Periodic Reporting for period 1 - SPeNTa-Brain (Synthetic Peptidic Nanovesicles for Targeting Paediatric Brain tumours)
Reporting period: 2019-04-01 to 2021-03-31
In this project, we aim to get closer to a solution for the devastating disease of brain cancer, especially for children with incurable brain tumours and lifespans of few months. Paediatric glioma are the leading cause of cancer-related death in children.
The limitations: Brain tumours are difficult to treat because of the special structure of our brain, that does not allow the passage and diffusion of most common anticancer drugs to reach the tumour. The brain is guarded by several barriers, with the most important and largest one the blood-brain barrier (BBB). In addition, gliomas are not defined lesions but they spread out within the brain, colonising several areas. This makes them extremely difficult to remove surgically and almost inaccessible to chemotherapy. Radiotherapy is the only option, although with severe side effects. Paediatric gliomas have a very poor prognosis and do not respond or frequently develop chemoresistance mechanisms to temozolomide (TMZ), one of the fewest drugs that crosses the BBB. Thus, there is an urgent need to develop innovative therapies, capable of reaching the brain and the tumours in a non-invasive way. To improve quality of these patients and to solve this burden, we propose here the use of nanomedicines as a non-invasive approach to treat brain cancer. Taking into account the progress made in nanomedicines design and the lessons learned from previous failures in clinical trials, we here design a new generation of super-selective nanomedicines that might represent the future of modern medicine allowing us to precisely target disease sites to improve efficacy and reduce side effects. Once validated, the versatility of this technology and concepts will allow its extension to the treatment of different solid tumours or even other CNS disorders (as versatile brain delivery system). We aim to combine different innovative concepts: (i)designing biodegradable polymersomes for brain delivery increasing the safety, avoiding unwanted accumulations; (ii)state-of the art equipment for characterization with a view for industrial development and translation of the technology; (iii) a novel TEM unit, to visualise the morphological characteristics of the polymersomes; (iv) super-selective binding that enables the specific targeting of tumour cells; (v) Combination therapy aiming to overcome chemo-resistance and seeking for synergy. Finally, the use of nanomedicines allows for personalized medicine, what means a paradigm shift in conventional treatments.
The limitations: Brain tumours are difficult to treat because of the special structure of our brain, that does not allow the passage and diffusion of most common anticancer drugs to reach the tumour. The brain is guarded by several barriers, with the most important and largest one the blood-brain barrier (BBB). In addition, gliomas are not defined lesions but they spread out within the brain, colonising several areas. This makes them extremely difficult to remove surgically and almost inaccessible to chemotherapy. Radiotherapy is the only option, although with severe side effects. Paediatric gliomas have a very poor prognosis and do not respond or frequently develop chemoresistance mechanisms to temozolomide (TMZ), one of the fewest drugs that crosses the BBB. Thus, there is an urgent need to develop innovative therapies, capable of reaching the brain and the tumours in a non-invasive way. To improve quality of these patients and to solve this burden, we propose here the use of nanomedicines as a non-invasive approach to treat brain cancer. Taking into account the progress made in nanomedicines design and the lessons learned from previous failures in clinical trials, we here design a new generation of super-selective nanomedicines that might represent the future of modern medicine allowing us to precisely target disease sites to improve efficacy and reduce side effects. Once validated, the versatility of this technology and concepts will allow its extension to the treatment of different solid tumours or even other CNS disorders (as versatile brain delivery system). We aim to combine different innovative concepts: (i)designing biodegradable polymersomes for brain delivery increasing the safety, avoiding unwanted accumulations; (ii)state-of the art equipment for characterization with a view for industrial development and translation of the technology; (iii) a novel TEM unit, to visualise the morphological characteristics of the polymersomes; (iv) super-selective binding that enables the specific targeting of tumour cells; (v) Combination therapy aiming to overcome chemo-resistance and seeking for synergy. Finally, the use of nanomedicines allows for personalized medicine, what means a paradigm shift in conventional treatments.
Within this action, we have been able to:
1. Demonstrate a facile and well-controlled synthesis of defined NPs morphologies using biocompatible, biodegradable and stimuli-responsive polypeptides as building blocks, which can be useful as drug delivery systems in a myriad of biomedical applications. Our strategy is highly significant and brings a new perspective to biodegradable NPs one-pot production based on poly(amino acids), particularly but not exclusively for application in the healthcare sector. Furthermore, the ROS-responsiveness and disassembly of our nanoparticles (that we monitor in situ thanks to LTEM) provide them with the ability to trigger their functional output under diseased/malfunctioning sites linked to mitochondria dysfunction. This is especially relevant in many pathologies including atherosclerosis, neurodegeneration, arthritis, diabetes, inflammation, cancer and metastasis where ROS is overproduced.
2.We followed a screening approach in which poorly water-soluble drugs are encapsulated in NPs to enhance drug solubility and facilitate intracellular delivery. By using a human pediatric glioma cell model, we demonstrated that our NPs mediated intracellular delivery of anticancer drugs. Additionally, when delivered in combination, drug-loaded NPs triggered both an enhanced drug efficacy and synergy compared to single drugs combinations. This is particular relevant since this versatile strategy can be further extended to other drug combinations to find new and effective synergistic drug combinations against paediatric glioma.
3.We have in deep investigated the mechanisms of transport across the BBB to the brain. To this aim we have used NPs with tunable amounts of ligands to a receptor present in the BBB used for transferring molecules from the blood to the brain side. We have elucidated the role of key actors (proteins) on the transport, and our findings show how depending on the amount of ligands used we can biase toward internalization in the cells and fast degradation and therefore no shuttling across, or a fast shuttling across the BBB. This is particularly relevant for the design of NPs to deliver drugs inside the brain for tumor treatments.
The work have been disseminated in several conferences as posters or oral presentations, including the well-known international ones: GRS and GRC Cancer nanotechnology conferences, Boston, 2019, ACS Fall San Diego, 2019, CRS Valencia Spain, 2019
This work has been also published in repositories (bioRxiv, ChemRxiv) and published in peer-reviewed journals. Although there are still some more publications coming after the end of the action, so far we have reported 8 publications.
All publications have been disseminated in social media (particularly Twitter) to help in their visibility.
1. Demonstrate a facile and well-controlled synthesis of defined NPs morphologies using biocompatible, biodegradable and stimuli-responsive polypeptides as building blocks, which can be useful as drug delivery systems in a myriad of biomedical applications. Our strategy is highly significant and brings a new perspective to biodegradable NPs one-pot production based on poly(amino acids), particularly but not exclusively for application in the healthcare sector. Furthermore, the ROS-responsiveness and disassembly of our nanoparticles (that we monitor in situ thanks to LTEM) provide them with the ability to trigger their functional output under diseased/malfunctioning sites linked to mitochondria dysfunction. This is especially relevant in many pathologies including atherosclerosis, neurodegeneration, arthritis, diabetes, inflammation, cancer and metastasis where ROS is overproduced.
2.We followed a screening approach in which poorly water-soluble drugs are encapsulated in NPs to enhance drug solubility and facilitate intracellular delivery. By using a human pediatric glioma cell model, we demonstrated that our NPs mediated intracellular delivery of anticancer drugs. Additionally, when delivered in combination, drug-loaded NPs triggered both an enhanced drug efficacy and synergy compared to single drugs combinations. This is particular relevant since this versatile strategy can be further extended to other drug combinations to find new and effective synergistic drug combinations against paediatric glioma.
3.We have in deep investigated the mechanisms of transport across the BBB to the brain. To this aim we have used NPs with tunable amounts of ligands to a receptor present in the BBB used for transferring molecules from the blood to the brain side. We have elucidated the role of key actors (proteins) on the transport, and our findings show how depending on the amount of ligands used we can biase toward internalization in the cells and fast degradation and therefore no shuttling across, or a fast shuttling across the BBB. This is particularly relevant for the design of NPs to deliver drugs inside the brain for tumor treatments.
The work have been disseminated in several conferences as posters or oral presentations, including the well-known international ones: GRS and GRC Cancer nanotechnology conferences, Boston, 2019, ACS Fall San Diego, 2019, CRS Valencia Spain, 2019
This work has been also published in repositories (bioRxiv, ChemRxiv) and published in peer-reviewed journals. Although there are still some more publications coming after the end of the action, so far we have reported 8 publications.
All publications have been disseminated in social media (particularly Twitter) to help in their visibility.
The main results have been covered in the previous section.
Impacts.
The research and training within this Action has undoubtedly help me to acquire novel skills and competences particularly in the fields of molecular engineering, biophysics and biomedical testing of nanomedicines (applied science). I have consolidated my multidisciplinary profile becoming a very unique and attractive professional profile. This Action has enlarged my scientific knowledge and surely has helped me to build a competitive CV. The improvement of my project management and risks evaluation skills as well as the gained experience in proposal’s, articles and patents writing and the networking performed during the dissemination of results have all led me to my next scientific endeavour as Research and Development Director of a well-stablished biotech company in Spain (PTS) where I have managed to co-fund my future salary with a competitive fellowship from the Spanish Ministry of Science : Torres Quevedo fellowship. This Action have also impacted on the research group I joined, where I have been able to participate in very fruitful collaborations with the lab members, whose results have been and are going to be published in the near future. I have also established fruitful collaborations and bridges with the company Somaserve (born from the Molecular bionics Lab), which has the possibilities to exploit the technologies of the action in the longterm (i.e. brain DDS) leading to successful products or even creating new job opportunities. Moreover, I have been able to link Somaserve to my new position now in PTS, where I will keep on collaborating with them. Last but not least, the aim of this fellowship is to reach novel brain DDs, to defeat paediatric glioma, being the future end-users, Children with incurable cancers. This project has allowed to obtain valuable preclinical information and can have a high impact in the society in near the future, specially now with the emergence of successful nanomedicines after the success of mRNA covid19 vaccines technologies.
Impacts.
The research and training within this Action has undoubtedly help me to acquire novel skills and competences particularly in the fields of molecular engineering, biophysics and biomedical testing of nanomedicines (applied science). I have consolidated my multidisciplinary profile becoming a very unique and attractive professional profile. This Action has enlarged my scientific knowledge and surely has helped me to build a competitive CV. The improvement of my project management and risks evaluation skills as well as the gained experience in proposal’s, articles and patents writing and the networking performed during the dissemination of results have all led me to my next scientific endeavour as Research and Development Director of a well-stablished biotech company in Spain (PTS) where I have managed to co-fund my future salary with a competitive fellowship from the Spanish Ministry of Science : Torres Quevedo fellowship. This Action have also impacted on the research group I joined, where I have been able to participate in very fruitful collaborations with the lab members, whose results have been and are going to be published in the near future. I have also established fruitful collaborations and bridges with the company Somaserve (born from the Molecular bionics Lab), which has the possibilities to exploit the technologies of the action in the longterm (i.e. brain DDS) leading to successful products or even creating new job opportunities. Moreover, I have been able to link Somaserve to my new position now in PTS, where I will keep on collaborating with them. Last but not least, the aim of this fellowship is to reach novel brain DDs, to defeat paediatric glioma, being the future end-users, Children with incurable cancers. This project has allowed to obtain valuable preclinical information and can have a high impact in the society in near the future, specially now with the emergence of successful nanomedicines after the success of mRNA covid19 vaccines technologies.