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

Background Absorbed doses for alpha-emitters are different from those for beta-emitters, as the high linear energy transfer (LET) nature of alpha-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-DPhe(1) - Tyr(3) -octreotate (DOTATATE), In-115-DOTATATE, Lu-175-DOTATATE and Bi-209-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 In-111-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with Cs-137, Lu-177-DTPA, Lu-177-DOTATATE, Bi-213-DTPA and Bi-213-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 Cs-137 and the relative biological effect (RBE) at 10% survival was calculated. Results IC50 of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq Bi-213-DOTATATE, in majority the dose was caused by alpha-particle radiation. Cellular internalization determined with In-111-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of Bi-213-DTPA and Bi-213-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of Bi-213. The survival of CA20948 after exposure to Lu-177-DOTATATE and the reference Cs-137 irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with Bi-213-DOTATATE, a factor 6 lower than the 18 Gy found for Lu-177-DOTATATE and also below the 5 Gy after Cs-137 external exposure. Conclusion Bi-213-DTPA and Bi-213-DOTATATE lead to a factor 6 advantage in cell killing compared to Lu-177-DOTATATE. The RBE at 10% survival by (213) Bi-ligand compared to Cs-137 was 2.0 whereas the RBE for Lu-177-DOTATATE was 0.3 in the CA20948 in vitro model.