The concept of spatial fractionation in radiotherapy was developed for better sparing of normal tissue in the entrance channel of radiation. Spatial fractionation utilizing proton minibeam radiotherapy (pMBRT) promises to be advantageous compared to X-ray minibeams due to higher dose conformity at the tumor. Preclinical in vivo experiments conducted with pMBRT in mouse ear models or in rat brains support the prospects, but the research about the radiobiological mechanisms and the search for adequate application parameters delivering the most beneficial minibeam therapy is still in its infancy. Concerning preclinical research, we consider glioma, non-small cell lung cancer and hepatocellular carcinoma as the most promising targets and propose investigating the effects on healthy tissue, especially neuronal cells and abdominal organs. The experimental setups for preclinical pMBRT used so far follow different technological approaches, and experience technical limitations when addressing the current questions in the field. We review the crucial physics parameters necessary for proton minibeam production and link them to the technological challenges to be solved for providing an optimal research environment. We consider focusing of pencil or planar minibeams in a scanning approach superior compared to collimation due to less beam halos, higher peak-to-valley dose ratios and higher achievable dose rates. A possible solution to serve such a focusing system with a high-quality proton beam at all relevant energies is identified to be a 3 GHz radio-frequency linear accelerator. We propose using a 16 MeV proton beam from an existing tandem accelerator injected into a linear post-accelerator, boosted up to 70 MeV, and finally delivered to an imaging and positioning end-station suitable for small animal irradiation. Ion-optical simulations show that this combination can generate focused proton minibeams with sizes down to 0.1 mm at 18 nA mean proton current - sufficient for all relevant preclinical experiments. This technology is expected to offer powerful and versatile tools for unleashing structured and advanced preclinical pMBRT studies at the limits and also has the potential to enable a next step into precision tumor therapy.

放射治疗中空间分级的概念是为了更好地保留放射线入射通道中的正常组织而开发的。利用质子微束放射疗法（pMBRT）进行空间分级与X射线微束相比，有望在肿瘤中获得更高的剂量一致性，因此具有优势。临床前体内用pMBRT在小鼠耳朵模型或大鼠大脑中进行的实验支持了这一前景，但是有关放射生物学机制以及寻找可提供最有益的微束治疗的适当应用参数的研究仍处于起步阶段。关于临床前研究，我们认为神经胶质瘤，非小细胞肺癌和肝细胞癌是最有希望的靶标，并建议研究其对健康组织，特别是神经元细胞和腹部器官的影响。迄今为止，用于临床前pMBRT的实验装置遵循不同的技术方法，并且在解决该领域的当前问题时遇到了技术限制。我们审查了质子微型束生产所必需的关键物理参数，并将它们与为提供最佳研究环境而需要解决的技术挑战联系在一起。我们认为，由于准直光束较少，峰谷比较高，可达到的剂量率较高，因此与准直相比，笔形或平面微型光束的聚焦方式要优于准直方式。在所有相关能量下为高质量的质子束提供服务的这种聚焦系统的可行解决方案被确定为3 GHz射频线性加速器。我们建议使用来自现有串联加速器的16 MeV质子束注入线性后加速器，升压至70 MeV，最后输送至适合小动物辐照的成像和定位终端站。离子光学模拟表明，这种组合可以在18 nA的平均质子电流下产生尺寸小于0.1 mm的聚焦质子微型束，足以进行所有相关的临床前实验。预计该技术将提供强大而通用的工具，以在极限条件下开展结构化和高级的临床前pMBRT研究，并且还有望使下一步进入精确的肿瘤治疗。