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

BACKGROUND: 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-DPhe(1)-Tyr(3)-octreotate (DOTATATE), (115)In-DOTATATE, (175)Lu-DOTATATE and (209)Bi-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 (111)In-DOTATATE were determined in CA20948 cells. CA20948 and BON were irradiated with (137)Cs, (177)Lu-DTPA, (177)Lu-DOTATATE, (213)Bi-DTPA and (213)Bi-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 (137)Cs and the relative biological effect (RBE) at 10% survival was calculated. RESULTS: IC(50) of (labelled) DOTATATE was in the nM range. Absorbed doses up to 7 Gy were obtained by 5.2 MBq (213)Bi-DOTATATE, in majority the dose was caused by α-particle radiation. Cellular internalization determined with (111)In-DOTATATE showed a linear relation with incubation time. Cell survival after exposure of (213)Bi-DTPA and (213)Bi-DOTATATE to BON or CA20948 cells showed a linear-exponential relation with the absorbed dose, confirming the high LET character of (213)Bi. The survival of CA20948 after exposure to (177)Lu-DOTATATE and the reference (137)Cs irradiation showed the typical curvature of the linear-quadratic model. 10% Cell survival of CA20948 was reached at 3 Gy with (213)Bi-DOTATATE, a factor 6 lower than the 18 Gy found for (177)Lu-DOTATATE and also below the 5 Gy after (137)Cs external exposure. CONCLUSION: (213)Bi-DTPA and (213)Bi-DOTATATE lead to a factor 6 advantage in cell killing compared to (177)Lu-DOTATATE. The RBE at 10% survival by (213)Bi-ligand compared to (137)Cs was 2.0 whereas the RBE for (177)Lu-DOTATATE was 0.3 in the CA20948 in vitro model.