Date of Award

Summer 8-14-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Jered C. Garrison

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in the US with very poor prognosis. All clinically available biomarkers and diagnostic tools either fail to detect early stage PDAC or suffer from low specificity and sensitivity. There is an urgent need for diagnostic agents with greater efficacy for PDAC detection and staging. Nanomaterials such as N-(2-Hydroxypropyl) methacrylamide (HPMA) copolymers can effectively target tumors, and offer novel opportunities for the development of effective diagnostic agents for cancer. However, a major problem of many nanomaterials-based diagnostics is their opsonization and sequestration by the mononuclear phagocyte system (MPS), leading to substantial accumulation in MPS tissues such as the liver and spleen. This MPS accumulation in non-target tissues can hinder identification of resident or nearby metastatic malignant lesions thereby decreasing the diagnostic efficacy.

In this thesis, we focused on developing new approaches in which radiolabeled HPMA copolymers can be synthetically modified to significantly reduce the MPS accumulation and/or to increase the tumor accumulation, thereby enhancing the diagnostic and/or radiotherapeutic efficacy of the agents. First, we evaluated the effectiveness of incorporating metabolic active linkers into HPMA copolymers to decrease the radioactivity retention in the liver and spleen in pancreatic tumor xenograft mice. We demonstrated that 177Lu-labeled HPMA copolymers conjugated with cathepsin B/S cleavable peptide linkers exhibited significant long-term reduction in hepatic and splenic radioactivity accumulation as compared to the non-cleavable control. Next we conjugated a 109 kDa HPMA copolymer with three different cathepsin S cleavable linkers and evaluated the structure-activity relationship with regard to the lengths of the linking groups on the in vitro and in vivo efficacy of 177Lu-labeled cathepsin S cleavable HPMA copolymers. Biodistribution results showed that the 177Lu-labeled HPMA copolymer with the shortest length linker had a significant enhancement in the tumor-to-non-target ratios, which was also confirmed by SPECT/CT imaging. Finally, the potential of active tumor targeting for PDAC was evaluated using a plectin-1 targeted peptide (PTP) conjugated HPMA copolymer on pancreatic cancer cells in vitro. Unfortunately, we found that incorporation of the PTP into the HPMA copolymer diminished the binding of the peptide, possibly due to steric hindrance.

Overall, our 177Lu-labeled cathepsin cleavable HPMA copolymer showed decreased MPS tissue accumulation and significant improvement in tumor-to-non-target organ ratio, and was successfully applied to SPECT/CT imaging of pancreatic tumors in a xenograft mouse model.

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Available for download on Saturday, July 15, 2017

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