Targeted Alpha Therapy with Thorium-227

Abstract

Targeted alpha therapy (TAT) can deliver high localized burden of radiation selectively to cancer cells as well as the tumor microenvironment, while minimizing toxicity to normal surrounding cell. Radium-223 (223 Ra), the first-in-class a-emitter approved for bone metastatic castration-resistant prostate cancer has shown the ability to prolong patient survival. Targeted Thorium-227 (227 Th) conjugates represent a new class of therapeutic radiopharmaceuticals for TAT. They are comprised of the a-emitter 227 Th complexed to a chelator conjugated to a tumor-targeting monoclonal antibody. In this review, the authors will focus out interest on this therapeutic agent. In recent studies 227 Th-labeled radioimmunoconjugates showed a relevant stability both in serum and vivo conditions with a significant antigen-dependent inhibition of cell growth. Unlike 223 Ra, the parent radionuclide 227 Th can form highly stable chelator complexes and is therefore amenable to targeted radioimmunotherapy. The authors discuss the future potential role of 227 Th TAT in the treatment of several solid as well as hematologic malignancies.

Atomic Nanogenerators in Targeted Alpha Therapies: Curie’s Legacy in Modern Cancer Management

“…Despite the fact that thorium preferentially exists in the oxidation state +4, it can possess different coordination numbers determined by the concrete chelating ligand [43]. 227 Th appears to be the most promising thorium radioisotope for utilization in TAT [21,44].…”

“…Despite the fact that thorium preferentially exists in the oxidation state +4, it can possess different coordination numbers determined by the concrete chelating ligand [ 43 ]. 227 Th appears to be the most promising thorium radioisotope for utilization in TAT [ 21 , 44 ]. The decay scheme of 227 Th is relatively similar to the one of 225 Ac, however, the half-life is almost doubled ( Figure 2 ).…”

Role of Her-2 in Gastrointestinal Tumours beyond Gastric Cancer: A Tool for Precision Medicine

“…The first in class anti-HER2 compound implemented in clinical trials is 212Pb-TCMC-trastuzumab, a radio-immunoconjugate of trastuzumab with an alpha emitting isotope [64]. More recently, the conjugates of 227Th have emerged as favored compounds, alpha-emitting and with a better stability both in serum and vivo conditions [65]. The advantage to use alpha vs. beta-emitters is related to short half-lives, short rage of actions to deliver localized higher burden of radiations [66].…”

Prostaatspecifiek membraanantigeen radioligandtherapie met alfastralers, een review

“…Daarentegen is de halfwaardetijd van 227 Th met 19,7 dagen als lang te bestempelen, waardoor mogelijk toch een hoge tumoropname met beperkte toxiciteit bereikt kan worden [5,22]. Bovendien komen bij het verval van 227 Th meerdere alfadeeltjes vrij (enigszins vergelijkbaar met 225 Ac), hetgeen aantrekkelijk is, mits deze wel in de tumor vrijkomen en niet re-distribueren naar gezonde organen [23,24].…”