Modelling anomalous transport of nanoparticles and DNA repair to improve radiotherapy

纳米粒子（NPs）在癌症护理的纳米医学革命中无处不在。在世界范围内，使用纳米粒子来增强放射治疗已经成为过去十年中高度活跃的研究领域。成功的体外和临床前实验已经导致了各种NP制剂的临床试验，包括氧化铪晶体和基于钆的制剂在各种癌症中的应用，包括前列腺癌、肝癌、口腔或口咽癌，以及软组织肉瘤、宫颈癌和脑转移。预测表明，成功的运输NPs到细胞核的结果，在放射治疗（RT）的几个数量级的剂量增强的增加。科视Christie/Manchester团队领导了位于曼彻斯特的英国癌症研究主要中心（Cancer Research UK Major Centre）和科视Christie NHS Foundation Trust之间的RT联合努力。本项目将重点研究放射治疗和肿瘤生物学中两个互补的未解决问题：1）揭示核团簇增强肿瘤细胞辐射损伤的物理和生物学途径; 2）揭示辐射损伤后修复过程中细胞核内DNA双链断裂（DSB）的异常运动机制和辐射诱导的染色体畸变。最近的实验表明，这两个问题涉及非马尔可夫异常运输过程：超扩散的细胞内运动和聚集的NP和分数扩散与主动运输的DSB在DNA修复过程中。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。有没有异常的超扩散运输与非线性反应的集群形成的理论模型，并没有在所有的异常DNA修复与染色质的主动运输的治疗。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，2）辐射诱导的DNA DSB的异常运输，并回答关键问题：在这两个问题中观察到的异常运输是否具有生物学意义？如何利用它来获得医疗利益？具体来说，超扩散提供更有效的动力学集群形成的核蛋白在接近辐射敏感的细胞器？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NP的异常转运，它们在活细胞内的簇形成和异常DNA修复是支持尖端和未来疗法的适当药代动力学描述的根本重要问题。

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.