A novel tumour-responsive formulation for delivering sonodynamic treatment of prostate cancer

There has been considerable development of therapies for locally-advanced and metastatic prostate cancer over the last 5-10 years. Whilst incremental improvements in survival have occurred they do suffer from limitations in their therapeutic ratio. This necessitates the development of improved targeted therapies that can successfully replace currently applied ablative or chemotherapeutic strategies for the management of advanced disease.

In the context of the proposed project, a strategic series of experiments will form the basis for the development and optimisation of a new treatment for advanced prostate cancer, called sonodynamic therapy (SDT). SDT employs ultrasound in combination with relatively non-toxic agents (sensitizers) for the production of cytotoxic reactive oxygen species and the subsequent confined ablation of tumours. Pre-clinical and some very limited clinical studies have suggested the efficacy and targeting capability of this therapeutic approach. However, SDT has yet to be fully characterised, clinically optimised and appropriately exploited for the treatment of prostate cancer. Although SDT offers promise, it remains poorly characterised and this hinders efficient translation to the clinic. Moreover, no clinically-acceptable therapeutic formulation has been developed for clinical application in order to increase intratumoral levels of sonosensitizing agents and achieve an improved therapeutic result based on SDT.

In the proposed project, a formulation based on multistimulus responsive sensitizer-containing nanoparticles that can accumulate in advanced prostate tumours and increase the therapeutic efficacy of SDT will be developed. Essentially, porfimer sodium, a clinically approved sensitizer, will be incorporated in polyglutamate-based nanoparticles. The tumour accumulative attribute of the formulation relies on the exploitation of the microenvironment of advanced prostate tumours, such as the overexpression of the proteolytic factors cathepsin B and prostate-specific membrane antigen (PSMA), that can degrade the nanoparticles, reduce their size and improve cellular uptake.

Initial parts of the proposed study will focus on the preparation and characterization of the sensitizer-containing nanoparticles. Strategic collation of data will lead to the extraction of mathematical equations that describe the response of the formulation to cathepsin B and acidic microenvironments, aiming to form a predictive model on the intratumoral performance of this formulation. A series of experiments using prostate cancer cell lines in three-dimensional culture will elucidate the efficacy of SDT in combination with this formulation and will evaluate the impact of PSMA expression and cathepsin B on the treatment result. Gene expression analysis (transcriptomics) of the treated cell samples will be employed to explore the events that occur post-treatment, at the molecular level. In the latter studies, markers for apoptosis, survival and metastatic niches will be investigated. Essentially, the pre-clinical studies completed in the context of this project aim to establish the efficacy of SDT and to support and refine subsequent in vivo studies that are required for the clinical translation of this therapeutic approach in prostate cancer.

Impact in Society: Health and quality of life
The proposed study will form the basis towards the clinical translation of an efficient therapy with reduced side-effects for patients with advanced prostate cancer. This work will potentially stimulate efforts for establishing sonodynamic therapy as a novel therapeutic strategy that can overcome the inefficiency and adverse effects of currently employed treatments, such as chemotherapy and radiotherapy. The versatility and non-invasive nature of sonodynamic therapy will minimize treatment-associated suffering, enabling early recovery of treated patients, minimizing the time spent in hospital. SDT, with further optimization and efficient clinical translation, has the potential to improve survival and quality of life by eliminating the need for further costly drug therapies.

Impact in Economy: Products and procedures, new companies, investment
In the context of this project, the development and characterization of a pharmaceutical formulation that responds to disease-associated and externally applied stimuli has the potential to lead to the development of new pharmaceutical product(s) for cancer, either for sonodynamic therapy or for conventional chemotherapy. In addition, commercial opportunities for the development of new technological platforms (e.g. ultrasound equipment) specialised for clinical sonodynamic therapy will be generated. These advancements will subsequently attract investments and will lead to the establishment of new companies. This progress will have an immediate effect on the development of new professional avenues and the generation of new and employment opportunities, with significant positive impact in society.

Impact on People: Skills and people pipeline
The proposed study and its outcomes will potentially stimulate strong interaction and collaboration of professionals from different professional and academic disciplines, including basic sciences (biochemistry, physics, biology), engineering, medicine and the industry, towards the successful clinical translation of SDT for the treatment of prostate cancer. Subsequently, the establishment of a novel therapeutic platform will facilitate the development of new skills and areas of expertise. Biochemists, biologists, physicists and engineers will work together with clinicians and advisors from the MHRA for completing the required preclinical studies towards the approval of the new formulation for first-in-man trials and the optimization of ultrasound treatment at clinical setting. These skills and expertise will potentially lead to the establishment of large research and development programs that will enhance national and international collaborations.