Modelling anomalous transport of nanoparticles and DNA repair to improve radiotherapy

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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.