Periodic Reporting for period 1 - DIRNANO (Directing the immune response through designed nanomaterials)
Período documentado: 2020-10-01 hasta 2022-09-30
The project deals with effective application of nanoparticles (NPs) for drug-gene delivery, therapy and diagnosis. Despite initial promises, NPs have proven to be under the expectations (relatively low patenting delivery and product market release). Although the success of anti-COVID nanovaccines has given some hope, we must understand the reasons of such difficulty. We focus on the innate ability of our body to scrutiny and clear NPs. If we could understand the chemical characteristics and the host agonists to ensure immunity evasion, we would have eliminated a major obstacle for future nanotheranostics development.
We want to speed up the formulation of NPs to reveal and treat high mortality human pathologies, so contributing to new technologies, based on NPs for mRNA delivery and gene therapy. The overall effect would be also positive on the pharma-industry economy and social general well-being in the european area.
We want to generate, screen, and study innovative nanosystem vectors and coatings, to “govern” their interaction with the immune system. This will help the rational design of immune-targeted NPs for anti-tumour vaccine and Tumour Associated Macrophage (TAM) modulation for indirect anticancer actions or of long-circulating safe-by-design nanovectors for effective drug delivery. We investigate several innovative polymers and lipids coats and their recognition by proteins and immune agonists. This will establish a mechanistic manipulation and a safe-by-design NPs. In vitro and in vivo studies will consolidate the structure-efficacy relationship for phagocyte escape and long-circulation of nonorthographic, antitumor actions via modulation of TAM or through affective anti neoplastic nanovaccines and dendritic cell targeting. NPs constructions (e-g- liposomes) will benefit from green sustainable chemistry procedures. To date the foreseen tasks of NP design and synthesis and host-nano biomolecular /immune interaction have reached a maturation stage. The effort of all actors and effective mitigation strategies allowed phD students potential expression.
We want to speed up the formulation of NPs to reveal and treat high mortality human pathologies, so contributing to new technologies, based on NPs for mRNA delivery and gene therapy. The overall effect would be also positive on the pharma-industry economy and social general well-being in the european area.
We want to generate, screen, and study innovative nanosystem vectors and coatings, to “govern” their interaction with the immune system. This will help the rational design of immune-targeted NPs for anti-tumour vaccine and Tumour Associated Macrophage (TAM) modulation for indirect anticancer actions or of long-circulating safe-by-design nanovectors for effective drug delivery. We investigate several innovative polymers and lipids coats and their recognition by proteins and immune agonists. This will establish a mechanistic manipulation and a safe-by-design NPs. In vitro and in vivo studies will consolidate the structure-efficacy relationship for phagocyte escape and long-circulation of nonorthographic, antitumor actions via modulation of TAM or through affective anti neoplastic nanovaccines and dendritic cell targeting. NPs constructions (e-g- liposomes) will benefit from green sustainable chemistry procedures. To date the foreseen tasks of NP design and synthesis and host-nano biomolecular /immune interaction have reached a maturation stage. The effort of all actors and effective mitigation strategies allowed phD students potential expression.
We successfully identified NPs with decreased protein binding (e.g. polymer cyclization, dendrimer molecular spacing). In specific cases we spot human serum corona agonists. We prepared sets of NPs where selected chemical features candidate to be the targeted by sentinel proteins were tested in non-homogenous coats.We combined polymer conditioning of nanoparticle surfaces to achieve staple tightly-packed long-chain random-coil configuration to minimize statistical protein intercalation/binding. Several polymer types (linear, branched, dendrimer or cyclic), having variable length and/or charge have been conceived and synthesised in the network. Most of them are already part of NP coatings, and few are ready for this. Physisorption of model proteins or complex mixtures have been investigated after coating of bulk or nano-materials. In specific cases the creation of heterogeneous coatings, starting from such chemicals, have been studied in vitro to assess the effect on protein adsorption, complement activation in sera and their capture by phagocytes and dendritic cells.
We selected two lists of promising coating candidates for better stealthing nanosystems or better immune targeting/nano vaccines NPs. To introduce pathway-specific complement inhibitors we made considerable progress and identified human protein agonists acting on defined chemical coats. These are amenable for cloning, antibody production and mutation to down or up-modulate immune recognition and opsonization for phagocytes and immune-triggering dendritic cells.
In this perceptive we also studied possible misleading preclinical-human extrapolations in NP medical translation by understanding species-specific NP immune recognition mechanisms.
We successfully initiate to study the therapeutic efficacy of drug and photosensitizer-carrying NPs targeting cancer and are proceeding in the goal of modulating tumor microenvironment immunosuppressive cells (e.g. TAM) using specific chitosan-based nanoformulations.
To improve the targeting of dendritic cells by tumour neoantigens-coupled NPs and the antitumor nanovaccination efficacy we already evaluated a first generation nanovaccine platform in a vaccination campaign, based on tumor specific peptides used as antigens. Although relevant antibody titre was obtained, we are already creating new 2nd generation nano-vaccines with improved immune delivery and adjuvancy.
We engaged in developing new green chemical synthetic methods for sustainable generation of complement inhibitors. Cholesterol analogues for liposomes but with reduced complement triggering potential were produced by chemistry protocol based on the use of the fungi.
We posed the base for the optimal progress of future project-works and career of ESR in both industry/private and academic/public sectors. An intersectoral environment was achieved, through the implementation of foreseen actions. Intersectoral secondments and collaborations were organized and in part already realized. We offered a Business School Class accompanying the rest of the project. ESRs benefited from the contact with R&Ds local and network-wide.
Management goals were satisfactorily implemented. Network organs were created, external advisors appointed, ensuring administrative, technical and scientific governing.
We developed nanoassembly strategies ahead the present scenario. A set of branched, dendrimer layer-by-layer and cyclic polymer formulations, and lipid-based coats, and their combination in heterogenous ways, is under the focus of a large interdisciplinary scientist’s pool. This created a unique environment in itself. The in-depth functional study of the corona provided brand new information on unexcepted agonists of the human body which could direct NPs efficacy.
We selected two lists of promising coating candidates for better stealthing nanosystems or better immune targeting/nano vaccines NPs. To introduce pathway-specific complement inhibitors we made considerable progress and identified human protein agonists acting on defined chemical coats. These are amenable for cloning, antibody production and mutation to down or up-modulate immune recognition and opsonization for phagocytes and immune-triggering dendritic cells.
In this perceptive we also studied possible misleading preclinical-human extrapolations in NP medical translation by understanding species-specific NP immune recognition mechanisms.
We successfully initiate to study the therapeutic efficacy of drug and photosensitizer-carrying NPs targeting cancer and are proceeding in the goal of modulating tumor microenvironment immunosuppressive cells (e.g. TAM) using specific chitosan-based nanoformulations.
To improve the targeting of dendritic cells by tumour neoantigens-coupled NPs and the antitumor nanovaccination efficacy we already evaluated a first generation nanovaccine platform in a vaccination campaign, based on tumor specific peptides used as antigens. Although relevant antibody titre was obtained, we are already creating new 2nd generation nano-vaccines with improved immune delivery and adjuvancy.
We engaged in developing new green chemical synthetic methods for sustainable generation of complement inhibitors. Cholesterol analogues for liposomes but with reduced complement triggering potential were produced by chemistry protocol based on the use of the fungi.
We posed the base for the optimal progress of future project-works and career of ESR in both industry/private and academic/public sectors. An intersectoral environment was achieved, through the implementation of foreseen actions. Intersectoral secondments and collaborations were organized and in part already realized. We offered a Business School Class accompanying the rest of the project. ESRs benefited from the contact with R&Ds local and network-wide.
Management goals were satisfactorily implemented. Network organs were created, external advisors appointed, ensuring administrative, technical and scientific governing.
We developed nanoassembly strategies ahead the present scenario. A set of branched, dendrimer layer-by-layer and cyclic polymer formulations, and lipid-based coats, and their combination in heterogenous ways, is under the focus of a large interdisciplinary scientist’s pool. This created a unique environment in itself. The in-depth functional study of the corona provided brand new information on unexcepted agonists of the human body which could direct NPs efficacy.
In the next two years, will test the nanoparticles candidates with best characteristics (coats, antigenicity and adjutancy) in vivo. We expect to obtain: 1) long-circulating stealth nanosystems outperforming the PEG-based 2) nano-vaccine with strong neoplastic antigen display and entering Antigen Presenting Cells capture, to increase “antitumor vaccination” efficacy. Targeting of TAM is also expected, to implement double anti-tumor strategies.
The impact on future trials and eventual market reach of some of our systems is expected to represent a breakthrough in nanomedicine cancer cure.
The parallel interdisciplinary and intersectoral formation of young researchers in this expanding technology, will contribute to the industrial and economic progress of the European area.
Articulated communication instruments and the outreach actions performed different publics and stake-holders will improve the awareness of society and next generations on the relevance of science and nanomedicine for socio-economic progress and human health. This will strengthen the possibility to grow new generations of scientists and businesswomen/men having a major understanding of science knowledge-based human progress.
The project will determine a general improvement of local phD schools in Europe, a general benefit of the overall educational systems competitivity.
The impact on future trials and eventual market reach of some of our systems is expected to represent a breakthrough in nanomedicine cancer cure.
The parallel interdisciplinary and intersectoral formation of young researchers in this expanding technology, will contribute to the industrial and economic progress of the European area.
Articulated communication instruments and the outreach actions performed different publics and stake-holders will improve the awareness of society and next generations on the relevance of science and nanomedicine for socio-economic progress and human health. This will strengthen the possibility to grow new generations of scientists and businesswomen/men having a major understanding of science knowledge-based human progress.
The project will determine a general improvement of local phD schools in Europe, a general benefit of the overall educational systems competitivity.