Periodic Reporting for period 2 - MIMIC-KeY (A KEY TO THE RATIONAL DESIGN OF EXTRACELLULAR VESICLES-MIMICKING NANOPARTICLES)
Okres sprawozdawczy: 2022-06-01 do 2023-11-30
Being able to target a specific tissue or cell type is the holy grail of targeted therapies such as drug delivery. However, this is still extremely challenging and, as a consequence, the clinical applications of this approach are still limited. Nature offers examples of selective targeting, being cancer metastasis a particularly striking one. Specific types of cancer metastasize selectively in determined organs showing the ability of cancer to recognize and target tissue-specific features. The mechanism of this tropism is under study but an increasing number of reports point out that the primary tumors secrete and selectively deliver extracellular vesicles (EVs) to a target tissue where these EVs can modify cellular behaviour.
This triggers the key question of the MIMIC-KEY project: can we synthesize targeted nanoparticles inspired by tumor-derived EVs to achieve selective tissue targeting?
In this framework cancer is not the disease to treat but a source of inspiration to fight other diseases, with a focus on metabolic disorders. This ambitious goal requires two main steps:1) understanding the molecular features that determine selective tissue targeting of EVs and 2) having the synthetic tool to mimic them in a clinically relevant formulation.
The comprehension of EVs targeting behaviour and cargo delivery in natural systems will be used to build up new artificial materials that have the same targeting capabilities, but are much more scalable and mono disperse of the natural EVs. This last step is crucial as the cost of isolating EVs, their polydisperse nature and regulatory difficulties make natural EVs not suitable for the clinic yet. The breakthrough idea of artificial EV-mimics is to use only essential building blocks and amplifying their therapeutic functions. They will thus overcome the current limitations of natural EVs and represent a challenge at the frontiers of research.
In the MIMIC-KEY project, cancer is not the disease to treat but a source of inspiration to build artificial EVs mimics able to fight other clinically unmet diseases, specifically metabolic bone disorders.
Metabolic bone diseases comprise a subset of pathologies caused by an altered relationship between bone resorption and bone formation. This disease yields to altered bone structure and subsequent frequent fractures and bone malformation.
This triggers the key question of the MIMIC-KEY project: can we synthesize targeted nanoparticles inspired by tumor-derived EVs to achieve selective tissue targeting?
In this framework cancer is not the disease to treat but a source of inspiration to fight other diseases, with a focus on metabolic disorders. This ambitious goal requires two main steps:1) understanding the molecular features that determine selective tissue targeting of EVs and 2) having the synthetic tool to mimic them in a clinically relevant formulation.
The comprehension of EVs targeting behaviour and cargo delivery in natural systems will be used to build up new artificial materials that have the same targeting capabilities, but are much more scalable and mono disperse of the natural EVs. This last step is crucial as the cost of isolating EVs, their polydisperse nature and regulatory difficulties make natural EVs not suitable for the clinic yet. The breakthrough idea of artificial EV-mimics is to use only essential building blocks and amplifying their therapeutic functions. They will thus overcome the current limitations of natural EVs and represent a challenge at the frontiers of research.
In the MIMIC-KEY project, cancer is not the disease to treat but a source of inspiration to build artificial EVs mimics able to fight other clinically unmet diseases, specifically metabolic bone disorders.
Metabolic bone diseases comprise a subset of pathologies caused by an altered relationship between bone resorption and bone formation. This disease yields to altered bone structure and subsequent frequent fractures and bone malformation.
Up to now major advancements in both steps 1 and 2 were achieved thanks to a synergistic combination of groundbreaking and multidisciplinary approaches spanning from inorganic, organic and supramolecular chemistry, biophysics, optics, molecular and cell biology, proteomics, clinical translation and mathematical modelling in an excellent partnership throughout Europe.
In particular, the natural EVs were so far isolated and deeply characterized, finding innovative approaches to characterize them from the targeting behaviour. Novel high-resolution biological techniques combining super-resolution microscopy and flow cytometry, proteomics analysis and multiscale simulations were developed and assessed to understand the targeting capabilities of natural EVs derived from tumor cells. Nanocapsules, nanocages and nanogels were prepared, functionalized and labelled with different dyes. Concerning the artificial EV-mimics, they are core-shell structures with smart features allowing a stimuli-responsive cargo release coated by a mobile, dynamic lipid bilayer shell, mimicking the functionalities of the natural EVs. Such EV-mimics are very promising at the moment to enable novel enzyme-based therapy against metabolic disease being tested in vitro and in vivo.
The breakthrough idea of artificial EV-mimics, using only essential building blocks and amplifying their therapeutic functions, will overcome the current limitations of natural EVs and represent a challenge at the frontiers of research.
In particular, the natural EVs were so far isolated and deeply characterized, finding innovative approaches to characterize them from the targeting behaviour. Novel high-resolution biological techniques combining super-resolution microscopy and flow cytometry, proteomics analysis and multiscale simulations were developed and assessed to understand the targeting capabilities of natural EVs derived from tumor cells. Nanocapsules, nanocages and nanogels were prepared, functionalized and labelled with different dyes. Concerning the artificial EV-mimics, they are core-shell structures with smart features allowing a stimuli-responsive cargo release coated by a mobile, dynamic lipid bilayer shell, mimicking the functionalities of the natural EVs. Such EV-mimics are very promising at the moment to enable novel enzyme-based therapy against metabolic disease being tested in vitro and in vivo.
The breakthrough idea of artificial EV-mimics, using only essential building blocks and amplifying their therapeutic functions, will overcome the current limitations of natural EVs and represent a challenge at the frontiers of research.
Within this project, the consortium is greatly advancing the current state of the art knowledges from different perspectives. Actually, from the biological point of view, proteins that are essential for EVs tropism to specific tissues are under discovery, but also the novel methodology which enables to identify them has been fully set. Furthermore, high resolution microscopy and flow cytometry techniques are enabling an unprecedent discovery of the proteins at EVs surface and same techniques are also available for the novel EV mimics and to evaluate their targeting and cargo transport functionalities. The teams are also exploring the dynamics of phospholipids once self-assembling in a lipidic bilayer as a vesicle or on a top of hard surface and has greatly advanced in the knowledge of which physical and chemical parameters are affecting the lipid behavior, fluidity, dynamics and rearrangements.
Concerning the formulation of EV-mimics, different solutions were studied and set, allowing to produce smart nanoparticles being highly reproducible even in high scale production, colloidally stable in aqueous and biological media up to in vivo environment, and reacting to specific endogenous stimuli. Furthermore, lipids formulations fairly mimicking at increasing levels of complexity are under development enabling to achieve an on demand, stimuli responsive platform with all the key and essential components to mimic the natural EVs with a fully artificial nanoconstruct.
Ad hoc in vitro and in vivo models have been established and specifically set to test the efficacy of the proposed approach towards bone metabolic diseases.
It is therefore clear the importance of the proposed research in different fields, from academic and scientific to industrial and socio-economic ones. First of all, the impact on healthcare is highly important, being the proof of concept of the present project designated to solve a rare disease and try to cover the gap over un unmet clinical need. Furthermore, the discovery on the key features enabling metastatic potential in EVs will advance enormously the knowledge on cancer metastasis and related diagnostic and therapeutic approaches. From a scientific point of view, the consortium is confident that a new class of advanced smart and biomimicking nanotools is under development, opening new horizons in nanomedicine and in many adjacent fields. From an industrial point of view, the production of standardized, purified, clinical grade artificial EV-mimics will positively impact on the pharmaceutical and biomedical industries. In a future perspective, the impact on the nano- and personalized medicine and the clinical translation is highlighted, but also the benefit for the society with the generation of new trends in pharmacology. The test-bed EV-mimics can also enable the extension of the design principles, as well as the imaging and analysis techniques to other nano-objects (e.g. proteins assembly, virus-like particles, polymeric or surfactant micelles), to develop a diverse library of materials and transfer concepts to corresponding disciplines, such as biophysics, polymer physics, synthetic chemistry, and nonequilibrium statistical mechanics.
The newly enabled technology can impact beyond clinical applications in the markets of cosmetics, paints and composite formulations. In general, the proposed research can in future bring to vast new job opportunities for highly skilled specialists in data analytics, modelling, synthetic chemistry, biology and translational medicine.
Concerning the formulation of EV-mimics, different solutions were studied and set, allowing to produce smart nanoparticles being highly reproducible even in high scale production, colloidally stable in aqueous and biological media up to in vivo environment, and reacting to specific endogenous stimuli. Furthermore, lipids formulations fairly mimicking at increasing levels of complexity are under development enabling to achieve an on demand, stimuli responsive platform with all the key and essential components to mimic the natural EVs with a fully artificial nanoconstruct.
Ad hoc in vitro and in vivo models have been established and specifically set to test the efficacy of the proposed approach towards bone metabolic diseases.
It is therefore clear the importance of the proposed research in different fields, from academic and scientific to industrial and socio-economic ones. First of all, the impact on healthcare is highly important, being the proof of concept of the present project designated to solve a rare disease and try to cover the gap over un unmet clinical need. Furthermore, the discovery on the key features enabling metastatic potential in EVs will advance enormously the knowledge on cancer metastasis and related diagnostic and therapeutic approaches. From a scientific point of view, the consortium is confident that a new class of advanced smart and biomimicking nanotools is under development, opening new horizons in nanomedicine and in many adjacent fields. From an industrial point of view, the production of standardized, purified, clinical grade artificial EV-mimics will positively impact on the pharmaceutical and biomedical industries. In a future perspective, the impact on the nano- and personalized medicine and the clinical translation is highlighted, but also the benefit for the society with the generation of new trends in pharmacology. The test-bed EV-mimics can also enable the extension of the design principles, as well as the imaging and analysis techniques to other nano-objects (e.g. proteins assembly, virus-like particles, polymeric or surfactant micelles), to develop a diverse library of materials and transfer concepts to corresponding disciplines, such as biophysics, polymer physics, synthetic chemistry, and nonequilibrium statistical mechanics.
The newly enabled technology can impact beyond clinical applications in the markets of cosmetics, paints and composite formulations. In general, the proposed research can in future bring to vast new job opportunities for highly skilled specialists in data analytics, modelling, synthetic chemistry, biology and translational medicine.