ADCs to be exceedingly potent in reducing tumor size by 81% with little to no toxicity in the animals. In addition to this, we aimed to develop a method of drug delivery combining liposomal formulations and HER2 targeted mAbs in the form of immunoliposomes to further increase the cytotoxic gold-payload content.

These nanocarriers are advantageous in that they have an extended blood circulation time, allowing for higher accumulation in the tumor, they are much more sensitive towards the tumor micro-environment, and they allow for precise control of drug release. We have demonstrated that immunoliposomes containing gold(I)-phosphane species are cytotoxic and selective to HER-2 positive breast cancer cells. The encapsulation of a gold compound containing a fluorescent phosphane, allowed us to study the localization of the free vs. encapsulated drug by confocal microscopy. These studies showed that while the free drug localizes to lysosomes to be sequestered and degraded, the encapsulated and targeted drug accumulated more inside the cells and localized to the mitochondria and ER, indicating that protection by liposomal vesicles prevents early degradation of the compound and better internalization. Taken together, the development of gold- based ADCs and immunoliposomes with specific targeting and cytotoxic abilities exhibit tremendous potential in the field of metal-based drugs and nanocarrier systems and may be highly relevant for clinical translation.

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