Modelling anomalous transport of nanoparticles and DNA repair to improve radiotherapy
Lead Research Organisation:
University of Manchester
Department Name: Mathematics
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.
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.
Publications
Alexandrov D
(2022)
Dynamics of intracellular clusters of nanoparticles
in Cancer Nanotechnology
Fedotov S
(2022)
Superdiffusion in self-reinforcing run-and-tumble model with rests.
in Physical review. E
Fedotov S
(2022)
Stochastic Model of Virus-Endosome Fusion and Endosomal Escape of pH-Responsive Nanoparticles
in Mathematics
Fedotov S
(2023)
Population heterogeneity in the fractional master equation, ensemble self-reinforcement, and strong memory effects.
in Physical review. E
Gavrilova A
(2024)
The role of kinesin-1 in neuronal dense core vesicle transport, locomotion and lifespan regulation in C. elegans.
in Journal of cell science
Gavrilova A
(2025)
Heterogeneous model for superdiffusive movement of dense core vesicles in C. elegans.
in Scientific reports
Han D
(2021)
Anomalous Stochastic Transport of Particles with Self-Reinforcement and Mittag-Leffler Distributed Rest Times
in Fractal and Fractional
| Description | Nanoparticles play a crucial role in nanodiagnostics, radiation therapy of cancer, and they are now widely used to effectively deliver drugs to specific sites, targeting whole organs and down to single cells, in a controlled manner. Therapeutic efficiency of nanoparticles greatly depends on their clustering distribution inside cells. We obtained an exact cluster density of nanoparticles as the steady-state solution of Smoluchowski's equation describing clustering due to the fusion of endosomes. We also analyzed the unsteady cluster distribution and compare it with the experimental data for time evolution of gold nanoparticle clusters in living cells. The development of accurate mathematical models for heterogeneous dynamics living inside cells has the potential to enable the design and optimization of various technological applications, for example, the design of effective drug delivery systems. Central questions in the analysis of anomalous dynamics are ergodicity and statistical ageing which allow for selecting the proper model for the description. It is believed that non-ergodicity and ageing occur concurrently. However, we found that the anomalous dynamics of endosomes inside living cells is paradoxical since it is ergodic but shows ageing. We showed that this behaviour is caused by ensemble heterogeneity that, in addition to space-time heterogeneity within a single trajectory, is an inherent property of endosomal motion. Our work introduced novel approaches for the analysis and modelling of heterogeneous dynamics inside cells. We analysed the process of end-joining during repair of DNA double-strand breaks (DSBs) after radiation damage. Experimental evidence has revealed that the dynamics of DSB ends exhibit subdiffusive motion rather than simple diffusion with rare directional movement. Traditional models often overlook the rare long-range directed motion. To address this limitation, we present a heterogeneous anomalous diffusion model consisting of subdiffusive fractional Brownian motion interchanged with short periods of long-range movement. Our model sheds light on the underlying mechanisms of heterogeneous diffusion in DSB repair and could be used to quantify the DSB dynamics on a time scale inaccessible to single particle tracking analysis. The model predicts that the long-range movement of DSB ends is responsible for the misrepair of DSBs in the form of dicentric chromosome lesions. |
| Exploitation Route | our results may be used in nanodiagnostics, radiation therapy of cancer, and for the effective deliver of drugs to specific sites, targeting whole organs and down to single cells. |
| Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
| Description | Since the therapeutic efficiency of nanoparticles greatly depends on their clustering distribution, our results have applications in nanodiagnostics, radiation therapy of cancer, and for effective delivery of drugs |
| First Year Of Impact | 2024 |
| Sector | Healthcare |
| Title | Research data for 'The role of kinesin-1 in neuronal dense core vesicle transport, locomotion and lifespan regulation in C. elegans' |
| Description | The data comprises:Original data showing dense core vesicle movement imaged in the ALA neuron in C. elegans in wildtype background (ida-1::GFP), and in kinesin-1 mutant backgrounds: unc-116(rh24sb79), klc-1(ok2609) and klc-2(km11). The original movie TIFF files and kymographs for each strain are included as zip files. The associated tracking data from KymoButler are included as excel files. This is the original data used for figures 2, 3, 4, S3, S4, S5, S6 and table 1 of the associated paper.Excel files of the original scoring data and statistical analysis of lifespan, aldicarb sensitivity and levamisole sensitivity are included, which relate to the text and figures 5c, 5d and figure 6. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2024 |
| Provided To Others? | Yes |
| URL | https://figshare.manchester.ac.uk/articles/dataset/_b_Research_data_for_The_role_of_kinesin-1_in_neu... |