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

Abstract

BackgroundAbsorbed 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.ResultsIC50 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.Conclusion213Bi-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.

Cellular dosimetry of [177Lu]Lu-DOTA-[Tyr3]octreotate radionuclide therapy: the impact of modeling assumptions on the correlation with in vitro cytotoxicity

“…Receptor-mediated endocytosis of the radiolabeled peptides plays a crucial role in causing cytotoxic effects for β-emitters, because of the large number of β traversals (10000-20000) required for cell killing [29]. Therefore, the quantification of cellular uptake is a critical step to accurately estimate the effect of PRRT.…”

“…We found that the cross-dose contribution to the total absorbed dose would be overestimated (+ 15%) if neighboring cells are modeled as is generally considered in past studies [8], rather than cells placed at 1 diameter as was done in our study. Moreover, during the follow-up days, we included the crossdose contribution by the cellular clusters newly formed due to proliferation, which was not taken into consideration in past studies as well [29,30]. We found out that the cross-dose contribution, within a cluster, increased linearly with the number of days, reaching 16% of the total absorbed dose.…”

DNA damage in leukocytes after internal ex-vivo irradiation of blood with the α-emitter Ra-223

“…In contrast to electrons and photons, α-particles have a short path-length of less than 0.1 mm and a high linear energy transfer (LET) and are capable to induce complex chromosome aberrations 6 , 7 . Several preclinical studies show a higher efficacy when treating tumours with α-particles as compared to the β-emitter Lu-177 8 – 10 .…”

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

“…Long confined to hematological tumors, they are now being considered for the potential treatment of solid tumors [ 192 ]. In vitro, α-labeled somatostatin analogs (DOTATOC and DOTATATE) demonstrated a significantly higher killing effect compared to 177 Lu [ 193 , 194 , 195 ]. [ 213 Bi]- and [ 225 Ac]-labeled DOTATOC ( 213 Bi: T 1/2 = 45.6 min, E α = 5.88 MeV; 225 Ac: T 1/2 = 9.92 d, E α = 5.83 MeV) have demonstrated promising therapeutic effects in pre-clinical animal studies [ 196 , 197 ]; whereas [ 213 Bi]-DOTATATE, investigated in human small cell lung carcinoma and rat pancreatic tumor models, demonstrated a great therapeutic effect in both small (50 mm 3 ) and large (200 mm 3 ) tumors, but with a higher probability for stable disease in small tumors [ 198 ].…”