Modelling anomalous transport of nanoparticles and DNA repair to improve radiotherapy

纳米粒子（NPs）在癌症治疗的纳米医学革命中无处不在。在过去十年中，在世界范围内，使用NPs增强放射治疗已成为一个高度活跃的研究领域。成功的体外和临床前实验导致了各种NP配方的临床试验，包括氧化铪晶体和钆基配方，用于各种癌症，包括前列腺癌、肝癌、口腔或口咽癌、软组织肉瘤、宫颈癌和脑转移。这些应用的效果高度依赖于NPs在细胞中的位置。预测表明，NPs成功转运到细胞核导致放射治疗（RT）期间剂量增强数个数量级的增加。克里斯蒂/曼彻斯特团队在曼彻斯特大学的英国癌症研究中心和克里斯蒂NHS基金会信托基金之间领导了RT的联合努力。在这个项目中，我们将专注于RT和癌症生物学中两个互补的尚未解决的问题：1)破解NP簇增强辐射对癌细胞损伤的物理和生物学途径，2)揭示辐射损伤和辐射诱导的染色体畸变后修复过程中细胞核内DNA双链断裂（DSBs）异常运动的机制。最近的实验表明，这两个问题都涉及非马尔可夫异常运输过程：DNA修复过程中NPs的超扩散胞内运动和聚集以及dsb主动运输的分数扩散。然而，大多数理论模型和蒙特卡罗模拟工具包是马尔可夫的。目前还没有关于异常超扩散运输与非线性簇形成反应的理论模型，也没有任何关于染色质主动运输的异常DNA修复的处理方法。我们曼彻斯特跨学科团队的主要挑战是开发新的非马尔可夫模型，用于1)NPs的异常随机运输和聚类，以及2)辐射诱导的DNA dsb的异常运输，并回答关键问题：观察到的异常运输在这两个问题中是否具有生物学益处？它如何被用于医疗利益？具体来说，超扩散是否为靠近辐射敏感细胞器的NPs簇形成提供了更有效的动力学？与标准扩散相比，双链断裂的异常转运是否会导致更有效的DNA修复？了解NPs的异常转运，它们在活细胞内的簇形成和异常DNA修复是支持正确的尖端和未来治疗的药代动力学描述的基础问题。

Nanoparticles (NPs) are ubiquitous in the nanomedicine revolution in cancer care. Worldwide, the use of NPs to enhance radiotherapy has emerged as a highly active field of research over the last decade. Successful in vitro and pre-clinical experiments have led to clinical trials for various NP formulations including hafnium oxide crystal and gadolinium based formulations in a variety of cancers including prostate, liver, oral cavity or oropharynx, and soft tissue sarcoma, cervical cancer and brain metastasis.The efficacy of these applications is highly dependent on the location of NPs in cells. Predictions show that successful transport of NPs to the nucleus results in an increase in dose-enhancement during radiation therapy (RT) of several orders of magnitude. The Christie/Manchester team leads a combined effort in RT between the Cancer Research UK Major Centre in Manchester which is a part of the University of Manchester and the Christie NHS Foundation Trust. In this project we will focus on two complementary unsolved problems in RT and cancer biology: 1) deciphering the physical and biological pathways by which NP clusters enhance the radiation damage to cancer cells, 2) unravelling the mechanisms of anomalous motility of DNA double strand breaks (DSBs) inside the nucleus during repair process after radiation damage and radiation induced chromosomal aberrations. Recent experiments revealed that both problems involve non-Markovian anomalous transport processes: super-diffusive intracellular motility and clustering of NPs and fractional diffusion with active transport of DSBs during the DNA repair process. However, most theoretical models and Monte Carlo simulation toolkits are Markovian. There are no theoretical models of the anomalous super-diffusive transport with non-linear reactions of cluster formation, and no treatment at all for anomalous DNA repair with active transport of chromatin. The main challenge for our Manchester interdisciplinary team is to develop new non-Markovian models for 1) anomalous stochastic transport and clustering of NPs and 2) anomalous transport of DNA DSBs induced by radiation and answer crucial questions: Is the observed anomalous transport biologically beneficial in both problems? How can it be exploited for medical benefit? Specifically, does the superdiffusion provide more effective dynamics for cluster formation of NPs in proximity to radiosensitive organelles? Does anomalous transport of double strand breaks lead to more effective DNA repair compared to standard diffusion? Understanding anomalous transport of NPs, their cluster formation inside living cells and anomalous DNA repair are problems of fundamental importance to underpin a proper pharmacokinetic description of cutting-edge and future therapies.