Exploring the Potential of High-Molar-Activity Samarium-153 for Targeted Radionuclide Therapy with [153Sm]Sm-DOTA-TATE

Abstract

Samarium-153 is a promising theranostic radionuclide, but low molar activities (Am) resulting from its current production route render it unsuitable for targeted radionuclide therapy (TRNT). Recent efforts combining neutron activation of 152Sm in the SCK CEN BR2 reactor with mass separation at CERN/MEDICIS yielded high-Am 153Sm. In this proof-of-concept study, we further evaluated the potential of high-Am 153Sm for TRNT by radiolabeling to DOTA-TATE, a well-established carrier molecule binding the somatostatin receptor 2 (SSTR2) that is highly expressed in gastroenteropancreatic neuroendocrine tumors. DOTA-TATE was labeled with 153Sm and remained stable up to 7 days in relevant media. The binding specificity and high internalization rate were validated on SSTR2-expressing CA20948 cells. In vitro biological evaluation showed that [153Sm]Sm-DOTA-TATE was able to reduce CA20948 cell viability and clonogenic potential in an activity-dependent manner. Biodistribution studies in healthy and CA20948 xenografted mice revealed that [153Sm]Sm-DOTA-TATE was rapidly cleared and profound tumor uptake and retention was observed whilst these were limited in normal tissues. This proof-of-concept study showed the potential of mass-separated 153Sm for TRNT and could open doors towards wider applications of mass separation in medical isotope production.

Keywords: DOTA-TATE; SSTR2; samarium-153; targeted radionuclide therapy.

Figure 1

[¹⁵³Sm]Sm-DOTA-TATE did not show any leaching of ¹⁵³Sm from the chelator in PBS at 37 °C, human serum at 37 °C and radiolabeling buffer at RT for at least 7 days. RT = room temperature.

Figure 2

[¹⁵³Sm]Sm-DOTA-TATE is internalized by SSTR₂-expressing CA20948 cells. Values represent mean ± standard deviation.

Figure 3

Percentage viability of CA20948 cells after [¹⁵³Sm]Sm-DOTA-TATE treatment (MBq/mL) or [¹⁵³Sm]Sm-DTPA treatment (MBq/mL). Values represent mean ± standard deviation. ** p < 0.01 for statistical differences relative to 0 MBq/mL [¹⁵³Sm]Sm-DOTA-TATE-treated cells and °° p < 0.01 for statistical differences relative to 0 MBq/mL [¹⁵³Sm]Sm-DTPA-treated cells, both obtained by linear modelling.

Figure 4

Surviving fraction expressed in percentages of CA20948 cells after [¹⁵³Sm]Sm-DOTA-TATE treatment (MBq/mL) or [¹⁵³Sm]Sm-DTPA treatment (MBq/mL). Values represent mean ± standard deviation. ** p < 0.01 for statistical differences relative to 0 MBq/mL [¹⁵³Sm]Sm-DOTA-TATE-treated cells and °° p < 0.01 for statistical differences relative to 0 MBq/mL [¹⁵³Sm]Sm-DTPA-treated cells, both obtained by linear modelling.

Figure 5

Ex vivo biodistribution over time expressed as standard uptake value of [¹⁵³Sm]Sm-DOTA-TATE in healthy mice. Values represent mean ± standard deviation (n = 3–4).

Figure 6

Ex vivo biodistribution over time expressed as standard uptake value of [¹⁵³Sm]Sm-DOTA-TATE in CA20948 xenografted mice. Values represent mean ± standard deviation (n = 3–4).

Figure 7

SPECT-CT images shown as maximum intensity projections for a mouse injected with 20 MBq of [¹⁵³Sm]Sm-DOTA-TATE. (A): Image obtained at 4 h post injection; (B): image obtained at 24 h post injection. The tumor (Tu) can be seen in the right shoulder. Other visible organs are kidneys (Ki), liver (Li) and bladder (Bl).