Title: Modelling anomalous transport of nanoparticles and DNA repair to improve radiotherapy
Funder: Engineering and Physical Sciences Research Council

Abstract: 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.

Lay abstract: The programme is divided into two parts: I. Mathematical modelling and numerical simulations, II. Experiments and validation of models. I. Mathematical modelling and numerical simulations. Measurable objectives for anomalous transport of nanoparticles (NPs) are: (1) obtain new non-linear integro-differential and asymptotic fractional PDEs for intracellular transport that describe the emergence of macroscopic non-homogeneous endosomal network and NPs clustering; (2) perform extensive numerical simulations to find spatial distributions of NPs and distributions of clusters of NPs within endosomes; (3) quantify radiation enhancement effects due to spatial distribution of NPs using multiscale Monte Carlo simulations. Measurable objectives for anomalous double strand breaks (DSB) repair are: (1) develop DNA repair model by implementing active movement of DSBs; estimate the relative importance of different types of fractional diffusion; (2) estimate the probabilities of misrepair, obtain the distributions of repair times; (3) implement the anomalous DNA repair model into the DaMaRiS toolkit to allow more accurate predictions of DSB induction at the individual base level and potentially implement it into the research version of Varian's clinical treatment planning software, Eclipse. II. Experiments and validation of models. Measurable objectives for anomalous transport of NPs are: (1) obtain superdiffusive trajectories of individual endosomes within living cells from existing high resolution microscopy videos; develop new deep learning neural networks for the analysis of single trajectories; use observations to test anomalous models and refine them using an iterative process; (2) extract the spatial and clustering distributions of NPs inside cells; validate the macroscopic fractional equations for an ensemble of organelles by a comparison between these distributions and outputs of models; (3) quantify the uptake of NPs via endocytosis depending on different cell types and perform imaging and irradiation experiments on different cell lines to measure the enhancement of transport and biological effect with NPs. Measurable objectives for anomalous DSB repair are: 1) use the existing experimental data for DNA DSB anomalous diffusion from the BioProton project to validate and refine the new anomalous DNA repair model in multiple cell lines; 2) test and validate the Manchester DaMaRiS nanodosimetry model with experimental data in relation to DNA damage and cell kill.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS