The foundations of specific radiobiological effects generated by laser-accelerated protons

目前，主流放射治疗(RT)主要利用对深层肿瘤显示不利能量沉积模式的X射线。高能带电粒子形式的IR在肿瘤中的能量沉积模式方面提供了重大改进。然而，目前粒子疗法的推广受到高成本和资源占用的阻碍。尽管有这些限制，粒子RT仍在全球范围内得到重点发展，德国与几个先进的质子和重离子治疗中心共同引领了这一发展。同时，新的带电粒子加速技术以更低的成本和更小的占地面积发展出有希望的粒子发生器，从而有望在临床试验中获得广泛的分布和可行性。本应用旨在研究这样一种带电粒子加速技术的辐射生物学效应：基于激光尾迹场加速原理的激光驱动等离子体加速。杜塞尔多夫大学在这一领域进行了大量投资，O·威利教授运营着一套200TW激光系统，专门用于生产激光加速质子(LAP)，这是拟议研究的基础。在B.Timmermann教授领导下的埃森大学诊所的西德质子中心(WPE)提供了所需的参考质子束(CAP)。LAP的放射生物学还处于初级阶段，相关信息现在才刚刚开始出现。在埃森大学诊所G.Iliakis教授的领导下，我们的联盟已经合作了几年来研究LAP的放射生物学效应，并取得了支持拟议研究的开创性发现。该提议测试了LAP表现出不同放射生物学的假设，因为每个脉冲都以皮秒波列的形式传输，并由一个粒子间距离非常短的大而密集的离子团组成。结果，剂量率达到109Gy秒的数量级，比回旋加速器高出9-11个数量级。因此，尽管LAP和CAP类似地引起水的辐射分解并产生短暂的初级自由基，但它们的生化和生物学后果不同，正如我们发现通过与NO依赖的途径相互作用产生较低的3-硝基酪氨酸所表明的那样。杜塞尔多夫大学的C.Suschek教授阐明了这种差异的机制基础。自由基产生平衡的变化将改变直接/间接影响以及细胞应激反应所产生的DNA损伤的类型。F·博格教授和G·伊利亚基斯教授对LAP的这些方面进行了深入的研究，重点研究了DNA双链断裂的形式和细胞对它们的反应。这项拟议的工作解决了LAP生物学的核心问题，为其未来在临床上的应用做好了准备，并有助于增强德国在粒子治疗领域的国际优势。

Current, mainstream Radiation Therapy (RT) predominantly utilizes X-rays that show unfavorable energy deposition patterns for deep-seated tumors. Energetic-charged-particle forms of IR offer major improvements in the energy deposition patterns in a tumor. Yet, the spreading of particle therapy is currently impeded by the high cost and resource footprint. Despite such limitations particle RT is emphatically pursued worldwide and Germany co-leads this development with several advanced proton and heavy ion therapy centers. In parallel, novel charged-particle acceleration technologies evolve promising particle generators at lower cost and smaller footprint, thus promising wide distribution and feasibility for clinical trials. The present application is designed to study the radiobiological effects of one such charged-particle acceleration technology: Laser-driven, plasma-acceleration, based on laser wake-field acceleration principles. The University of Düsseldorf has made large investments in this field and Professor O. Willi operates a 200 TW laser system dedicated to the production of laser-accelerated protons (LAP) that is the basis of the proposed research. The West German Proton Center Essen (WPE) at the University Clinics Essen under Prof. B. Timmermann provides the required reference proton beams (CAP). The radiobiology of LAP is at its infancy and relevant information is only now beginning to emerge. Our consortium under the leadership of Prof. G. Iliakis at the University Clinics Essen, has cooperated for several years to study the radiobiological effects of LAP and has made seminal discoveries underpinning the proposed studies. The proposal tests the hypothesis that LAP exhibit different radiobiology because each pulse is delivered in picosecond wave-trains and consists of a large, dense ion cluster with very short inter-particle distances. As a result dose rates in the order of 109 Gy/sec are reached that are up to 9-11 orders of magnitude greater than those achieved by a cyclotron. It follows that although LAP and CAP are similarly causing water radiolysis and generate short-lived primary radicals, their biochemical and biological consequences differ as indicated by our discovery of lower production of 3-nitrotyrosine through interaction with NO-dependent pathways. Prof. C. Suschek at the University of Düsseldorf elucidates the mechanistic underpinnings of such differences. Changes in the balance of radical production will modify the type of DNA damage generated by direct/indirect effects, as well cellular stress responses. These aspects of LAP are investigated in depth by Prof. F. Boege and Prof. G. Iliakis focusing on forms of DNA double strand breaks generated and the cellular responses to them. The proposed work addresses central questions of the biology of LAP, prepares their future application in the clinic and helps to enhance the clear edge of Germany in the field of particle therapy internationally.