All ETDs from UAB

Advisory Committee Chair

Eugenia Kharlampieva

Advisory Committee Members

Mark Bolding

Tracy Hamilton

Pengfei Wang

Kurt Zinn

Document Type

Dissertation

Date of Award

2019

Degree Name by School

Doctor of Philosophy (PhD) College of Arts and Sciences

Abstract

Modern medicine employs many drugs in its disease treatment methods. This is because they provide the best permanent solutions to complicated ailments. However the usefulness of these drugs is mitigated by several factors, namely that of specific release. Common drug delivery mechanisms lack the specificity needed to ensure that release is limited to the diseased area, which can lead to unnecessary side effects. By utilizing medical imaging, both drug delivery devices and physiology can be observed by physicians, which can greatly increase the specificity of drug delivery. Specifically, utilizing a very inert medical imaging modality, such as ultrasound, guarantees minimum collateral damage to the patient upon completion of treatment. By utilizing ultrasound as both an imaging and therapy delivery mechanism, we can create a true “theranostic” system, which can take advantage of both therapeutic and diagnostic aspects of the same device. Furthermore, by utilizing layer-by-layer deposition to create this device, the structure-property relationships can be closely monitored and tweaked to fit a plethora of circumstances. In the following dissertation, a novel theranostic approach utilizing layer-by-layer microcapsules along with both therapeutic and diagnostic ultrasound is explored as a specific drug delivery device. In addition, the ultrasound sensitivity, along with the mechanical effects of ultrasound on these microcapsules, are explored; the structure-property relationships which govern the responsiveness to ultrasound-based mechanical stimuli are investigated as well. The assembly of the poly(N-vinylpyrrolidone) (PVPON) polymers with tannic acid (TA) into flat films and 3D microcapsules, and relevant characterizations thereof are described. The potential for these microcapsules in conjunction with ultrasound as theranostic drug carriers are discussed, and proof of concept studies with biological cell studies are reported. Chapter 2 explores the development of a novel algorithm for quantifying the molecular ultrasound signal for binding microbubbles is developed, and tested for accuracy in ultrasound imaging applications. This algorithm provides a correlation between the molecular ultrasound signal and tangible biological functions, such as flow rate and contrast agent binding density. All variables in the algorithm are tested for their use and correlated to a physical aspect. Finally, a high R2 value for the novel algorithm towards its objective correlation parameters provides proof of concept for use in discerning molecular ultrasound signal to applicable parameters for use in clinical settings. Chapter 3 demonstrates how microbubbles can be utilized for in-vivo imaging and disease diagnosis using non-invasive ultrasound image quantifications. The ability to use Molecular ultrasound imaging for early detection of kidney inflammatory effects was shown using P-Selectin or VCAM-1 (vascular cell adhesion molecule 1). These biomarkers were imaged using targeted microbubbles injected into rat kidney ischemia models. After 24 hours, kidney ischemia could be visually identified using ultrasound imaging, which was confirmed after histology. This positive correlation between imaging and histology provides proof that this early warning system can be utilized to greatly decrease kidney ischemia detection times. Chapter 4 discusses the use of pulsed high intensity ultrasound (pHFIU) as an improvement upon traditional therapeutic ultrasound in use with theranostic drug delivery agents utilizing layer-by-layer microcapsules with PVPON and TA which were previously developed. The usefulness of this modified approach has been shown to be effective in terms of creating safer and more specific ultrasound-guided drug delivery by lowering temperature and delivered power. The effect of pHIFU on these microcapsules is explored utilizing controlled drug delivery and permeability. Additionally, structure-property relationships between TA/PVPON systems and ultrasound pressure is explored, leading to quantification of imaging correlations.

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