Periodic Reporting for period 4 - CheSSTaG (Chemotactic Super-Selective Targeting of Gliomas)
Período documentado: 2022-06-01 hasta 2023-04-30
We propose the design of a completely new platform for drug delivery for addressing a critical challenge in medicine brain delivery. We are focussing the approach to glioma and brain tumours combining our existing repertoire of molecular engineering tools based around our established approach to design responsive nanoparticles known as Polymersomes.
We are integrating them with new features using clinically safe and biodegradable components that will make them able to target cells as a function of their phenotypic compositions as well as to propel toward glucose gradients so to deliver large therapeutic payload into the central nervous systems. Here we are focussing further on targeting cancer cells harbouring within the healthy. We are developing a platform that converts bioinformatic characterisation of tissues and cells into multiplexed systems capable of interacting via the combination of many weak interaction only with wanted cells creating truly personalised medicine. We are also integrating this with the ability to navigate glucose (as well as other metabolites) gradients to enable long range targeting and effective delivery.
We are integrating them with new features using clinically safe and biodegradable components that will make them able to target cells as a function of their phenotypic compositions as well as to propel toward glucose gradients so to deliver large therapeutic payload into the central nervous systems. Here we are focussing further on targeting cancer cells harbouring within the healthy. We are developing a platform that converts bioinformatic characterisation of tissues and cells into multiplexed systems capable of interacting via the combination of many weak interaction only with wanted cells creating truly personalised medicine. We are also integrating this with the ability to navigate glucose (as well as other metabolites) gradients to enable long range targeting and effective delivery.
We have successfully synthesised metaboisable copolymers.
We have proved that the insertion of new membrane pores such as alpha-hekmolysisn and DNA origami pores, can allow propulsion and ultimately chemotaxis.
We have paved a solid theoretical background for phenotypic targeting that is now allowing us to both crossing the blood brain barrier and target brain tumour cells with high level of selectivity.
We have proved that the insertion of new membrane pores such as alpha-hekmolysisn and DNA origami pores, can allow propulsion and ultimately chemotaxis.
We have paved a solid theoretical background for phenotypic targeting that is now allowing us to both crossing the blood brain barrier and target brain tumour cells with high level of selectivity.
The project comprises 5 work packages (WPs):Metabolic block copolymers (WP1),Topological engineering (WP2), Chemotaxis (WP3), Super-Selectivity (WP4), and Neurobiology (WP5). With the exception of WP5 starting in year 3, all the WPs started in year 1.
WP1. (Beyond state of the art) In our pursuit of designing novel biodegradable copolymers, our research has culminated in the development of a novel class of polyesters derived from intermediates of the Krebs cycle. These polyesters exhibit characteristics that not only meet the stringent requirements for biodegradability and controlled cargo release but also demonstrate remarkable immunomodulatory properties upon hydrolysis. Specifically, the byproducts of their hydrolysis serve as immunomodulators, enabling precise control over specific inflammatory states. This unique attribute renders them potent agents capable of eliciting profound anti-inflammatory or immune-modulatory effects. Thus, our findings hold promise for the advancement of therapeutic interventions targeting inflammatory conditions, cancer, and neurodegenerative, this has served as bases for a successful ERC PoC grant (MAIN) .
WP2. (Beyond state of the art) We have finallu optmised a protocol for the bottom-up fabrication of patchy polymersomes, characterized by high yield and precise control over size and topology. Additionally, significant advancements have been made in the synthesis of ABC triblock copolymers. These copolymers are currently under evaluation for their potential application in the design of bi-functional nanomedicines. Leveraging their unique structure, with hydrophilic segments denoted as A and C, we aim to achieve an asymmetric distribution of two distinct phenotypic ligand combinations. This innovative approach holds promise for targeting dual biological effects, thereby enhancing therapeutic outcomes.
WP3 (Beyond state of the art) Significant advancements have been achieved in our analytical and computational capabilities, marking substantial progress in our research endeavors. Notably, we have successfully identified the optimal microfluidic geometry and developed a functional analytical model for comprehending diffusiophoresis and osmophoresis phenomena. Moreover, beyond our initial focus on synthetic vesicles, our investigations have extended to natural systems, wherein we have effectively demonstrated chemotaxis in naturally occurring systems. This demonstration serves as a critical milestone, elucidating the minimal conditions required for chemotaxis in proto cells. Furthermore, our research scope has expanded to encompass endogenous trafficking vesicles, including exosomes, wherein we have provided evidence supporting the presence of chemotactic conditions within these vital signaling units. These findings collectively enrich our understanding of cellular dynamics and hold significant implications for diverse biomedical applications.
WP4 (Beyong state of the art) Considerable progress has been achieved in advancing our theoretical framework, now cristne Phenotypic Association Theory (PAT), accompanied by the development of a computational model aimed at facilitating prediction and design tasks. Effective experimental protocols have been established, and efforts are currently underway to integrate and scale these protocols to enhance throughput. Furthermore, we are actively merging our experimental and computational approaches, leveraging machine learning methods to develop more predictive design tools. This integrated approach enables the creation of therapeutic interventions where biological activity is synergistically combined with precise targeting mechanisms. Additionally, our research efforts have extended to understanding the tropism of the current SARS-CoV-2 virus, leveraging the mathematical framework developed by our team, which aligns well with the multivalent nature of the virus. These interdisciplinary endeavors underscore our commitment to advancing both fundamental understanding and practical applications in biomedical research.
WP5. (Beyong state of the art) During the development of our proposed approach targeting glioma, we conducted detailed investigations into the macromolecular transport across the blood-brain barrier. Our studies revealed a crucial process regulated by receptors LRP1 and LRP8, along with the BAR domain protein syndapin-2. This process plays a pivotal role in maintaining brain homeostasis but becomes dysregulated in glioma and its associated vasculature. As a result, we have devised strategies to target both healthy and tumor-associated vasculature using distinct phenotypes. Additionally, our observations indicate that this pathway is also vital for controlling the transport of misfolded proteins such as amyloid beta and tau. Through multivalent targeting, we demonstrated modulation of LRP1 receptors, thereby restoring impaired transport observed in aging and neurodegenerative conditions. This modulation holds promise for the development of novel dementia therapies. Encouraged by these findings, we have recently submitted a new Proof of Concept (PoC) application to explore translational possibilities for our research.
WP1. (Beyond state of the art) In our pursuit of designing novel biodegradable copolymers, our research has culminated in the development of a novel class of polyesters derived from intermediates of the Krebs cycle. These polyesters exhibit characteristics that not only meet the stringent requirements for biodegradability and controlled cargo release but also demonstrate remarkable immunomodulatory properties upon hydrolysis. Specifically, the byproducts of their hydrolysis serve as immunomodulators, enabling precise control over specific inflammatory states. This unique attribute renders them potent agents capable of eliciting profound anti-inflammatory or immune-modulatory effects. Thus, our findings hold promise for the advancement of therapeutic interventions targeting inflammatory conditions, cancer, and neurodegenerative, this has served as bases for a successful ERC PoC grant (MAIN) .
WP2. (Beyond state of the art) We have finallu optmised a protocol for the bottom-up fabrication of patchy polymersomes, characterized by high yield and precise control over size and topology. Additionally, significant advancements have been made in the synthesis of ABC triblock copolymers. These copolymers are currently under evaluation for their potential application in the design of bi-functional nanomedicines. Leveraging their unique structure, with hydrophilic segments denoted as A and C, we aim to achieve an asymmetric distribution of two distinct phenotypic ligand combinations. This innovative approach holds promise for targeting dual biological effects, thereby enhancing therapeutic outcomes.
WP3 (Beyond state of the art) Significant advancements have been achieved in our analytical and computational capabilities, marking substantial progress in our research endeavors. Notably, we have successfully identified the optimal microfluidic geometry and developed a functional analytical model for comprehending diffusiophoresis and osmophoresis phenomena. Moreover, beyond our initial focus on synthetic vesicles, our investigations have extended to natural systems, wherein we have effectively demonstrated chemotaxis in naturally occurring systems. This demonstration serves as a critical milestone, elucidating the minimal conditions required for chemotaxis in proto cells. Furthermore, our research scope has expanded to encompass endogenous trafficking vesicles, including exosomes, wherein we have provided evidence supporting the presence of chemotactic conditions within these vital signaling units. These findings collectively enrich our understanding of cellular dynamics and hold significant implications for diverse biomedical applications.
WP4 (Beyong state of the art) Considerable progress has been achieved in advancing our theoretical framework, now cristne Phenotypic Association Theory (PAT), accompanied by the development of a computational model aimed at facilitating prediction and design tasks. Effective experimental protocols have been established, and efforts are currently underway to integrate and scale these protocols to enhance throughput. Furthermore, we are actively merging our experimental and computational approaches, leveraging machine learning methods to develop more predictive design tools. This integrated approach enables the creation of therapeutic interventions where biological activity is synergistically combined with precise targeting mechanisms. Additionally, our research efforts have extended to understanding the tropism of the current SARS-CoV-2 virus, leveraging the mathematical framework developed by our team, which aligns well with the multivalent nature of the virus. These interdisciplinary endeavors underscore our commitment to advancing both fundamental understanding and practical applications in biomedical research.
WP5. (Beyong state of the art) During the development of our proposed approach targeting glioma, we conducted detailed investigations into the macromolecular transport across the blood-brain barrier. Our studies revealed a crucial process regulated by receptors LRP1 and LRP8, along with the BAR domain protein syndapin-2. This process plays a pivotal role in maintaining brain homeostasis but becomes dysregulated in glioma and its associated vasculature. As a result, we have devised strategies to target both healthy and tumor-associated vasculature using distinct phenotypes. Additionally, our observations indicate that this pathway is also vital for controlling the transport of misfolded proteins such as amyloid beta and tau. Through multivalent targeting, we demonstrated modulation of LRP1 receptors, thereby restoring impaired transport observed in aging and neurodegenerative conditions. This modulation holds promise for the development of novel dementia therapies. Encouraged by these findings, we have recently submitted a new Proof of Concept (PoC) application to explore translational possibilities for our research.