Tumor-Specific Nanocontrast Agents for Improved Detection of Pancreatic Cancer - PROJECT SUMMARY/ABSTRACT Abstract. Pancreatic adenocarcinoma (PDAC) is a highly aggressive form of cancer that has high mortality and late stage diagnosis. Undergoing chemotherapy and subsequent surgery for tumor resection is the only potentially curative options for patients with PDAC. However, differentiation between benign disease, e.g., fibrosis, and tumor tissue is difficult. Currently, this differentiation is based on visual inspection and palpation of the operating surgeon. This poor differentiation can often result in incomplete resection of tumor, leading to likely reoccurrence of cancer in the pancreas or as distant metastases. Multispectral optoacoustic tomography (MSOT) is an emerging modality which has recently entered clinical testing and exhibits high resolution, real-time, and depth penetration suitable for intraoperative imaging. MSOT has the capability of identifying multiple molecular agents simultaneously, but current lacks tumor-specific contrast agents for identifying cancer to provide such information. Development of PDAC-specific contrast agents for MSOT represents the potential for improved detection of PDAC in an intraoperative setting. While small molecule dyes and antibody-drug conjugates have been evaluated, low signal has resulted due to non-specificity or few contrast molecules reaching the tumor. To overcome these limitations, my objective is to: 1) develop targeted, tumor-specific nanocontrast agent (P-MSN), and 2) test P-MSN for detection of pancreatic cancer in vivo using MSOT. Building upon my experience with constructing mesoporous silica nanoparticles, I am proposing the development of a new, tumor-targeted nanocontrast agent, P-MSN, which exhibits three unique features for improved PDAC tumor-specificity: 1) small (<50 nm diameter); 2) tumor-specific cargo release with pH-sensitive (PVA-PAAm) gatekeeper; and 3) introduction of Plectin-1 active targeting peptide. The development of a tumor-specific nanocontrast agent could increase the accuracy of PDAC identification using MSOT compared to hemoglobin alone. I hypothesize that through the dual-targeting of PDAC, i.e. the use of plectin-1-targeting peptide (PTP) to provide specificity to tumor cells, and MSN gatekeeping with P(VA-AAm), to target and release contrast specifically in the acidic tumor microenvironment, the developed MSNs will facilitate improved detection of PDAC by MSOT. To test this hypothesis, I propose the following aims: 1) Develop a tumor-specific nanocontrast agent (P-MSN), and 2) Assess efficacy of tumor-specific nanocontrast (P-MSN) for detection of PDAC in vivo by MSOT. The impact of this study is the development of a pancreatic cancer specific nanocontrast agent that has potential to identify molecular features and improve identification of pancreatic cancer using MSOT. If successful, our studies will provide “first-in-class” pancreatic cancer specific contrast agent which could be used intraoperatively to clearly differentiate between malignant and benign tissue to ensure complete resection of tumor in PDAC patients.
