Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide

Auger electron emitters (AEEs) are attractive tools in targeted radionuclide therapy to specifically irradiate tumour cells while sparing healthy tissues. However, because of their short range, AEEs need to be brought close to sensitive targets, particularly nuclear DNA, and to a lower extent, cell membrane. Therefore, radioimmunoconjugates (RIC) have been developed for specific tumour cell targeting and transportation to the nucleus. Herein, we assessed, in A-431(CEA-luc) and SK-OV-3(1B9) cancer cells that express low and high levels of HER2 receptors, two In-111-RIC consisting of the anti-HER2 antibody trastuzumab conjugated to NLS or TAT peptides for nuclear delivery. We found that NLS and TAT peptides improved the nuclear uptake of In-111-trastuzumab conjugates, but this effect was limited and non-specific. Moreover, it did not result in a drastic decrease of clonogenic survival. Indium-111 also contributed to non-specific cytotoxicity in vitro due to conversion electrons (30% of the cell killing). Comparison with [I-125]I-UdR showed that the energy released in the cell nucleus by increasing the RIC's nuclear uptake or by choosing an AEE that releases more energy per decay should be 5 to 10 times higher to observe a significant therapeutic effect. Therefore, new Auger-based radiopharmaceuticals need to be developed.

Automated summary

Auger electron emitters (AEEs) are used in targeted radionuclide therapy to irradiate tumor cells specifically while protecting healthy tissues. Radioimmunoconjugates (RIC) have been developed for tumor cell targeting and transportation to the nucleus, with NLS and TAT peptides improving nuclear uptake of In-111-trastuzumab conjugates, albeit with limited and non-specific effects. In-111 also contributes to non-specific cytotoxicity in vitro, and further research is needed to develop more effective Auger-based radiopharmaceuticals.