title: High vascular delivery of EGF, but low receptor binding rate is observed in AsPC-1 tumors as compared to normal pancreas.
abstract: OBJECTIVE
  Cellular receptor targeted imaging agents present the potential to target extracellular molecular expression in cancerous lesions; however, the image contrast in vivo does not reflect the magnitude of overexpression expected from in vitro data. Here, the in vivo delivery and binding kinetics of epidermal growth factor receptor (EGFR) was determined for normal pancreas and AsPC-1 orthotopic pancreatic tumors known to overexpress EGFR.
  
  
  METHODS
  EGFR in orthotopic xenograft AsPC-1 tumors was targeted with epidermal growth factor (EGF) conjugated with IRDye800CW. The transfer rate constants (k(e), K₁₂, k₂₁, k₂₃, and k₃₂) associated with a three-compartment model describing the vascular delivery, leakage rate and binding of targeted agents were determined experimentally. The plasma excretion rate, k (e), was determined from extracted blood plasma samples. K₁₂, k₂₁, and k₃₂ were determined from ex vivo tissue washing studies at time points ≥ 24 h. The measured in vivo uptake of IRDye800CW-EGF and a non-targeted tracer dye, IRDye700DX-carboxylate, injected simultaneously was used to determined k₂₃.
  
  
  RESULTS
  The vascular exchange of IRDye800CW-EGF in the orthotopic tumor (K₁₂ and k₂₁) was higher than in the AsPC-1 tumor as compared to normal pancreas, suggesting that more targeted agent can be taken up in tumor tissue. However, the cellular associated (binding) rate constant (k₂₃) was slightly lower for AsPC-1 pancreatic tumor (4.1 × 10(-4) s(-1)) than the normal pancreas (5.5 × 10(-4) s(-1)), implying that less binding is occurring.
  
  
  CONCLUSIONS
  Higher vascular delivery but low cellular association in the AsPC-1 tumor compared to the normal pancreas may be indicative of low receptor density due to low cellular content. This attribute of the AsPC-1 tumor may indicate one contributing cause of the difficulty in treating pancreatic tumors with cellular targeted agents.
authors.affiliation: Thayer School of Engineering, Dartmouth College, 8000 Cummings Hall, Hanover, NH 03755, USA. kimberley.s.samkoe@dartmouth.edu
authors.forename: Kimberley S
authors.initials: KS
authors.lastname: Samkoe
authors.forename: Kristian
authors.initials: K
authors.lastname: Sexton
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Tichauer
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Hextrum
authors.forename: Omar
authors.initials: O
authors.lastname: Pardesi
authors.forename: Scott C
authors.initials: SC
authors.lastname: Davis
authors.forename: Julia A
authors.initials: JA
authors.lastname: O'Hara
authors.forename: P Jack
authors.initials: PJ
authors.lastname: Hoopes
authors.forename: Tayyaba
authors.initials: T
authors.lastname: Hasan
authors.forename: Brian W
authors.initials: BW
authors.lastname: Pogue
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004815:Epidermal Growth Factor / Q000097:blood / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008954:Models, Biological; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000473:pathology*; D011485:Protein Binding; D023041:Xenograft Model Antitumor Assays
chemical_list: D005456:Fluorescent Dyes; D004815:Epidermal Growth Factor; D066246:ErbB Receptors