Role of damaged mitochondrial transfer in alpha-particle generator 212 Pb radiation-induced bystander effect.

Rationale: ²¹² Pb, a promising in vivo alpha - particle generator of ²¹² Bi, has aroused much interest as a therapeutic radionuclide. For the development of targeted alpha therapy (TAT), it is important to determine the contribution of targeted effects in irradiated cells, and also of non-targeted effects in non-irradiated bystander cells. Currently, the critical roles of mitochondrial transfer in cellular crosstalk have garnered significant attention. However, the specific involvement of damaged mitochondrial transfer in orchestrating this alpha-particle radiation-induced bystander effect (RIBE) needs to be further explored. Methods: A novel alpha-emitting radiopharmaceutical, ²¹² Pb-hydrogel nanoparticles (HNPs), was synthesized and subsequently evaluated its theranostics effects. The impact of irradiated cell-conditioned media (ICCM), collected at different times post- ²¹² Bi irradiation, on bystander cancer cells regarding cell viability was also investigated. Additionally, damaged mitochondria were isolated and cultured with non-irradiated bystander cells to assess their role. Results: ²¹² Pb-HNPs exhibited efficient therapeutic antitumor effects in vitro , including increased GSH depletion, ROS accumulation, and mitochondrial damage in irradiated tumor cells. In vivo studies demonstrated its imaging potential through SPECT/CT, and RNA sequencing results indicated activation of oxidative stress-related pathways in irradiated tumors. Additionally, ICCM influenced the viability of non-irradiated bystander cells, suggesting a radiation-induced bystander effect by the alpha-particle ²¹² Bi. Interestingly, damaged mitochondria isolated from ICCM were observed to enter co-cultured non-irradiated bystander cells. Further experiments confirmed that the transfer of damaged mitochondria results in the death of non-irradiated bystander cells. Conclusion: The present study highlights the theranostic potential of the alpha-particle generator ²¹² Pb and, more importantly, elucidates the role of damaged mitochondrial transfer in alpha-particle RIBE. These findings provide a novel theoretical mechanism for the antitumor effects of alpha-particles and expand the clinical application prospects of TAT.
Competing Interests: Competing Interests: The authors have declared that no competing interest exists.
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