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Ultrasound-triggered and targeted combination therapy: Inhibiting angiogenesis and inducing cytotoxicity in colorectal cancer
Paul, Vinod
Paul, Vinod
Date
2025-12
Author
Advisor
Type
Dissertation
Degree
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29.330-2025.02a Vinod Paul.pdf
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Description
A Doctor of Philosophy Dissertation in Materials Science and Engineering by Vinod Paul entitled, “Ultrasound-triggered and targeted combination therapy: Inhibiting angiogenesis and inducing cytotoxicity in colorectal cancer”, submitted in December 2025. Dissertation advisor is Dr. Ghaleb Husseini and dissertation co-advisor is Dr. William Pitt. Soft copy is available (Dissertation, Completion Certificate, Approval Signatures, and AUS Archives Consent Form).
Abstract
Liposome-based nanodrug delivery systems offer a promising strategy to mitigate the side effects associated with conventional chemotherapy. Tumor growth and progression are regulated by multiple pathways, which are often inadequately addressed by single-agent therapies. To overcome this limitation, combinatorial approaches employing multiple therapeutics have gained increasing attention. In this study, a multifunctional liposomal formulation was developed that co-encapsulated regorafenib and 5-fluorouracil and was further functionalized with ramucirumab for active targeting. Liposomes were prepared by the thin-film hydration method, yielding uniformly sized vesicles below 200 nm that were stable at 4 °C and at room temperature. Encapsulation efficiency of regorafenib was optimized by varying cholesterol molar ratios, and drug content was quantified using UV–Vis spectroscopy and high-performance liquid chromatography (HPLC). The functionalized liposomes were designed to bind vascular endothelial growth factor receptors (VEGFR), which are overexpressed on endothelial cells in the tumor microenvironment, thereby enhancing site-specific drug delivery. The dual-drug system exhibited synergistic cytotoxicity against HCT116 colorectal cancer cells, with regorafenib providing broad-spectrum inhibition of angiogenesis and tumor proliferation. Ultrasound-triggered release further enabled temporal control over drug delivery. Tube formation assays demonstrated that the combination of ramucirumab and regorafenib effectively disrupted angiogenesis. Sonosensitivity of the liposomes was confirmed by encapsulating calcein and monitoring its release under 20 kHz ultrasound at varying power densities. Additional stability studies indicated minimal leakage of encapsulated drug at 37 °C and enhanced release at 42 °C. Overall, the synthesized multifunctional liposomal platform integrates targeted delivery, combinational therapy, and ultrasound responsiveness.