Date of Award

5-31-2022

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physics, Applied

First Advisor

Jonathan Celli

Second Advisor

Mohamed A. Gharbi

Third Advisor

Chandra Yelleswarapu

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human malignancies. PDAC is characterized by dense fibrous stroma which obstructs drug delivery and also plays complex tumor-promoting roles through paracrine crosstalk. Photodynamic Therapy (PDT) is a light-based modality which has been demonstrated to be clinically feasible and effective for tumors of the pancreas. Here, we use in vitro heterocellular 3D co-culture models in conjunction with imaging, bulk rheology and microrheology methods to investigate the impact of verteporfin-based PDT on cellular and non-cellular (ECM) components of PDAC stroma. By measuring the rheology of ECM before and after PDT we find that softening of ECM is concomitant with an increase in transport of nanoparticles. At the same time, photodestruction of stromal fibroblasts, leads to enhanced tumor response to PDT, especially in fibroblasts exhibiting iCAF (tumor promoting) phenotypic traits. Collectively these results in 3D tumor models suggest that photodynamic stromal depletion (PSD) could be used to enhance subsequent drug delivery and improve tumor response to treatment. Here we specifically evaluate this approach to improve delivery and response of recently developed RNA nanomedicine agents, demonstrated to be effective in targeting overexpressed microRNAs in PDAC linked with poor survival (onco-miRs).

Comments

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