Background: Up to now, prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy mainly focused on b-emitting radionuclides. Herein, two new 213Bi-labeled agents for PSMA-targeted a therapy of prostate cancer (PCa) are reported. Methods: The biodistribution of 213Bi-labeled small-molecule inhibitor PSMA I&T and nanobody JVZ-008 was evaluated in mice bearing PSMA-positive LNCaP xenografts. DNA damage response was followed using LNCaP cells and LNCaP xenografts. Results: In vitro, 213Bi-PSMA I&T and 213Bi-JVZ-008 therapy of LNCaP cells led to increased number of DNA double-strand breaks (DSBs), detected as 53BP1 and cH2AX nuclear foci. In vivo, tumor uptake of 213Bi-PSMA I&T and 213Bi-JVZ-008 was 5.75% – 2.70%ID/g (injected dose per gram) and 2.68% – 0.56%ID/g, respectively, with similar tumor-to-kidney ratios. Furthermore, both agents induced in vivo DSBs in the tumors, which were detected between 1 hour and 24 hours after injection. 213Bi-PSMA I&T induced significantly more DSBs than 213Bi-JVZ-008 ( p < 0.01). Conclusions: 213Bi-PSMA I&T and 213Bi-JVZ-008 showed efficient and rapid tumor targeting and produced DSBs in PSMA-expressing LNCaP cells and xenografts. These promising results require further evaluation of 213Bi-labeled agents with regard to their therapeutic efficacy and toxicity for PCa therapy.

NONNEKENS J;  CHATALIC K.L.S.;  MOLKENBOER- KUENEN Jannike;  BEERENS Cecile;  BRUCHERTSEIFER Frank;  MORGENSTERN Alfred;  VELDHOVEN-ZWEISTRA Joke;  SCHOTTELIUS Margret;  WESTER Hans-Jürgen;  VAN GENT D;  VAN WEERDEN W.M.;  BOERMAN Otto;  DE JONG Marion;  HESKAMP Sandra; 

2017-03-22

MARY ANN LIEBERT

JRC99096

1084-9785,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC99096,   

10.1089/cbr.2016.2155,