title: [177Lu]Bz-DTPA-EGF: Preclinical characterization of a potential radionuclide targeting agent against glioma.
abstract: Patients with glioblastoma multiforme have a poor prognosis due to recurrences originating from spread cells. The use of radionuclide targeting might increase the chance of inactivating single tumor cells with minimal damage to surrounding healthy tissue. As a target, overexpressed epidermal growth factor receptors (EGFR) may be used. A natural ligand to EGFR, the epidermal growth factor (EGF) is an attractive targeting agent due to its low molecular weight (6 kDa) and high affinity for EGFR. 177Lu (T(1/2) = 6.7 days) is a radionuclide well suited for treatment of small tumor cell clusters, since it emits relatively low-energy beta particles. The goal of this study was to prepare and preclinically evaluate both in vitro and in vivo the [177Lu]Bz-DTPA-EGF conjugate. The conjugate was characterized in vitro for its cell-binding properties, and in vivo for its pharmacokinetics and ability to target EGFR. [177Lu]Bz-DTPA-EGF bound to cultured U343 glioblastoma cells with an affinity of 1.9 nM. Interaction with EGFR led to rapid internalization, and more than 70% of the cell-associated radioactivity was internalized after 30 minutes of incubation. The retention of radioactivity was good, with more than 65% of the 177Lu still cell-associated after 2 days. Biodistribution studies of i.v. injected [177Lu]Bz-DTPA-EGF in NMRI mice demonstrated a rapid blood clearance. Most of the radioactivity was found in the liver and kidneys. The liver uptake was receptor-mediated, since it could be significantly reduced by preinjection of unlabeled EGF. In conclusion, [177Lu]Bz-DTPA-EGF seems to be a promising candidate for locoregional treatment of glioblastoma due to its high binding affinity, low molecular weight, and ability to target EGFR in vivo.
authors.affiliation: Division of Biomedical Radiation Sciences, Uppsala University, Uppsala, Sweden. Asa.Liljegren@bms.uu.se
authors.forename: Asa Liljegren
authors.initials: AL
authors.lastname: Sundberg
authors.forename: Lars
authors.initials: L
authors.lastname: Gedda
authors.forename: Anna
authors.initials: A
authors.lastname: Orlova
authors.forename: Alexander
authors.initials: A
authors.lastname: Bruskin
authors.forename: Erik
authors.initials: E
authors.lastname: Blomquist
authors.forename: Jörgen
authors.initials: J
authors.lastname: Carlsson
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical; D004815:Epidermal Growth Factor / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005909:Glioblastoma / Q000532:radiotherapy*; D006801:Humans; D008187:Lutetium / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D004369:Pentetic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
chemical_list: D002614:Chelating Agents; D011868:Radioisotopes; D019275:Radiopharmaceuticals; D008187:Lutetium; D004815:Epidermal Growth Factor; D004369:Pentetic Acid