Advancing imaging techniques for assessing inflammation and fibrosis associated with inflammatory bowel disease
Date
2025-03-19
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-2058-1194
Type
Thesis
Degree Level
Doctoral
Abstract
Inflammatory bowel disease (IBD) is a chronic condition that requires accurate early diagnosis and routine monitoring to enable timely treatment and enhance patient outcomes. Current diagnostic techniques are often invasive, costly, unsuitable for routine monitoring, and may not be sensitive to subtle inflammation and fibrosis. This thesis explores three innovative imaging techniques for rapid, noninvasive detection of active inflammation and fibrosis associated with IBD. Positron emission tomography (PET) enables whole-body imaging of molecular and cellular processes in vivo. We developed lipid-shelled “radiodroplets” as a PET agent. Radiodroplets were dual-labeled with a commercial P-selectin antibody and Zirconium-89, demonstrating biodistribution through the reticuloendothelial system with no nonspecific accumulation in the gastrointestinal tract. Preliminary in vivo results demonstrated targeted radiodroplet accumulation within the inflamed bowel of a mouse with acute colitis, highlighting their potential for imaging active inflammation. Ultrasound molecular imaging (USMI) provides a widely accessible and well tolerated alterative for monitoring inflammation at known disease sites. To address the lack of clinically translatable targeted microbubbles for USMI, we systematically optimized the design of selectin-targeted microbubbles. The conventional preclinical streptavidin-biotin coupling method was replaced with strain-promoted alkyne-azide click chemistry. A P-selectin-specific RNA aptamer, modified to reduce nuclease-mediated degradation, was tested as an alternative to commercial non-human antibodies. RNA aptamer-functionalized microbubbles successfully detected active inflammation in two murine models of acute colitis. We then evaluated replacing the RNA aptamer, with a naive DNA aptamer targeting murine and human P-/E-selectin, designed without costly nuclease-resistant modifications. These DNA aptamer-functionalized microbubbles detected inflammation in murine and rabbit colitis models using preclinical and clinical ultrasound systems, showing significant signal enhancement and support for future clinical translation. Quantitative magnetic resonance imaging (MRI) provides valuable insights into macromolecular tissue changes, with the potential to detect fibrosis, a significant complication associated with IBD. We assessed bowel fibrosis in a rat model of chronic IBD using T2 relaxation time estimates. Our findings reveal a strong negative correlation between T2 relaxation time and collagen content in fibrotic rat bowel tissue, supporting its potential use for detecting bowel fibrosis. This thesis advances PET, USMI, and MRI applications for imaging subclinical inflammation and fibrosis, with potential for future integration into the IBD patient imaging framework.
Description
Keywords
molecular imaging, inflammatory bowel disease, PET imaging, ultrasound molecular imaging, quantitative MRI
Citation
Degree
Doctor of Philosophy (Ph.D.)
Department
Medicine
Program
Health Sciences