Combined Magneto-Optical and Fluorescence Lifetime Imaging Microscopy: Towards Cellular Level Magnetic Hyperthermia

Advances in conventional cancer treatments such as chemotherapy and radiotherapy have provided vast improvements in cancer survival rates over recent years. However these techniques inevitably lead to the damage of some healthy tissue and cells, resulting in harmful side effects. Many researchers around the world are therefore working to develop targeted cancer therapies that are tumor-specific, and so destroy cancer cells without affecting surrounding healthy tissue. One such technique, known as hyperthermia, uses heat sources to induce cancer cell death by transiently raising the local temperature in the tumor to above 42 deg C. However, generating local heating in a controlled and non-invasive fashion is difficult with conventional techniques. An alternative method is to use magnetic hyperthermia (or 'thermotherapy') which is an experimental cancer treatment that uses microscopic magnetic particles (nanoparticles) that are only 1/5000th of the width of a human hair. These nanoparticles can channel the energy from an external high-frequency alternating magnetic field in order to create local hot spots. As heating can only occur where nanoparticles are present, the technique is truly local and effects can be obtained by accumulating nanoparticles within tumors.

Magnetic hyperthermia has produced encouraging results that show it can reduce the size of tumors, and in recent clinical trials where it was combined with radiotherapy, a significant effect on cancer survival times was reported. However these results were achieved by dispersing very concentrated magnetic nanoparticle fluids around the tumor. Although this represents local heating of the tumor, in order to prevent the cancer from spreading it is essential to kill each and every cancer cell, and so a cellular level heating effect is required. Much work has therefore focused on labelling individual cancer cells with magnetic nanoparticles, either by binding them to cell membranes or by allowing them to be engulfed by the cells. In principle these particles should then be able to heat the cells directly to trigger cell death. However the results of such experiments to date have been somewhat disappointing because it seems the magnetic and heating properties of the nanoparticles can change once they are associated with cells.

In order to understand this behaviour it is first necessary to be able to probe the properties of the nanoparticles in real cellular environments, and to see how these vary depending on the microscopic location of the particles, i.e. where they reside inside or externally to cells. The ability to make such measurements would enable a systematic evaluation of how the design and location of the nanoparticles, as well as the magnetic field conditions used, could favourably enhance the magnetic properties and consequently the cellular level heating. Such a study would dramatically boost research on magnetic hyperthermia, taking it much closer to realisation as a viable clinical therapy. However at present no such instrument exists in order to perform this work. Therefore the aim of this project is to create a new type of microscope that can probe both the magnetic and heating properties of nanoparticles in cellular environments. This will be done by exploiting the magnetic dependence of certain optical phenomena, such as the well-known Faraday effect, and combining them with specialist fluorescence based techniques to measure local temperature. As the various components of the instrument take shape they will be used to evaluate the performance of a range of bespoke nanoparticles in order to understand how sufficiently strong cellular-level magnetic hyperthermia effects can be achieved. We are confident that the new instrument produced in this project will provide the step-change advancement required in nanoparticle evaluation to enable magnetic hyperthermia to be a viable and essential technology in the fight against cancer.

This is a multidisciplinary project that aims to foster 2-way cross sector interactions between the academic and clinical sectors in order to grow interdisciplinary knowledge. In addition, impact activities will build bridges between the Physical Sciences and Biomedical communities by demonstrating how techniques and expertise can be translated in both directions across the Life Science interface. At its core the project will have a dramatic impact on knowledge through the creation of new techniques and instrumentation. This will enable the mechanisms for achieving sizeable magnetic hyperthermia in real cellular environments to be finally resolved - something that has been an obstacle to translating this highly interesting and useful physical effect into a viable therapy to treat cancer. This new knowledge, coupled with the new tools that will be developed, will ultimately enable targeted cancer treatments that will reduce the required doses of conventional chemo or radiotherapy and their corresponding unpleasant side effects, leading to shorter patient recovery times. In addition to societal impact, this will have downstream economic benefits by allowing patients to return to work sooner with cost savings for both their employer and the National Health Service (NHS).

Additional economic benefits will come from commercial exploitation of the technology developed in the project. This includes both the instrument development work, and the new nanoparticle designs that will be obtained for optimised cellular level hyperthermia. In particular, the instrument that will be developed in the project could help create a new market for magneto-optics in biomedicine, with knock-on academic and commercial impact in both the Physical and Life Science communities. Finally, the project will train the next generation of multidisciplinary researchers and clinicians, who will have the knowledge and expertise to build on the results of the project, and to facilitate translation of the technology into the cancer clinic.