Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Dr. Aaron Mohs

Abstract

Pancreatic ductal adenocarcinoma is highly lethal and surgical resection is the only potential curative treatment for the disease. Tumor-specific intraoperative fluorescence imaging could improve staging and surgical resection, thereby improving prognosis. In the first study, hyaluronic acid derived NPs with physico-chemically entrapped indocyanine green, termed NanoICG, were utilized for intraoperative near infrared fluorescence detection of pancreatic cancer. NanoICG accumulated significantly in an orthotopic pancreatic ductal adenocarcinoma model with safety profile both in vitro and in vivo. To maximize tumor signal, while minimizing signal in healthy pancreas and RES capture of macromolecules, in the next study, we describe the rational development of a series of hyaluronic acid (HA) conjugates that vary in molecular weight and are conjugated to near-infrared fluorescent (NIRF) dyes that have differences in hydrophilicity, serum protein binding affinity, and clearance mechanism. We systematically investigated the roles of each of these properties on tumor accumulation, relative biodistribution, and the impact of intraoperative imaging of orthotopic, syngeneic pancreatic cancer. Overall, each HA-NIRF conjugate displayed intra-pancreatic tumor enhancement compared to uninvolved pancreas at 24 and 96 h. Regardless of HA molecular weight, Cy7.5 conjugation directed biodistribution to the liver, spleen, and bowels. Conjugation of IRDye-800 to 5 and 20 kDa HA resulted in low liver and spleen signal, while preserving tumor contrast enhancement up to 14-fold compared to healthy pancreas. When IRDye800 was conjugated to 100 kDa HA, the conjugate preferentially distributed to RES organs. When assessing the imaging efficacy of HA-based conjugates in hepatic metastases, those that accumulated to the liver utmost (HA100k-Cy7.5, HA100k-IRDye800, NanoICG) turned to aid the identification of hepatic malignancy with hypo-contrast. These studies demonstrate that by tuning HA molecular weight and the physicochemical properties of the conjugated moiety, in this case a NIRF probe, peritoneal biodistribution can be substantially altered to achieve optimized delivery to tumors with robust contrast enhancement for intraoperative imaging to abdominal tumors. Aside from assisting the accurate delineation of primary tumor, HA-NIRF conjugates demonstrated potential for identification of occult metastases in the intraoperative setting, as a versatile tool for accurate staging.

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