213-Bi-DOTATATE for Targeted Alpha Therapy in Neuroendocrine Tumours

Abstract

Targeted alpha therapy (TAT) is promising for improvement of current peptide receptor radionuclide therapy for patient with metastatic neuroendocrine tumours. Due to the high LET of alpha particles, the possibility to cause double strand breaks in the DNA of a tumour cell is much higher than after therapy using beta particle emitters. At the same time, healthy tissues can be spared because of the short path length of alpha particles. _213_ Bismuth (_213_ Bi, an alpha emitter with a half-life of 46 min) was eluted from a _225_ Ac/_213_ Bi generator. _213_ Bi was attached to a peptide via a chelator, in our case a somatostatin analogue with the DOTA chelator, DOTA-Tyr3-octreotate (DOTATATE). In this thesis, _213_ Bi-DOTATATE was used for TAT to investigate whether it is superior compared to DOTATATE labelled with beta particle emitters, like _177_ Lu-DOTATATE for treatment of neuroendocrine tumours with somatostatin receptor expression. The stability of _213_ Bi-DOTATATE was investigated; the labelled peptide showed high stability up to 2 h after labelling. _213_ Bi-DOTATATE showed higher therapeutic efficacy in vitro compared to _177_ Lu-DOTATATE; a 5x more tumour cells killing potency was found. _213_ Bi-DOTATATE prolonged survival in xenografted mice with different tumour models with varying somatostatin receptor density and tumour size. Potential renal toxicity could be managed by renal protectant L-lysine application. Furthermore, biodistribution was imaged by a special SPECT camera dedicated to small animals imaging. Overall, _213_ Bi-DOTATATE showed to be promising for TAT for treatment of neuroendocrine tumours with somatostatin expression