Date of Award

2022

Document Type

Thesis (Ph.D.)

Department or Program

Engineering Sciences

First Advisor

Geoffrey Luke

Abstract

Cancer is a cluster of diseases, and 1.8 million Americans are newly diagnosed each year. Treatment issues such as drug instability, the occurrence of severe side effects, as well as resistance make the need for solutions to improve conventional methods, like chemotherapy, apparent. Nano-sized drug-delivery platforms, particles loaded with therapeutic molecules that escape the immune system clearance and accumulate at the tumor site, were proposed as one of these solutions. Despite the expansion of the field, several aspects still need to be addressed: inconsistent delivery of the drugs, inability of measuring the effective dose being delivered to the tumor, lack of predictability of a response.

Hence, the field of nanotheranostics was born, that combines drug-delivery nanoparticulate systems with imaging capabilities. By enabling a noninvasive visualization of delivered therapeutic molecules, nanotheranostics offer the opportunity of rapid optimization of drug delivery systems during in vivo testing. This insight into the kinetics and the fate of nanoparticle-encapsulated therapeutics can aid validate basic properties without needing to wait a long time for a pathological outcome. In the clinic, this feature would allow for a fast response in modifying a treatment course.

This work describes a versatile nanotheranostic platform capable of triggered release of therapeutic molecules and strong ultrasound imaging contrast simultaneously. The activatable release is designed to minimize off-target effects, while the ultrasound contrast can enable visualization of the delivered dose to a region of interest.

The particles described herein consist of a shell-core structure, with a perfluorocarbon iii core that can be externally vaporized by acoustical or optical stimuli. The activation generates highly echogenic microbubbles, together with the release of the loaded compounds. Notably, the release of the payload is correlated to the ultrasound magnitude after activation, enabling the basis for ultrasound dose-monitoring. The design, synthesis and characterization of perfluorocarbon nanodroplets aimed at several applications are described. These include co-delivery of hydrophobic and hydrophilic chemotherapeutics, delivery of a-PD-L1 immunecheckpoint inhibitors together with chemotherapeutics, as well as multimodal imaging capabilities.

Overall, this work contributes towards expanding the utility of perfluorocarbon nanodroplets towards combinatorial therapies, and proposes necessary improvements for increased translatability of the technology.

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