Investigating the bioeffects of perfluoroalkyls towards advanced image-guided protein delivery technologies

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- Author:
- Lawanprasert, Atip
- Graduate Program:
- Bioengineering
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 02, 2023
- Committee Members:
- Scott Medina, Chair & Dissertation Advisor
Daniel Hayes, Major Field Member
Daniel Hayes, Program Head/Chair
William Hancock, Major Field Member
Joseph Cotruvo, Outside Unit & Field Member - Keywords:
- Drug Delivery
Fluorine
Ultrasound
Protein - Abstract:
- Recently perfluorocarbon (PFC) materials have emerged as building blocks in the design of acoustically responsive therapeutics and imaging agents. This has been driven by the exceptional electronegativity of fluorine and the stability of PFCs. In addition, certain PFC liquids undergo liquid-to-gas phase changes in response to acoustic pressure; thereby serving as ultrasound imaging contrast agents and delivery vehicles. In combination, these capabilities enable PFCs to nucleate the design of image-guided drug delivery technologies that can be used to deliver therapeutic biomolecules, with recent attention on proteins and nucleic acids vectors. By controlling the response of these platforms with exogenous ultrasound their bioactive functions can be selecting activated at a target site with spatiotemporal precision. However, the deployment of PFC-mediated image guided drug delivery is far from simple as they face a multitude of limitations. First, it is difficult to control acoustic responsiveness of PFC carriers which is essential for multiplexed drug delivery. Secondly, the bioinert nature of PFCs makes loading hydrophilic biomolecule cargoes extremely challenging. To address these two drawbacks, and open new translation opportunities for PFC-based biotechnologies, here I explore the utility of a privileged amphiphilic perfluoroalkyl, perfluorononanoic acid (PFNA), to alter the acoustic response and drug delivery potential of PFC emulsions. In the first application, I demonstrate that PFNA can be used as an emulsifier to prepare PFC droplet emulsions that can be tuned in their ultrasound activation threshold, thereby generating carriers that can release multiple cargoes in an orthogonal and controlled manner. In preparation for future biologic delivery applications, I next studied the interaction of PFNA with proteins, and mechanistically demonstrated how this compound coats the surface of the biologic to enable their dispersion into non-aqueous PFC solvents. Lastly, I illustrate how PFC-dispersed proteins, with the aid of our PFNA coating strategy, can lead to thermally stable and intrinsically sterile protein formulations. The fundamental knowledge gained from this work sheds light on the unknown assembly properties of perfluoroalkyls and reveals unusual and desirable biophysical properties.
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