TY - JOUR
T1 - Tuned near infrared fluorescent hyaluronic acid conjugates for delivery to pancreatic cancer for intraoperative imaging
AU - Qi, Bowen
AU - Crawford, Ayrianne J.
AU - Wojtynek, Nicholas E.
AU - Talmon, Geoffrey A.
AU - Hollingsworth, Michael A.
AU - Ly, Quan P.
AU - Mohs, Aaron M.
N1 - Funding Information:
We thank Megan B. Holmes and Dr. Joshua J. Souchek for generous help with mice handling, intraoperative IGS detection and necropsy. We also thank Ziling Zhao for assisting with FC data collection. Thomas C. Caffrey and Kelly A. O’Connell provided technical support for the orthotopic pancreatic cancer model. We also thank Tom Bargar for assisting with TEM imaging. We thank UNMC Flow Cytometry Core facility and UNMC Tissue Science Core Facility for instruction on FC data acquisition and analysis and sectioning and staining of pancreatic tissue. This work was supported in part by the National Institutes of Health [grant numbers R00CA153916, R01EB019449, P50CA127297, P20GM 103480, U01CA210240, 1S10RR17846, 1S10RR027940, and P30CA036727 (Fred and Pamela Buffett Cancer Center at UNMC)], the Nebraska Cattlemen’s Ball Development Fund, and the Nebraska Research Initiative.
Funding Information:
We thank Megan B. Holmes and Dr. Joshua J. Souchek for generous help with mice handling, intraoperative IGS detection and necropsy. We also thank Ziling Zhao for assisting with FC data collection. Thomas C. Caffrey and Kelly A. O'Connell provided technical support for the orthotopic pancreatic cancer model. We also thank Tom Bargar for assisting with TEM imaging. We thank UNMC Flow Cytometry Core facility and UNMC Tissue Science Core Facility for instruction on FC data acquisition and analysis and sectioning and staining of pancreatic tissue. This work was supported in part by the National Institutes of Health [grant numbers R00CA153916, R01EB019449, P50CA127297, P20GM 103480, U01CA210240, 1S10RR17846, 1S10RR027940, and P30CA036727 (Fred and Pamela Buffett Cancer Center at UNMC)], the Nebraska Cattlemen's Ball Development Fund, and the Nebraska Research Initiative.
Publisher Copyright:
© The author(s).
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Biodistribution
KW - Fluorescence guided surgery
KW - Hyaluronic acid
KW - Pancreatic ductal adenocarcinoma
KW - Serum protein binding
UR - http://www.scopus.com/inward/record.url?scp=85080903661&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85080903661&partnerID=8YFLogxK
U2 - 10.7150/thno.40688
DO - 10.7150/thno.40688
M3 - Article
C2 - 32206099
AN - SCOPUS:85080903661
SN - 1838-7640
VL - 10
SP - 3413
EP - 3429
JO - Theranostics
JF - Theranostics
IS - 8
ER -