Department of Nuclear Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Institute of Nuclear Medicine, Tongji University School of Medicine, Shanghai, China.
Theranostics. 2024 Oct 14;14(17):6768-6782. doi: 10.7150/thno.101922. eCollection 2024.
Pb, a promising alphaparticle generator of 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. A novel alpha-emitting radiopharmaceutical, 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-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. Pb-HNPs exhibited efficient therapeutic antitumor effects , including increased GSH depletion, ROS accumulation, and mitochondrial damage in irradiated tumor cells. 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 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. The present study highlights the theranostic potential of the alpha-particle generator 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.
作为铋的一种有前途的阿尔法粒子发生剂，Pb 作为治疗性放射性核素引起了广泛关注。为了开发靶向 alpha 治疗（TAT），确定辐照细胞中的靶向效应以及未辐照旁观者细胞中的非靶向效应的贡献非常重要。目前，线粒体转移在细胞串扰中的关键作用引起了广泛关注。然而，受损线粒体转移在调节这种 alpha 粒子辐射诱导的旁观者效应（RIBE）中的具体作用仍需进一步探索。
一种新型的 alpha 发射放射性药物 Pb-水凝胶纳米颗粒（HNPs）被合成，并随后评估了其治疗效果。还研究了辐照细胞条件培养基（ICCM）对旁观者癌细胞活力的影响，ICCM 是在 Bi 辐照后不同时间收集的。此外，还分离和培养受损线粒体与非辐照旁观者细胞，以评估其作用。
Pb-HNPs 表现出有效的抗肿瘤治疗效果，包括增加 GSH 耗竭、ROS 积累和辐照肿瘤细胞中的线粒体损伤。研究表明，它通过 SPECT/CT 具有成像潜力，RNA 测序结果表明辐照肿瘤中氧化应激相关途径被激活。此外，ICCM 影响非辐照旁观者细胞的活力，表明 alpha 粒子 Bi 诱导了旁观者效应。有趣的是，从 ICCM 中分离出的受损线粒体被观察到进入共培养的非辐照旁观者细胞。进一步的实验证实，受损线粒体的转移导致非辐照旁观者细胞的死亡。
本研究强调了 alpha 粒子发生剂 Pb 的治疗潜力，更重要的是，阐明了受损线粒体转移在 alpha 粒子 RIBE 中的作用。这些发现为 alpha 粒子的抗肿瘤作用提供了一种新的理论机制，并扩展了 TAT 的临床应用前景。
