Nanoparticle-based Approaches to Brain Injury and Studies for Improved Detectability toward Better Delivery Characterization

Authors

Hunter A. Miller, University of Nebraska-LincolnFollow

First Advisor

Forrest M. Kievit

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Agricultural and Biological Systems Engineering

Date of this Version

8-2024

Document Type

Dissertation

Citation

A dissertation presented to the faculty of the Graduate College of the University of Nebraska in partial fulfillment of requirements for the degree of Doctor of Philosophy

Major: Biological Engineering

Under the supervision of Professor Forrest M. Kievit

Lincoln, Nebraska, August 2024

Comments

Copyright 2024, Hunter A. Miller. Used by permission

Abstract

The clinical translation of nanoparticle (NP) therapeutics for brain injury has been slow despite preclinical promise. The causes of disconnect between preclinical and clinical outcomes is multifactorial, but insufficient delivery is noteworthy. Preclinical delivery characterization often lacks, obscuring mechanisms of failure, slowing development. Multimodal imaging is a promising strategy to improve delivery characterization, combining the strengths of various modalities. Magnetic resonance imaging (MRI) and luminescence imaging are a suitable combination for multimodal imaging, expanding the spatial and temporal resolution of either alone, but further material development is needed to enhance detectability. One problem is the interference of cellular autofluorescence in luminescence imaging. The use of sensitized lanthanide luminophores, with emission lifetimes multiple orders of magnitude longer than autofluorescence, has been shown as an effective interference mitigation strategy in small molecule chelates as well as NP systems.

This dissertation covers the assessment of several surface-coordinating ligands for enhanced photoluminescence of ultrasmall Eu₂O₃ NPs. Among the tested species, quinaldic acid (QA) and kynurenic acid (KA) were previously unreported for the sensitization of NPs, while terephthalic acid (TA) was previously used in a different Eu NP model. NP characterization showed consistent core structure, effective ligand coordination, and enhancement of Eu³⁺ emissions over tissue lysate autofluorescence. TA, QA, and KA provided signal-to-tissue-noise fold enhancements of 75, 89, and 108, respectively with time-gating. KA was further investigated as a co-sensitizer with DPA to enable the UV-A excitation of KA while passivating the surface with DPA to enhance emission intensity and lifetime. Using KA with DPA enhanced Eu³⁺ emission relative to tissue lysate autofluorescence, providing a 797-fold increase with time-gating. Comparison of that co-sensitized NP to Rhodamine B in a model of mounted tissue imaging showed a 15-fold improvement in detection limit on a number concentration basis. This work showed the efficacy of Eu sensitization with novel species, and it motivates further investigation toward mixed Gd/Eu NPs for multimodal imaging.

Advisor: Forrest M. Kievit

Recommended Citation

Miller, Hunter A., "Nanoparticle-based Approaches to Brain Injury and Studies for Improved Detectability toward Better Delivery Characterization" (2024). Dissertations and Doctoral Documents from University of Nebraska-Lincoln, 2023–. 181.
https://digitalcommons.unl.edu/dissunl/181