A novel tumour-responsive formulation for delivering sonodynamic treatment of prostate cancer
Lead Research Organisation:
University College London
Department Name: Surgical Biotechnology
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.
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.
Planned Impact
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.
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.
People |
ORCID iD |
Nikolitsa Nomikou (Principal Investigator) |
Publications

Hadi M
(2021)
Investigating the performance of a novel pH and cathepsin B sensitive, stimulus-responsive nanoparticle for optimised sonodynamic therapy in prostate cancer
in Journal of Controlled Release

Hadi MM
(2023)
Nanotechnology-augmented sonodynamic therapy and associated immune-mediated effects for the treatment of pancreatic ductal adenocarcinoma.
in Journal of cancer research and clinical oncology


Description | Our team has developed a treatment that uses low-intensity sound waves (at ultrasound frequency) in combination with non-toxic agents, called sensitizers, for the site-specific / targeted destruction of tumours. We propose that this method, called sonodynamic therapy, has significant potential in efficiently treating prostate cancer, improving survival and quality of life. Sonodynamic therapy offers fundamental advantages over chemotherapy, radiotherapy and surgery. It is not associated with adverse side effects. In addition, unlike other minimally-invasive and site-specific treatments, sonodynamic therapy is suitable for a broader group of patients, including those with advanced or "multifocal" disease (multiple small lesions located in the prostate). Moreover, this treatment method can activate the patient's immune system to fight cancer and any metastasis, while chemotherapy and surgery tend to weaken the immune system. We recently developed a pharmaceutical preparation that carries a sensitizer and increases its concentration within the tumour mass. The pharmaceutical preparation responds to a number of characteristics of the cancerous environment for maximizing the anticancer activity of the sensitizer during exposure to the sound waves. This is very important for improving the efficiency of sonodynamic therapy to eradicate cancer. Thus far, we have clear evidence to demonstrate that. Our recent studies in experimental animals carrying prostate tumours showed that, after one single sonodynamic treatment with this pharmaceutical preparation, the tumour size decreased by more than 50% within one day, while animals presented no complications or adverse effects from the treatment. This would have been impossible using conventional treatments, such as chemotherapy or radiotherapy. |
Exploitation Route | Based on the outcomes of the study, further studies have followed aiming to support a detailed pre-clinical portfolio leading to clinical translation, as well as a well-defined strategy for proceeding with first-in-man trials, will be in place. The corresponding new work programmes are designed not only to demonstrate the therapeutic potential and safety of the proposed treatment approach, but also to identify means of maximising the therapeutic effect for achieving improved clinical outcomes (i.e. by introducing immune check-point inhibitors in the treatment plan). Once the new programme objectives are successfully achieved and the translational potential of the proposed therapeutic approach is established, our team will be in a strong position to liaise with the Medicines and Healthcare products Regulatory Agency (MHRA) for planning the key remaining pre-clinical tests (e.g. toxicology for GMP product, dose-range escalation study, as well as a study to establish repeat dose toxicity in a non-rodent species) for subsequent initiation of clinical trials. Current technological platforms (i.e. ultrasound equipment) specialised for clinical ultrasound treatment in the 0.5-2 MHz frequency range, will be adjusted for transrectal intervention. |
Sectors | Education Healthcare Manufacturing including Industrial Biotechology Pharmaceuticals and Medical Biotechnology |
Description | Consultation on Newly Notified Procedure: IP1111 Sonodynamic Photodynamic Therapy |
Geographic Reach | National |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Description | Augmenting the effect of sonodynamic therapy for prostate cancer |
Amount | £20,558 (GBP) |
Organisation | St Peter's Trust for Kidney, Bladder and Prostate Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2024 |
Description | DTP 2018-19 University College London |
Amount | £15,580,958 (GBP) |
Funding ID | EP/R513143/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2018 |
End | 09/2023 |
Description | Delivering multimodal treatment in colorectal cancer using sonodynamic therapy in combination with nanotechnology |
Amount | £49,825 (GBP) |
Organisation | Bowel & Cancer Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2019 |
End | 04/2021 |
Description | Engineering and Physical Sciences Research Council Standard Grant |
Amount | £366,153 (GBP) |
Funding ID | EP/R035008/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2018 |
End | 08/2021 |
Description | Optimizing sonodynamic therapy based on Artificial Intelligence for the clinical translation of prostate cancer |
Amount | £12,000 (GBP) |
Organisation | The Royal Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2022 |
End | 03/2024 |
Description | UCL Therapeutic Acceleration Support Fund |
Amount | £74,088 (GBP) |
Funding ID | MC_PC_17180 PO 4050678018 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 02/2020 |
Title | Sonodynamic treatment in three-dimensional matrices |
Description | For sonodynamic treatment, a three-dimensional (3D) cell culture system based on fibrin-collagen hydrogel that has been developed and optimized in house is employed. Cells are embedded in the extracellular matrix-resembling 3D structures. Thus far, in vitro experiments on sonodynamic therapy have been performed in two-dimensional mode, i.e. using target cell monolayers. However, for ultrasound-mediated in vitro treatments, the energy delivered to the target cell population cannot be easily controlled, due to ultrasound reverberation and/or interference developed at the interfaces with air or hard material (e.g. plastic surfaces). In particular, it has been demonstrated that the appearance of ring interference patterns (harmonics) and standing waves caused by reflections at interfaces can cause local maximal pressure amplitude increase by up to the factor of 5. A "sealed" target cell population seeded within a flexible material has provided reproducibility and, therefore, promises transferable in vivo results. Importantly, transmission of ultrasound through the 3D matrix system has been verified in my earlier studies |
Type Of Material | Physiological assessment or outcome measure |
Year Produced | 2018 |
Provided To Others? | No |
Impact | The efficacy of the treatment approach is investigated using three-dimensional cell culture systems based on extracellular matrix technology. The significance of this approach is that it better resembles the in vivo cell organisation, than the monolayer-based culture does. In particular, for ultrasound-mediated in vitro treatments, the energy delivered to the target cell population cannot be easily controlled, due to ultrasound reverberation and/or interference developed at the interfaces with air or hard material (e.g. plastic surfaces). In my own previous studies, I have observed that by embedding them in matrices, target cells can be protected from exposure to extreme acoustic pressures caused by the afore-mentioned phenomena during in vitro treatments. Thus far, in the literature, in vitro studies on sonodynamic therapy investigating the efficacy of this approach have employed monolayer-based cultures, disregarding the lack of treatment control using this experimental setting. Essentially, this project will establish new protocols for assessing the efficacy of sonodynamic therapy, as well as other novel energy-based treatment approaches, using improved in vitro systems that better resemble the in vivo conditions. The latter is also important for providing improved in vitro means that will enable consistent refinement of the treatment parameters prior to embarking on in vivo experimentation. This will potentially reduce the number of experimental animals utilized for optimizing new treatment approaches for cancer. |
Description | Development and design of clinical ultrasound equipment for sonodynamic therapy of prostate cancer |
Organisation | University of Oxford |
Department | St Catherine's College |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-ordination of joint grant applications. |
Collaborator Contribution | Guidance and expertise on the design of ultrasound equipment for treating prostate cancer with sonodynamic therapy. |
Impact | This collaboration is multidisciplinary. It involves, engineering, physics, chemistry, biology and biomedicine. There are joint research outputs in the form of publications. |
Start Year | 2020 |
Description | Exploitation of the tumour microenvironment for developing novel theranostic formulations for cancer |
Organisation | Ulster University |
Department | School of Pharmacy and Pharmaceutical Sciences. |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | In the context of this project, my team has studied the effect of distinctive characteristics of the tumour mocroenvironment, such as hypoxia and acidic pH, in the performance of a polyglutamate-based nanoparticulate formulation for delivering sonodynamic treatment. The expression and secretion profiles of a key proteolytic enzyme, cathepsin B, which is overexpressed in malignant tumours, were studied in detail. The findings were shared with leading academics in sonodynamic therapy at Ulster University, towards the development of a preclinical portfolio that includes in vivo studies for testing the efficacy of the formulation in experimental animal models. Professor Anthony McHale and Professor John Callan have a long and successful record of performing in vivo studies for demonstrating the effect of sonodynamic therapy and similar treatment modalities that involve tumour sensitisation and the application of externally-applied stimuli, such as ultrasound and light. The partnership also has led to the submission of a joint EPSRC standard proposal for a project that is supported by findings from the current EPSRC grant and aims to develop a formulation for combined near-infra red intraoperative imaging and treatment of cancer. The new EPSRC application is led by me and the partners from Ulster University, who will manage the in vivo experimentation, have been included as co-applicants. |
Collaborator Contribution | The partners from Ulster University have supported the efficient progression of the current project by offering expert advice on formulation preparation and characterization, as well as an early insight in subsequent in vivo experimentation that will fully demonstrate the potential of the system developed during the project. They have also offered me access to specialized equipment based in their laboratory facilities at Ulster University. The partners have also contributed to the submission of a new EPSRC grant, as co-applicants. |
Impact | The collaboration with Ulster University is multi-disciplinary, involving the following disciplines: Chemistry, biomaterials, physics (acoustics), optics, biology and biochemistry. There are a number of joint research publications that have resulted from this partnership. |
Start Year | 2017 |
Description | Ultrasound dosage for prostate cancer treatment in sonodynamic therapy |
Organisation | University College London |
Department | Department of Medical Physics and Biomedical Engineering |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | N/A |
Collaborator Contribution | Support with ultrasound treatment measurements |
Impact | Disciplines: physics-biomedical science |
Start Year | 2023 |
Description | Using Artificial Intelligence to optimize irradiation of the prostate using extracorporeal ultrasound |
Organisation | Peking University Third Hospital |
Country | China |
Sector | Hospitals |
PI Contribution | Joint grant proposal Knowledge exchange |
Collaborator Contribution | Joint grant proposal Knowledge exchange |
Impact | Successful grant application to the Royal Society UK. Multidisciplinary: medicine-physics-biochemistry-engineering-biology |
Start Year | 2022 |
Title | Nanoparticles for Cancer Diagnosis and Therapy |
Description | The present invention relates generally to methods and materials for use in photothermal or sonodynamic therapy. The invention novel nanoparticles for use in delivering sensitizers to solid tumour target, wherein the nanoparticles are composed of a polymers or co-polymer of monomers linked by peptide bonds, wherein the polymer or co-polymer comprises one or both of glutamate or derivatised glutatamic acid, and optionally a further, different, monomer which is a naturally occurring amino acid or synthetic monomer having a side chain group, wherein the polymer or co-polymer is not composed only of glutamate. The pendant groups and/or side chains of the polymer or co-polymer interact non-covalently with the sensitizer. |
IP Reference | US 16/385,591 |
Protection | Patent granted |
Year Protection Granted | 2019 |
Licensed | No |
Impact | Securing further funding for clinical translation |
Description | Interaction with a regulatory consultant |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Policymakers/politicians |
Results and Impact | For the design of preclinical efficacy studies that will enable the progression to phase I clinical trials using the proposed system, the project team has received professional consultation from Dr David Jones, who is a former senior nonclinical assessor at the UK Medicines and Healthcare products Regulatory Agency (MHRA) and a current consultant at ApconiX (UK). |
Year(s) Of Engagement Activity | 2022 |
Description | Presentation at scientific meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | Presentation of the work at the CRUK City of London/Radnet Combination therapies meeting |
Year(s) Of Engagement Activity | 2023 |
Description | Presentation at the Centre of Advanced Biomedical Imaging |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | a 90' presentation of the project, discussing the progress and how the research approach can be improved with the use of advanced facilities |
Year(s) Of Engagement Activity | 2019 |
Description | Recent advances in prostate cancer diagnosis and treatment |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Supporters |
Results and Impact | A new partnership with a lead clinician in prostate cancer facilitated the organisation of an evening session, where patients, philanthropists, charitable organisations and investors had the opportunity to learn about sonodynamic therapy and our findings from this research. Since then, we hold regular sessions with members from the public, in which we present any advancements in our research. These events have led to further investment on this research by private donors. |
Year(s) Of Engagement Activity | 2019 |
Description | Webinar delivery |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Delivery of a webinar on the potential of sonodynamic therapy for the treatment of prostate cancer. The webinar facilitated a discussion that has widened the knowledge of the the audience in the field of locoregional cancer ablation. The webinar was recorded and has been published online, as an open access source. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.youtube.com/watch?v=uKEy-q6rwug&feature=youtu.be |