First Advisor

Robert M. Strongin

Term of Graduation

Spring 2020

Date of Publication

5-12-2020

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Chemistry

Department

Chemistry

Language

English

Subjects

Fluorescent probes -- Diagnostic use, Xanthene dyes, Pancreas -- Tumors -- Identification, Pancreas -- Cancer -- Imaging, Pancreas -- Cancer -- Spectroscopic imaging

DOI

10.15760/etd.7333

Physical Description

1 online reource (xi, 163 pages)

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest human malignancies with an extremely poor 5-year survival rate of below 5%. Surgical resection is the most effective treatment of choice because chemotherapy and radiation therapy do not improve life expectancy. Residual tumor after PDAC surgery is common due to a lack of PDAC targeted intraoperative contrast agents to confirm clear margins.

Fluorescence imaging has the potential to improve surgery outcome and PDAC patients' survival rate via the use of highly PDAC-specific molecular probes to facilitate tumor identification. This thesis describes the application of a focused library of benzoxanthene fluorophores for PDAC margin assessment. This work shows the utility of fluorophore 12 in the ex vivo staining of human PDAC tissue. When 12 was used for ex vivo staining of healthy pancreas and PDAC tissue, it displayed visually higher localization in the PDAC-associated ductal epithelial cells compared to the healthy tissue. We optimized the ex vivo staining conditions such as fluorophore concentration, fluorophore incubation and washing time, for clinical translation. A receiver operator characteristic (ROC) curve analysis was used as a non-subjective evaluation for effective contrast between cancer and healthy tissue, confirming high throughput and efficient screening for the investigated parameters.

The need for dyes that are active in the near-infrared region (NIR) region (>700 nm) and have large Stoke shifts led to the design and synthesis of a benzo[a]xanthene library. Among other advantages, imaging in the NIR results in reduced tissue damage and reduced photobleaching of the fluorophore. The benzo[a]xanthene library shows at least two-fold enhanced brightness compared to the benzo[c]xanthene library, along with no significant bathochromic shift, as predicted by density functional theory (DFT) calculations. Compound 8, a regioisomer of 12 with analogous physicochemical properties, showed selectivity for PDAC but was not as optimal as 12. The functionalization of the benzo[c]xanthene chromophore with a cyanine chromophore moiety was proposed towards developing NIR-active fluorophores. The synthesis of cyanine-xanthene hybrids was begun. Once the synthesis is optimized, the hybrid dyes will be screened for PDAC selectivity and subsequently used for PDAC margin assessment.

Rights

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).

Persistent Identifier

https://archives.pdx.edu/ds/psu/33276

Available for download on Wednesday, May 12, 2021

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