Design of multifunctional phosphorous dendritic systems for drug delivery

Dendritic molecules - dendrimers and dendrons - are hyperbranched macromolecules, composed of monomers associated radially from a central core. Due to their repetitive structure, dendritic molecules can be considered as polymers, but in contrast to polymers, they are never synthesized by polymerization reactions, but step-by-step in an iterative fashion, creating layers.
Dendrimers are widely used in different fields of science and technology, such as catalysis, materials chemistry and regenerative and cell biology. In particular, the last direction is highly emerging, since new innovative therapeutics are now required for modern medicine, with dendrimer exhibiting a number of prospective properties. When modified with hydrophobic moieties, dendrimers and dendrons can form supramolecular associates in water media. This is very useful for the delivery of poorly bioavailable bioactive molecules into cells.
The goal of the project is to develop novel dendrimer-based biomaterials for drug delivery and translational medicine.
The objectives of the project are:
1. Overall training – Trainings to make the Fellow a highly skilled independent researcher with a strong knowledge base
2. Multifunctional dendrimers and dendrons – Development of strategies to obtain dendritic systems bearing different functional groups
3. Self-organization of dendritic molecules – Study of the formation of supramolecular assemblies by the multifunctional dendrons/dendrimers.
4. Drug binding – Study of the drug complexation with cationic dendrimers and with the dendron-based supramolecular assemblies.
5. Biological effect – Screening of the biological properties of formulations obtained
6. Industrial application – Harmonizing the developments made and products obtained with industrial requirements for easier transfer into practice.
These objectives have been fully accomplished. The results obtained bring new, highly efficient therapeutic constructions for antitumor therapy. Furthermore, the project has set a background for future developments in the field, including production of novel therapeutics.

The project was oriented to the applied research in an emerging area – better therapeutics.
The project provided results having both fundamental and practical importance. The Fellow has designed several novel examples of different families of amphiphilic dendritic molecules and demonstrated their robustness as drug carriers into tumor cells. These results will serve as a basis for future development of the field of drug delivery by multi-functionalized hyperbranched systems and their assemblies. He has also developed a simple and efficient way to obtain neutral hydrogels impregnated with therapeutic dendrimer-based constructions, which can be used for local drug delivery.
The project has also produced results possessing an interest for the future industrial transfer. The intention of the Fellow to produce industry-compatible synthesis techniques was realized at the last stages of the project implementation. The synthesis of dendritic species can be also optimized for industrial-scale production, if their activity will be validated in future biological experiments. Furthermore, there were highly promising data on biological activity of metal-bearing amphiphilic dendrons towards glioblastoma stem-like cells. Since these dendrons possessed strong cytotoxic activity in contrast to the standard care drug temozolomide, the development of this direction can bring novel antitumor formulations.
As it was planned in the proposal, the dissemination was oriented towards different audiences, both to specialists and to general public.
The project results have been published in 5 research papers, 1 paper submitted.
The Fellow disseminated his findings in the COST NANO2CLINIC consortium (>260 teams from 42 countries), where he addressed to colleagues from different fields as well as to SME representatives. The Fellow is also administrator of the YouTube channel of the Consortium (https://www.youtube.com/channel/UCoj8Co96qGHBmAceQqkRDfg).
Furthermore, the Fellow took part in public activities French Science Festival “Fête de la Science 2020” (https://www.youtube.com/watch?v=pgnhqXFC6rk&feature=emb_logo) and European Researchers Night-2021 (https://exploreur.univ-toulouse.fr/voyage-au-coeur-des-nanomedicaments-avec-evgeny-apartsin) where he presented his work to the audience. To inform public about the progress of the project as well as about recent advances in dendrimer science, the Fellow created a Facebook page “Dendrimers at home” (https://www.facebook.com/dendrimersathome).
Finally, the Fellow decided that it is important to disseminate the most demonstrative results among students specializing in biomedical sciences and biomaterials design. To do this, he included some data obtained in the frame of the project into the lecture course “Biomaterials: properties, design, applications” that the Fellow delivers.

In this project, we designed novel smart soft materials based on dendrimers and dendrons for the antitumor drug delivery. The rational design of dendritic architecture permitted us to assemble in a controllable way nano- and macrosized materials containing bioactive low-molecular entities and macromolecules. The therapeutic potential of drug-loaded constructions has been validated in several models of aggressive tumors exhibiting drug resistance and thus requiring new means of therapy. Having proven the biological activity of dendritic-based formulations, we have optimized the chemical synthesis adjusting it for the needs of industry (simple synthesis and purification, large scale).
We expect that the result of the project will greatly contribute into the development of new, safe and efficient, nanotherapeutics for tackling tumors.

Periodic Reporting for period 1 - EUREKA (Design of multifunctional phosphorous dendritic systems for drug delivery)

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