Title: A novel tumour-responsive formulation for delivering sonodynamic treatment of prostate cancer
Funder: Engineering and Physical Sciences Research Council

Abstract: 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.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS