背景：磁共振（MR）引导的放射治疗计划的引入为治疗诊断纳米粒子开辟了新的空间，以减少急性毒性，同时改善局部控制。在这项工作中，合成并验证了第二代 AGuIX® 纳米粒子 (AGuIX-Bi)。 AGuIX-Bi 显示可保持 MR 阳性对比度，同时通过用更高 Z Bi3 替换一些 Gd3 阳离子来进一步放大辐射剂量。这些下一代纳米颗粒基于 AGuIX® 平台，目前正在与放射治疗相结合的多个 II 期临床试验中进行评估。方法：在这种临床可扩展的方法中，AGuIX® 用作初始螯合平台，将 Gd3 交换为 Bi3。 AGuIX-Bi 纳米粒子以三种 Gd/Bi 比例合成，每种比例都保持 MR 对比度，同时进一步放大相对于 Bi3 的辐射剂量。在人类非小细胞肺癌模型中体外和体内评估了纳米粒子的安全性、有效性和治疗潜力。结果：我们证明，增加纳米粒子中的 Bi3 与更多的 DNA 损伤相关，并提高体内疗效，肿瘤生长具有统计学上显着的延迟，并且测试的最大 Bi/Gd 比率完全消退 33%。通过我们的合成方法添加 Bi3 导致纳米颗粒的药代动力学略有改变，并延长了肿瘤高积累期，但没有观察到毒性证据。结论：我们证实了 AGuIX-Bi 与选定比例 30Gd/70Bi 放射治疗的安全性和增强疗效。这些结果为患者翻译提供了重要证据。© 作者。

Background: The introduction of magnetic resonance (MR)-guided radiation treatment planning has opened a new space for theranostic nanoparticles to reduce acute toxicity while improving local control. In this work, second-generation AGuIX® nanoparticles (AGuIX-Bi) are synthesized and validated. AGuIX-Bi are shown to maintain MR positive contrast while further amplifying the radiation dose by the replacement of some Gd3+ cations with higher Z Bi3+. These next-generation nanoparticles are based on the AGuIX® platform, which is currently being evaluated in multiple Phase II clinical trials in combination with radiotherapy. Methods: In this clinically scalable methodology, AGuIX® is used as an initial chelation platform to exchange Gd3+ for Bi3+. AGuIX-Bi nanoparticles are synthesized with three ratios of Gd/Bi, each maintaining MR contrast while further amplifying radiation dose relative to Bi3+. Safety, efficacy, and theranostic potential of the nanoparticles were evaluated in vitro and in vivo in a human non-small cell lung cancer model. Results: We demonstrated that increasing Bi3+ in the nanoparticles is associated with more DNA damage and improves in vivo efficacy with a statistically significant delay in tumor growth and 33% complete regression for the largest Bi/Gd ratio tested. The addition of Bi3+ by our synthetic method leads to nanoparticles that present slightly altered pharmacokinetics and lengthening of the period of high tumor accumulation with no observed evidence of toxicity. Conclusions: We confirmed the safety and enhanced efficacy of AGuIX-Bi with radiation therapy at the selected ratio of 30Gd/70Bi. These results provide crucial evidence towards patient translation.© The author(s).