Theranostics 2020; 10(8):3413-3429. doi:10.7150/thno.40688

Research Paper

Tuned near infrared fluorescent hyaluronic acid conjugates for delivery to pancreatic cancer for intraoperative imaging

Bowen Qi1, Ayrianne J. Crawford2, Nicholas E. Wojtynek2, Geoffrey A. Talmon3, Michael A. Hollingsworth2,4, Quan P. Ly4,5, Aaron M. Mohs1,5,6,✉

1. Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
2. Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
3. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
4. Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
5. Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States
6. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States

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Citation:
Qi B, Crawford AJ, Wojtynek NE, Talmon GA, Hollingsworth MA, Ly QP, Mohs AM. Tuned near infrared fluorescent hyaluronic acid conjugates for delivery to pancreatic cancer for intraoperative imaging. Theranostics 2020; 10(8):3413-3429. doi:10.7150/thno.40688. Available from http://www.thno.org/v10p3413.htm

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Abstract

The prognosis of pancreatic cancer remains poor. Intraoperative fluorescence imaging of tumors could improve staging and surgical resection, thereby improving prognosis. However, imaging pancreatic cancer with macromolecular delivery systems, is often hampered by nonspecific organ accumulation.

Methods: We describe the rational development 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.

Results: Each HA-NIRF conjugate displayed intrapancreatic tumor enhancement. Regardless of HA molecular weight, Cy7.5 conjugation directed biodistribution to the liver, spleen, and bowels. Conjugation of IRDye800 to 5 and 20 kDa HA resulted in low liver and spleen signal while enhancing the tumor up to 14-fold compared to healthy pancreas, while 100 kDa HA conjugated to IRDye800 resulting in liver and spleen accumulation.

Conclusion: 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 intraoperative abdominal imaging.

Keywords: Pancreatic ductal adenocarcinoma, hyaluronic acid, fluorescence guided surgery, biodistribution, serum protein binding