Conjugated Polymer Nanoparticles for Near Infrared Fluorescence Imaging

In this work we will produce a fluorescent nanoparticle system for high performance clinical near infrared (NIR) in vivo imaging, an extremely promising technology that is currently being held back by the use of poorly performing organic dyes as fluorescent imaging agents.

NIR light, at wavelengths between 700 and 1000 nm, exhibits high tissue penetration and can therefore be used to non-invasively visualise structures inside the body. High performance NIR in vivo imaging has long been mooted as a highly promising alternative to nuclear imaging techniques, as it exhibits improved sensitivity and resolution, as well the obvious benefit of replacing the use of the radioactive tracer materials which pose a risk to both patients and clinicians. Although NIR imaging will be useful for a variety of diagnostic applications, it is currently considered to be particularly promising for imaging of the lymphatic system, specifically in relation to its role in cancer metastasis.

NIR imaging is not currently used in the clinical setting due to a lack of strong and stable NIR contrast agents. Small molecule organic dyes are commercially available and have been investigated as NIR contrast agents, but their weak fluorescence emission limits their practical use. Development, approval and commercialization of NIR imaging agents with enhanced performance over organic dyes will be a vital step towards maximising the potential of NIR in vivo imaging.

In the work proposed herein, nanoparticles will be synthesised from conjugated polymers which exhibit extremely strong absorption and fluorescence emission. Conjugated polymer nanoparticles (CPNs) have emerged as highly promising fluorescent probes for in vivo imaging as they exhibit excellent optical properties whilst lacking the intrinsically toxic ingredients found in other fluorescent nanoparticles such as quantum dots (cadmium, for example). NIR fluorescence will be achieved by combining CPNs with NIR-dyes to create a system which couples high energy absorption with efficient energy transfer to produce strong NIR fluorescence brightness. The key feature of these nanoparticles is that both their excitation and emission maxima will be in the NIR - an absolute prerequisite for NIR in vivo imaging, and a functionality that has not been achieved in CPNs to date.

A second defining feature of our strategy to develop CPNs as NIR imaging agents is the incorporation of extensive in vitro and preliminary in vivo safety testing as an intrinsic part of the nanoparticle design phase (i.e. Safety-by-Design). This forward-thinking approach will ensure that a clinically viable system is chosen for investigation from the start, thus promoting maximum efficiency of project time and funding.

The programme to generate and optimise a high performance, safe NIR-emitting nanoparticle system will be completed in three phases: 1) Systematic investigation of nanoparticle properties (optical, physicochemical and in vitro safety) from selected combinations of conjugated polymers and NIR dyes; 2) Selection of one nanoparticle system for subsequent optimization and comprehensive in vitro safety testing; 3) in vivo performance evaluation and preliminary in vivo safety testing.

This project is extremely timely as global interest in CPNs is increasing rapidly. The KCL investigators have been at the forefront of this exciting area of research over the last five years, and have already made a significant contribution by being one of the first groups internationally to produce conjugated polymer nanoparticles and transfer them into biomedical applications. The further expansion of this work towards clinical applications in NIR imaging will strengthen the UK lead in the rapidly evolving sector of medical engineering.

The project to develop conjugated polymer nanoparticles for near infrared imaging is an international, multi-disciplinary collaborative initiative. The project will have a positive impact on science, industry, health care and society both in the UK and internationally.

1) Economy: CPNs are fast emerging as highly promising fluorescent imaging probes, which we believe will soon supersede quantum dots as the next generation of fluorescent nanoparticles in biomedicine. This highly translational technology holds great potential for intellectual property (IP) development and commercial exploitation. KCL will pursue and protect any IP generated through the Business and Innovation Section. Imaging Sciences will pursue the translation to clinic through a dedicated post, linked with the BRC whose only aim is to handle the necessary requirements as dictated by the Medicines and Healthcare products Regulatory Agency.

2) Knowledge: Our work will simultaneously contribute towards fundamental knowledge of the optical and physicochemical properties of conjugated polymer nanomaterials designed as imaging agents. Further, the study will provide both in vitro and in vivo safety data on these systems, as well generate a proof-of-concept for the performance of an optimised system as an in vivo imaging agent. This information will be of high interest to academic and industrial scientists across a wide range of disciplines.

3) Stakeholders: Due to the potentially translational nature of the project, it will be of high importance to engage not only academic scientists, but specific stakeholder groups that may be involved in the future of technology development or use. Stakeholders include: a) Funders (research councils, charities, finance and industry), b) Developers (industrial partners, clinical research organisations, regulators), c) Users (clinicians and health care staff) and d) Beneficiaries (patients or representatives from patient group organisations). To effectively engage stakeholders in the fundamental issues at the core of this project, and to learn from individuals directly impacted by the technology, two interactive workshops will be organised at 15 and 33 months in the project timeline. Facilitated discussions will be conducted in workshop break-out groups to capture information such as the most prevalent patient needs, user requirements necessary for successful implementation in the clinic, barriers to commercial development and input from the regulatory authorities. Knowledge gained from each of the workshops will be compiled into two summary papers, which will be published as review articles in a peer-reviewed journal following each event.

4) Society: Beyond sharing our research outcomes with immediate stakeholders, we strongly believe that there is a large benefit in directly engaging the public with our work. A better general public knowledge of the challenges facing the health care sector and of new biomedical technologies will benefit and educate society in general. Secondly, by sharing our knowledge and understanding of biomedical nanotechnologies with the public we will be contributing responsibly to the ongoing public dialogue about the risk/benefit balance of nanotechnology. Philip Howes (PH) is ideally placed to undertake this due to a background in the public understanding of science. This can be achieved through his usual channels for dissemination, such as the Institute of Making and through regular publications in The Guardian.

5) People: The preparation of trained researchers able to contribute intellectually and economically to the UK is a goal of this project. When combined with the latest cutting edge science provided by the project, international multi-disciplinary training, dialogue with stakeholders and IP development, the project will provide the specific training required to best promote the scientific career of Philip Howes, the Researcher Co-Investigator in this project.