2022 Thayer Investiture

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PhD Thesis Defense: Catalina-Paula Spatarelu

Jun

30

Thursday
10:00am - 11:00am ET

ECSC B05 / Online

For Zoom link contact catalina-paula.spatarelu.TH@dartmouth.edu.

"Phase-changing nanodroplets as nanotheranostic platform for combination cancer therapy"

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 increasing prevalence of the disease make the need for solutions designed to improve conventional methods, like chemotherapy, apparent. Nano-sized drug-delivery platforms, nanometric particles that can be loaded with therapeutic molecules, escape the immune system clearance and accumulate at the tumor site to deliver their payload, were proposed as one of the 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 of the systems 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 nature of the 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 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 in vitro is correlated to the ultrasound signal 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 that can be switched on externally.

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

Thesis Committee

  • Geoffrey Luke (chair)
  • Kimberley Samkoe
  • Jack P. Hoopes
  • Emily Day (University of Delaware)

Contact

For more information, contact Theresa Fuller at theresa.d.fuller@dartmouth.edu.