Final Report Summary - NANODISCAN (Nano-technology enabled repositioning of Disulfiram as an anti-cancer stem cell agent)
Background: Disulfiram (DS), an old antialcoholism drug, possesses excellent anti-CSC activity with low toxicity to normal cells. Due to the very short half-life in bloodstream (~4 min), the clinical application of DS in cancer treatment has been limited. In this project, we took the advantage of the IIF’s very strong technical knowhow in the fields of cancer research, molecular pharmacology, anticancer drug development and nano-encapsulation to set up collaborative network with institutions in the UK, Europe and China to develop a long-circulating DS nano-formulation for cancer treatment.
Objectives: Originally, this project aims to achieve the following scientific targets. 1. To develop long circulating nano-encapsulated DS (DS-NPs); 2. To perform cell assays to confirm the activity of DS-NPs against breast and liver cancer cells; 3. To determine the anticancer efficacy of DS-NPs in breast and liver cancer xenograft bearing nude mice and investigate the in vivo anticancer mechanisms; 4. To evaluate the pharmacokinetics of DS-NPs in mice and determine the biodistribution and biostability.
Results and Conclusion: The original research plan was limited to pluronic micelle encapsulation in breast and liver cancers. The very promissing pilot data encouraged us to expend our study into other nano-formulations of DS and cancer types. In collaboration with our partners in Europe (Dr Yoncheva, Sofia Universitiy, Bulgaria; Prof Juan Irache, University of Navarra, Spain), China (Prof Bin He, Sichuan University; Prof Xiuwu Bian, Southwest Cancer Institute), UK (Prof Wenguo Jiang, Cardiff University) and the researchers and PhD students in University of Wolverhampton, Dr Zhipeng Wang (the IIF) has fulfilled the following tasks. 1. Encapsulation and characterization of DS-poly lactic-co-glycolic acid (PLGA) and DS-polymeric micelles (PM); 2. Examination of in vitro cytotoxicity of DS-NPs in liver and breast cancer cell lines; 3. Investigation of the in vitro molecular anticancer mechanisms of DS-NPs in liver and breast cancer cell lines; 4. Examination of the anticancer efficacy and mechisms of DS-NPs in breast, liver, lung cancer and glioblastoma xenografts.
For the detail of the achievements in the past 24 months, please refer to the attached papers and unpublished data. Briefly, this project has generated the following results. 1. In order to compared with liposome encapsulated DS (Lipo-DS), we performed in vitro and in vivo studies to examine the effect of Lipo-DS on human breast cancer cell lines and xenografts. Lipo-DS improved the in vivo anticancer effect but at a relatively high dosage (75mg/kg). At this dosage level, some necrotic cells were observed in the vital organs, e.g. liver and kidney, of the experimental mice. 2. We have developed two long circulating DS-NPs e.g. DS-PLGA and DS-PM. Both formulations showed very satisfactory encapsulation efficiency, partical size, zeta potential and release profiles. The half-life of the free DS in serum is only last for 30 seconds in serum. PLGA and PM encapsulation extended the half-life of DS to more than 4 hours. 3. DS-PLGA showed very strong in vivo anticancer effect on liver cancer xenografts at a very low dose (10mg/kg) which is equavilant to about 1/5 of the clinically used antialcoholism dose in human. No non-specific toxicity was observed in the vital organs e.g. liver, lung and kidney. 4. DS-PLGA shows very strong anticancer activity in the intracranial glioblastoma multiforme (GBM) model (Fig.2). 5. DS-PLGA strongly inhibits the in vitro migration and invasion of HCC cells at an extremely low concentration (5nM) and blocks the metastasis in vivo (Fig.3). Due to the chemoresistance of GBM cells and blood brain barrier, the prognosis of GBM and lung cancer remains very poor. Although these two cancer types were not originally included in our work plan, the very encouraging data prompted us to expand our study. The pilot data from this project led to secure the funding from British Lung Foundation. In collaboration with Queen Mary University of London, University of Norttingham and University of the Balearic Islands, Spain, we will support Prof Bin He in Sichuan University, China to apply for H2020 MSCA IF for further investigation of the novel formulation of DS-NPs in targeting GBM. 6. The data generated from this project have been led to filing two patents. 7. The data have been presented in SET for Britain at UK Parliament and awarded Silver Prize. 8. We have published papers in peer-reviewed journals and conferences. More papers are under preparation.
The socio-economic impacts of the project: The ultimate goal of this study is trying to translate DS into cancer therapeutics. Based on this study, we have built up wider network with more European academic and industrial partners in Spain, Greece, Germany and Hungry and will collaboratively apply for further EU grant to support the industrial scale-up at GMP standard and finally put our product into clinical trial. Therefore, the completion of this project will lead to development a novel anticancer drug which will be highly beneficial to the economy and cancer patients in the EU countries.
Objectives: Originally, this project aims to achieve the following scientific targets. 1. To develop long circulating nano-encapsulated DS (DS-NPs); 2. To perform cell assays to confirm the activity of DS-NPs against breast and liver cancer cells; 3. To determine the anticancer efficacy of DS-NPs in breast and liver cancer xenograft bearing nude mice and investigate the in vivo anticancer mechanisms; 4. To evaluate the pharmacokinetics of DS-NPs in mice and determine the biodistribution and biostability.
Results and Conclusion: The original research plan was limited to pluronic micelle encapsulation in breast and liver cancers. The very promissing pilot data encouraged us to expend our study into other nano-formulations of DS and cancer types. In collaboration with our partners in Europe (Dr Yoncheva, Sofia Universitiy, Bulgaria; Prof Juan Irache, University of Navarra, Spain), China (Prof Bin He, Sichuan University; Prof Xiuwu Bian, Southwest Cancer Institute), UK (Prof Wenguo Jiang, Cardiff University) and the researchers and PhD students in University of Wolverhampton, Dr Zhipeng Wang (the IIF) has fulfilled the following tasks. 1. Encapsulation and characterization of DS-poly lactic-co-glycolic acid (PLGA) and DS-polymeric micelles (PM); 2. Examination of in vitro cytotoxicity of DS-NPs in liver and breast cancer cell lines; 3. Investigation of the in vitro molecular anticancer mechanisms of DS-NPs in liver and breast cancer cell lines; 4. Examination of the anticancer efficacy and mechisms of DS-NPs in breast, liver, lung cancer and glioblastoma xenografts.
For the detail of the achievements in the past 24 months, please refer to the attached papers and unpublished data. Briefly, this project has generated the following results. 1. In order to compared with liposome encapsulated DS (Lipo-DS), we performed in vitro and in vivo studies to examine the effect of Lipo-DS on human breast cancer cell lines and xenografts. Lipo-DS improved the in vivo anticancer effect but at a relatively high dosage (75mg/kg). At this dosage level, some necrotic cells were observed in the vital organs, e.g. liver and kidney, of the experimental mice. 2. We have developed two long circulating DS-NPs e.g. DS-PLGA and DS-PM. Both formulations showed very satisfactory encapsulation efficiency, partical size, zeta potential and release profiles. The half-life of the free DS in serum is only last for 30 seconds in serum. PLGA and PM encapsulation extended the half-life of DS to more than 4 hours. 3. DS-PLGA showed very strong in vivo anticancer effect on liver cancer xenografts at a very low dose (10mg/kg) which is equavilant to about 1/5 of the clinically used antialcoholism dose in human. No non-specific toxicity was observed in the vital organs e.g. liver, lung and kidney. 4. DS-PLGA shows very strong anticancer activity in the intracranial glioblastoma multiforme (GBM) model (Fig.2). 5. DS-PLGA strongly inhibits the in vitro migration and invasion of HCC cells at an extremely low concentration (5nM) and blocks the metastasis in vivo (Fig.3). Due to the chemoresistance of GBM cells and blood brain barrier, the prognosis of GBM and lung cancer remains very poor. Although these two cancer types were not originally included in our work plan, the very encouraging data prompted us to expand our study. The pilot data from this project led to secure the funding from British Lung Foundation. In collaboration with Queen Mary University of London, University of Norttingham and University of the Balearic Islands, Spain, we will support Prof Bin He in Sichuan University, China to apply for H2020 MSCA IF for further investigation of the novel formulation of DS-NPs in targeting GBM. 6. The data generated from this project have been led to filing two patents. 7. The data have been presented in SET for Britain at UK Parliament and awarded Silver Prize. 8. We have published papers in peer-reviewed journals and conferences. More papers are under preparation.
The socio-economic impacts of the project: The ultimate goal of this study is trying to translate DS into cancer therapeutics. Based on this study, we have built up wider network with more European academic and industrial partners in Spain, Greece, Germany and Hungry and will collaboratively apply for further EU grant to support the industrial scale-up at GMP standard and finally put our product into clinical trial. Therefore, the completion of this project will lead to development a novel anticancer drug which will be highly beneficial to the economy and cancer patients in the EU countries.