Specific aim:
Surgical resection remains among the most promising treatments for improving prognosis of cancer patients. However, pancreatic ductal adenocarcinoma(PDAC), one of the deadiest forms of cancer, presents more obstacles to successful surgical intervention than other forms of cancer. In this proposal, the mechanism of targeting and long-term circulation effects of hyaluronic acid (HA)-derived near infrared fluorescence(NIRF) contrast agents are explored to identify the factors that affect the sensitivity and consistency for identifying canerous tissue and delineating tumor margins in PDAC, with the goal of ultimately improving surgical outcome.
In this proposal, two aims are presented to investigate the in vivo fate of the promising agents.
The overarching hypothesis of this proposal is that through optimization of targeting and long-term circulation, the use of HA-based macromolecular contrast agents will lead to improved surgical resection. Prelimilary data shows significant accumulation of HA-based contrast agents within the pancreas in an orthotopic PDAC model, resulting in improved contrast for pancreatic lesions relative to non-diseased portions of the pancreas. These findings suggest that further improvement and optimization of these contrast agents could lead to improved prognosis in PDAC patients who undergo interventional surgery.
Aim 1: characterization and subcellular localization of HA-based contrast agents.
The targeting mechanisms and specificity of cellular uptake are integral to obtaining contrast in intraoperative imaging. We hypothesize that CD44-mediated cellular uptake will lead to higher signal in cancerous PDAC cells and subsequently a higher degree of endocytosis of HA-based contrast agents when compared to non-malignant cells.
Aim 2: optimization of systemic circulation of HA-based contrast agents.
The enhanced pharmacokinetic profile that can be afforded through the use of macromolecular agents is important for selective accumulation in cancerous pancreatic tissue. The enhancement is further realized when using naturally occurring biopolymers such as HA. We hypothesize that the enhanced signal and contrast obtained using HA-based macromolecular NIRF imaging agents stems from the low plasma protein association and macrophage uptake, and that CD44 expression will be co-localized with NIRF signal.
Successful completion of these aims will result in detailed understanding of the underlying mechanisms in increased contrast from HA-derived NIRF contrast agents. The results and insights obtained in achieving these aims broaden the applicability of HA-based carrier for imaging probe delivery and promote clinical translation of HA-based contrast agents in PDAC detection with the ultimate goal of improving surgical outcomes. In addition, the deeper investigation of the pharmacokinetics of HA-based contrast agents is extensible to macromolecular contrast agents based on other polymers, expanding the impact and importance of this work.
Significance
Pancreatic ductal adenocarcinoma (PDAC) is highly lethal and surgical resection is the only potential curative treatment for the disease.[1,2] At present, patient survival after resection of PDAC remains poor and more than 80% of patients suffer disease relapse due to incomplete removal of tumor tissue.[3] fluorescence imaging offers a potential method to detect pancreatic cancer intraoperatively to maximize malignant tissue resection[4]. Existing literature reported the use of fluorophore conjugated monoclonal antibody probes for pancreatic cancer detection with improved specificity, however, efficacy was limited by naturally existing cellular targets that are often heterogeneously expressed in tumors and in possibly low abundance compared to background signals.[5] Therefore a more sensitive, generally applicable intraoperative imaging probe is desperately needed to aid surgeons to confirm suspected pancreatic masses and elucidate positive margins.
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