In Vitro comparison of 213Bi- and 177Lu-radiation for peptide receptor radionuclide therapy

• Published in: PloS one Vol. 12; no. 7; p. e0181473
• Main Authors: Chan, Ho Sze, de Blois, Erik, Morgenstern, Alfred, Bruchertseifer, Frank, de Jong, Marion, Breeman, Wouter, Konijnenberg, Mark
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2017; Public Library of Science (PLoS)
• Subjects: Absorption, Radiation; Alpha rays; Background radiation; Binding energy; Biological effects; Biology and Life Sciences; Biotechnology; Bismuth; Brochures; Cell culture; Cell Line, Tumor; Cell lines; Cell survival; Cell Survival - radiation effects; Cesium radioisotopes; Computer simulation; Curvature; Cytotoxicity; Deposition; Dose-Response Relationship, Radiation; Dosimeters; Dosimetry; Drug dosages; Emitters; Energy transfer; Exposure; Humans; In vitro methods and tests; Incubation; Internalization; Irradiated; Irradiation; Killing; Kinetics; Linear Energy Transfer; Linear energy transfer (LET); Lutetium; Mathematical models; Medicine; Methods; Models, Biological; Monte Carlo Method; Monte Carlo simulation; Nuclear medicine; Octreotide - analogs & derivatives; Octreotide - pharmacology; Organometallic Compounds - administration & dosage; Organometallic Compounds - pharmacology; Peptides; Physical Sciences; Radiation; Radiation therapy; Radioisotopes; Radioisotopes - administration & dosage; Radioisotopes - pharmacokinetics; Radiometry; Radiopharmaceuticals - administration & dosage; Radiopharmaceuticals - pharmacokinetics; Reaction kinetics; Receptors; Receptors, Somatostatin - metabolism; Research and Analysis Methods; Somatostatin; Somatostatin receptors; Studies; Survival; α Radiation; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0181473

Absorbed doses for α-emitters are different from those for β-emitters, as the high linear energy transfer (LET) nature of α-particles results in a very dense energy deposition over a relatively short path length near the point of emission. This highly localized and therefore high energy deposition can lead to enhanced cell-killing effects at absorbed doses that are non-lethal in low-LET type of exposure. Affinities of DOTA-DPhe1-Tyr3-octreotate (DOTATATE), 115In-DOTATATE, 175Lu-DOTATATE and 209Bi-DOTATATE were determined in the K562-SST2 cell line. Two other cell lines were used for radiation response assessment; BON and CA20948, with a low and high expression of somatostatin receptors, respectively. Cellular uptake kinetics of 111In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with 137Cs, 177Lu-DTPA, 177Lu-DOTATATE, 213Bi-DTPA and 213Bi-DOTATATE. Absorbed doses were calculated using the MIRDcell dosimetry method for the specific binding and a Monte Carlo model of a cylindrical 6-well plate geometry for the exposure by the radioactive incubation medium. Absorbed doses were compared to conventional irradiation of cells with 137Cs and the relative biological effect (RBE) at 10% survival was calculated. IC50 of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq 213Bi-DOTATATE, in majority the dose was caused by α-particle radiation. Cellular internalization determined with 111In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of 213Bi-DTPA and 213Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of 213Bi. The survival of CA20948 after exposure to 177Lu-DOTATATE and the reference 137Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with 213Bi-DOTATATE, a factor 6 lower than the 18 Gy found for 177Lu-DOTATATE and also below the 5 Gy after 137Cs external exposure. 213Bi-DTPA and 213Bi-DOTATATE lead to a factor 6 advantage in cell killing compared to 177Lu-DOTATATE. The RBE at 10% survival by 213Bi-ligand compared to 137Cs was 2.0 whereas the RBE for 177Lu-DOTATATE was 0.3 in the CA20948 in vitro model.