Palladium-activated prodrug therapy: a novel focal therapy for localised cancers of unmet need
Lead Research Organisation:
University of Edinburgh
Department Name: Edinburgh Cancer Research Centre
Abstract
Despite significant advances in the diagnosis and treatment of the earliest stages of cancer, the highest life-threatening risks and therapeutic challenges still remain in developing effective treatment of patients diagnosed with locally advanced or metastatic tumours. For most localised tumours the current treatment is surgical resection, often followed by adjuvant radiotherapy and/or chemotherapy. The potential benefit of such therapies in any stage of the cancer must be weighed against possible adverse effects that can severely impair a patient's quality of life. Unfortunately, even with adjuvant chemotherapy to treat some aggressive cancers like glioblastoma multiforme, the median survival is only improved around 2 months, while associated side effects are very severe. In addition, for localised prostate cancer, significant controversy remains on the optimal treatment options. Due to side effects (incontinence, impotence, bowel problems) of existing treatments (surgery or radiotherapy), current standard of care is active surveillance consisting of regular hospital tests (e.g. prostate biopsies and MRI scans), aimed at deferring intervention. Because of the lack of therapies providing a better balance between treatment efficacy and related toxicities, many of these cancers eventually evolve into a more aggressive form with increased risk of pre-mature death. Therefore, what is needed then are novel drug delivery strategies that can reduce the side effect profile of the treatment whilst maximising therapeutic efficacy.
To provide a safer and more effective strategy to those localised cancers, we have devised a novel therapeutic approach that will allow concentrating drug activity only at the cancer area, thereby reducing the severe adverse effects associated with chemotherapy. The technology is based on a novel strategy pioneered at the Edinburgh Cancer Research Centre at the University of Edinburgh that enables full control over where chemotherapy takes action through the use of solid metal devices made of an element called palladium. This metal, which is completely safe to patients (it is already employed in dentistry), can be shaped into implantable devices and possesses exceptional chemical properties that facilitate the local release of anticancer drugs. By implantation inside localised tumour, orally-given drug precursors will only become "active" at the cancer site upon interaction with the palladium device. Given the reusability of this device, this treatment could be repeated as many times as necessary. The unique modulatory capabilities of this novel approach will not only reduce drug presence in healthy organs but will also facilitate personalized treatments to be implemented according to the progression and severity of the disease, thereby reducing side effects and maximizing the efficacy of the therapy. Due to its novelty, such healthcare technology will make a major impact in the Pharma sector and, in turn, in the NHS and people of the UK and worldwide by improving the quality of life and life expectancy of patients suffering from untreatable tumours.
To provide a safer and more effective strategy to those localised cancers, we have devised a novel therapeutic approach that will allow concentrating drug activity only at the cancer area, thereby reducing the severe adverse effects associated with chemotherapy. The technology is based on a novel strategy pioneered at the Edinburgh Cancer Research Centre at the University of Edinburgh that enables full control over where chemotherapy takes action through the use of solid metal devices made of an element called palladium. This metal, which is completely safe to patients (it is already employed in dentistry), can be shaped into implantable devices and possesses exceptional chemical properties that facilitate the local release of anticancer drugs. By implantation inside localised tumour, orally-given drug precursors will only become "active" at the cancer site upon interaction with the palladium device. Given the reusability of this device, this treatment could be repeated as many times as necessary. The unique modulatory capabilities of this novel approach will not only reduce drug presence in healthy organs but will also facilitate personalized treatments to be implemented according to the progression and severity of the disease, thereby reducing side effects and maximizing the efficacy of the therapy. Due to its novelty, such healthcare technology will make a major impact in the Pharma sector and, in turn, in the NHS and people of the UK and worldwide by improving the quality of life and life expectancy of patients suffering from untreatable tumours.
Planned Impact
(1) Impact in Healthcare. The proposed research programme aims to develop a novel drug release technology that will benefit cancer patients by enhancing efficacy and reducing side effects of chemotherapy. Specifically, it will provide a first-line therapy for patients diagnosed with locally-advanced primary tumours, such as localised prostate cancer and glioblastoma multiforme, two unmet clinical needs with >25,000 new diagnosed cases per year just in the UK. The proposed strategy significantly differentiates from other technologies enabling focal treatment of disease (e.g. photodynamic therapy, brachytherapy or controlled-release implants) because -unlike those- it will enable multidose regimes and easy dose regulation by controlling the quantity of prodrug administered. In addition, this research programme will allow exploiting the benefits of this novel approach with a variety of chemotherapeutics with different mode of actions to appropriately tailor the treatment to different cancers and stages. These advantages will facilitate responsive treatments to be implemented in a personalized manner according to the progression and severity of the disease.
(2) Impact in Economy. Novel IP may be generated and commercially exploited due to the originality and potential medical impact of such a technology in the Pharma sector. Early engagement with a VC group (Epidarex), mediated by UoE's Tech offices, has provided a defined route map to attract private funds and support the translation of the technology into the clinic: strong preclinical validation with demonstrated efficacy and safety to treat each cancer indication in clinically relevant animal models. Consequently, we have formed a multidisciplinary team that includes prostate cancer surgeon Prof Heung and neurosurgeon Dr Brennan, who will support the preclinical and clinical validation of the technology. Once the strategy has been validated in vivo, engagement with VC / Pharma will be pursued further to form a commercialization vehicle (start-up or collaborative venture) and progress the technology into human trials. A sound infrastructure exists to support commercialization: Edinburgh Research & Innovation and Edinburgh BioQuarter (UoE and College of Medicine's technology offices, respectively) will support IP protection and licensing; will provide advice and mentoring for the creation of spin-out companies; and links to Pharma / investors that would allow further development opportunities. Importantly, besides the University's track record in IP commercialisation, the PI has significant experience in this sector as inventor of 6 patents for a variety of technologies and co-founder of 2 spin-out companies.
(2) Impact in Economy. Novel IP may be generated and commercially exploited due to the originality and potential medical impact of such a technology in the Pharma sector. Early engagement with a VC group (Epidarex), mediated by UoE's Tech offices, has provided a defined route map to attract private funds and support the translation of the technology into the clinic: strong preclinical validation with demonstrated efficacy and safety to treat each cancer indication in clinically relevant animal models. Consequently, we have formed a multidisciplinary team that includes prostate cancer surgeon Prof Heung and neurosurgeon Dr Brennan, who will support the preclinical and clinical validation of the technology. Once the strategy has been validated in vivo, engagement with VC / Pharma will be pursued further to form a commercialization vehicle (start-up or collaborative venture) and progress the technology into human trials. A sound infrastructure exists to support commercialization: Edinburgh Research & Innovation and Edinburgh BioQuarter (UoE and College of Medicine's technology offices, respectively) will support IP protection and licensing; will provide advice and mentoring for the creation of spin-out companies; and links to Pharma / investors that would allow further development opportunities. Importantly, besides the University's track record in IP commercialisation, the PI has significant experience in this sector as inventor of 6 patents for a variety of technologies and co-founder of 2 spin-out companies.
Publications
Adam C
(2018)
Bioorthogonal Uncaging of the Active Metabolite of Irinotecan by Palladium-Functionalized Microdevices.
in Chemistry (Weinheim an der Bergstrasse, Germany)
Adam C
(2022)
A 5-FU Precursor Designed to Evade Anabolic and Catabolic Drug Pathways and Activated by Pd Chemistry In Vitro and In Vivo.
in Journal of medicinal chemistry
Braun J
(2024)
A Pd-labile fluoroquinolone prodrug efficiently prevents biofilm formation on coated surfaces
in Organic & Biomolecular Chemistry
Bray TL
(2018)
Bright insights into palladium-triggered local chemotherapy.
in Chemical science
Chow SY
(2022)
Targeted Molecular Construct for Bioorthogonal Theranostics of PD-L1-Expressing Cancer Cells.
in JACS Au
Delgado-Gonzalez A
(2018)
Metallofluorescent Nanoparticles for Multimodal Applications.
in ACS omega
Liu S
(2023)
Introduction to nanozymes.
in Journal of materials chemistry. B
Ortega-Liebana MC
(2022)
Truly-Biocompatible Gold Catalysis Enables Vivo-Orthogonal Intra-CNS Release of Anxiolytics.
in Angewandte Chemie (International ed. in English)
Ortega-Liebana MC
(2022)
Truly-Biocompatible Gold Catalysis Enables Vivo-Orthogonal Intra-CNS Release of Anxiolytics.
in Angewandte Chemie (Weinheim an der Bergstrasse, Germany)
Description | We have developed, patented and published a novel strategy that enables -for the first time- to devise a completely inactive precursor of the chemotherapeutic drugs including vorinostat, doxorubicin, 5FU, SN-38 (active metabolite of irinotecan) and paclitaxel that are rapidly uncaged by a bioorthogonal method that uses either Palladium or Gold catalysis. The strategy has been validated in cell-based assays and ex vivo (tumoural tissue). In vivo PK and safety studies have been performed with the nominated candidate prodrug (glocafur) and the Pd-devices, which have been shown to be harmless. Efficacy experiments were perform to assess this strategy in a colon cancer model in mice. Results showed local prodrug activation, with local chemotherapy-induced necrotic areas in the tumour, although total tumour size was not changed. Our results indicates that the drug generated (5FU) is not sufficiently potent to kill the whole tumour, although it can kill the core of the tumour.. |
Exploitation Route | In combination with the intratumoral implantation of Pd-devices, this novel prodrug strategy could be used to mediate focal chemotherapy of localized cancers and thus reduce systemic side effects of current therapeutic interventions. Discussions with investors and VC have provided positive feedback about the prospects of the technology. Efficacy studies were indicated as key to secure investment. The plan is to complete the efficacy studies and attract financial support from private partners to form a spinout company that could progress this technology to clinical trials. |
Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | 799874 NANOBOTS - Tumor-Targeting Nanoengineered Bioorthogonal Technologies to Fight Metastatic Cancers |
Amount | € 183,455 (EUR) |
Funding ID | 799874 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 11/2018 |
End | 11/2020 |
Description | 891973 BOOMCHEMBAGS - Towards spatially-controlled, bioorthogonal, CuAAC-mediated assembly of targeted oncoprotein degraders |
Amount | € 212,934 (EUR) |
Funding ID | 891973 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 06/2021 |
End | 05/2023 |
Description | Bioorthogonal Gold Chemistry to Explore Novel Biomedical Applications |
Amount | £513,210 (GBP) |
Funding ID | EP/S010289/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2018 |
End | 03/2022 |
Description | Collaboration with Universidad de Zaragoza |
Organisation | University of Zaragoza |
Country | Spain |
Sector | Academic/University |
PI Contribution | We created a collaboration with the Institute of Nanosciences of Aragon (Universidad of Zaragoza) to merge Edinburgh's expertise in bioorthogonal catalysis with INA's expertise in nanosciences. Using INA's nanodevices, the Unciti-Broceta's lab discovered novel chemical properties of gold. The Unciti-Broceta's lab then developed gold-funcionalised devices that were able to perform uncaging reactions in vivo. |
Collaborator Contribution | The INA provided expertise in the characterisation and analysis of the nanoparticles and metal-functionalised solid scaffolds developed in the Unciti-Broceta's lab. The INA also provided a range of metallic and bimetallic nanoparticles. |
Impact | This is a multidisciplinary collaboration that has so far helped to generate two research publications in world-leading journals: (i) Pérez-López et al. Gold-Triggered Uncaging Chemistry in Living Systems, Angew. Chemie Int. Ed., 2017, 56, 12548-12552; and (ii) Rubio-Ruiz et al. High-Precision Photothermal Ablation using Biocompatible Palladium Nanoparticles and Laser Scanning Microscopy. ACS Applied Materials & Interfaces 2018, 10, 3341-3348. |
Start Year | 2016 |
Description | Collaboration with the University of Glasgow |
Organisation | University of Glasgow |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We are the inventors of a new technology that could impact cancer treatments |
Collaborator Contribution | Expertise in surgical oncology, specifically in prostate cancer |
Impact | Multidisciplinary collaboration encompassing medicinal chemistry, drug discovery, clinical medicine and surgical oncology |
Start Year | 2016 |
Title | BIOORTHOGONAL COMPOUNDS COMPRISING A PROPARGYL GROUP FOR TREATING CANCER |
Description | A method of preparing an active agent or a salt thereof from a prodrug first compound (1) comprising a propargyl group connected to an oxygen that is directly or indirectly connected to the active agent is provided, wherein the bond between the propargyl group and the oxygen is cleaved by reacting the first compound with palladium or gold, thereby releasing the active agent. Prodrug compositions suitable for use in the method are also provided. |
IP Reference | WO2017199028 |
Protection | Patent application published |
Year Protection Granted | 2017 |
Licensed | No |
Impact | We are currently in negotiation with VC firms to create a spin-out company around this IP. |
Description | Interview for regional radio station |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | The interview was uploaded to twitter and facebook by the radio station and actively shared by social media |
Year(s) Of Engagement Activity | 2019 |
URL | https://cadenaser.com/emisora/2019/09/11/radio_algeciras/1568207619_506858.html |
Description | Public Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | > 60 people attended a keynote lecture I gave for the InnovationNation - Biotechnology event 2016 |
Year(s) Of Engagement Activity | 2016 |
URL | https://twitter.com/eicc/status/720524251586031616 |
Description | Radio interview |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Radio interview to talk about the research related to this project |
Year(s) Of Engagement Activity | 2018 |
Description | Talk at the CRUK Staff Roadshow |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | I gave a talk at the annual CRUK Staff Roadshow for Scotland. It was an inspiring audience of supporters and patients helping CRUK across Scotland. Many questions followed the presentation and I participated in a round table for a debate. |
Year(s) Of Engagement Activity | 2017 |
Description | Talk to University of Edinburgh ECAT students |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Professional Practitioners |
Results and Impact | Talk at ECATRIP seminar organized by ECAT (clinical) Fellows of the University of Edinburgh |
Year(s) Of Engagement Activity | 2019 |
Description | Visit to CIRRUS LOGIC |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Industry/Business |
Results and Impact | I presented the work developed in my lab regarding the Palladium and Gold-activated prodrugs to the company Cirrus Logic. Over 25 staff members of the company attended the talk and most of them asked about the technology and healthcare impact. There were discussions during lunch with several members and the company decided to donate funds to the Edinburgh Cancer Research Centre. |
Year(s) Of Engagement Activity | 2017 |