PhD Dissertation Final Oral Defense (October 2024)
Title of Dissertation: Immunoliposomes with High-frequency Ultrasound and Microbubble-mediated Triggering for Herceptin-positive Targeted Breast Cancer Therapy
Candidate: Waad H. Abuwatfa
Program: PhD in Materials Science and Engineering
Supervisors: Dr. Ghaleb Husseini and Dr. William G. Pitt
Abstract
The functionalization of liposomes with monoclonal antibodies offers a strategy to enhance liposome specificity and mitigate chemotherapeutic side effects. Specifically, this study synthesized doxorubicin (DOX)-loaded immunoliposomes targeting the overexpressed human epidermal growth factor receptor 2 (HER2) in HER2-positive breast cancer, using an anti-HER2 monoclonal antibody. These immunoliposomes were triggered by high-frequency ultrasound (HFUS) combined with microbubbles (MBUS) to enhance cavitation, aiming to uncover the biological mechanisms at play. The liposomes were characterized in terms of size, lipid content, protein concentration and stability. Comprehensive in vitro analyses were conducted to study the platform’s cell viability, drug uptake and apoptosis signaling pathways. Additionally, release kinetics were evaluated at 1 MHz and 3 MHz, frequencies akin to those used in clinical imaging. The findings supported the hypothesis that combining active targeting with MBUS as an external triggering mechanism resulted in a highly synergistic controlled release system. Functionalization with HER2 antibodies significantly enhanced the drug activity and sonosensitivity of the formulation. Moreover, Western blot analysis confirmed that this system successfully downregulated the PI3K/AKT pathway, leading to apoptosis, underpinning the therapeutic potential of this targeted drug delivery approach.
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