Event

PhD Dissertation Defense: Jose F. Delgado

Monday, October 21, 2024
1:00 p.m.
AJC5104
Rachel Chang
301 405 8268
rachel53@umd.edu

Title: Development of an X-ray and ultrasound imageable poloxamer-based gel for image-guided local percutaneous delivery

Committee members:

Dr. Bradford J. Wood, Director, Center for Interventional Oncology, Clinical Center, National Institutes of Health, Bethesda, Maryland (Chair)

Dr. Huang-Chiao Huang, Assistant Professor, Fischell Department of Bioengineering, University of Maryland, College Park, Maryland (Co-chair)

Dr. Jenna Mueller, Assistant Professor, Fischell Department of Bioengineering, University of Maryland, College Park, Maryland

Dr. Helim Aranda-Espinoza, Associate Professor, Fischell Department of Bioengineering, University of Maryland, College Park, Maryland

Dr. Luz Martinez-Miranda, Professor, Department of Materials Science. University of Maryland, College Park, Maryland, Dean's Representative

Abstract:

Liver cancer is the sixth most common cancer worldwide, with a high mortality rate, as few patients are candidates for surgery after diagnosis. Systemic administration of cancer therapeutics causes adverse effects due to the high systemic exposure required to achieve local therapeutic levels in the target tumor tissue. Intra-tumoral injections have the potential to reduce systemic toxicity by delivering drug therapy locally, possibly increasing bioavailability at the site of action with reduced uptake in non-target healthy tissue. Although intra-tumoral injection is finding applications in the clinical setting, there is a knowledge gap in the standardization of injection parameters, techniques, imaging tools, and formulations to provide optimal localized drug depositions that leverage image guidance or image-ability.

One of the major clinical challenges in intra-tumoral injections is that the injected anti-cancer agents can leak into vessels or adjacent tissue outside the intended treatment region, even under x-ray and ultrasound image guidance. The second major clinical challenge is that due to the free-flow nature of low-viscosity injected drugs, local deposition in tissue is invisible, unpredictable, and variable, being highly dependent on physician technique. To address these unmet clinical needs, this thesis proposes using a thermosensitive hydrogel based on a poloxamer block copolymer as a drug delivery carrier for highly localized and predictable percutaneous needle delivery in hepatic tumors. This drug delivery vector is engineered to be imageable under both ultrasound and X-ray imaging via phospholipid-based microbubbles and iodine contrast agents, respectively.

Our central hypothesis is that multi-modality image-guided injection parameters and techniques significantly influence gel and drug distribution, impacting drug bioavailability in ex vivo and in vivo models. To prove this hypothesis, we have the following specific aims: Aim 1) Develop and characterize a candidate gel formulation, imageable under X-rays and ultrasound. Aim 2) Optimize methods for needle-based image-guided, minimally invasive, localized gel deposition. Aim 3) Identify the impact of injection parameters and techniques on local drug dose distribution of therapeutics incorporated into imageable gels. Aim 4) Determine the influence of injection parameters and techniques on drug-gel distribution after image-guided hepatic injection of gels in a swine model. We expect to elucidate and support the optimization and standardization of image-guided intra-tumoral injection techniques using drug-gel combinations. The potential downstream impact is broad for a variety of therapeutic agents delivered by local injection, which are currently being delivered clinically with non-standardized techniques.