Periodic Reporting for period 2 - VAHVISTUS (Integrative development of smart drug-vector nanostructures for adaptive delivery to target cells) Reporting period: 2019-03-01 to 2022-02-28 Summary of the context and overall objectives of the project International and multidisciplinary VAHVISTUS project addressed research and innovation staff mobility, knowledge sharing, new skills acquisition, and career development. The Project focused on a two-dimensional mobility: international and intersectoral. The Consortium was created for integrative development of smart drug-vector nanostructures (DVNs), which can be used for adaptive delivery of active substances into the target tumour or parasite infected cells. The ambitious scientific objectives were achieved through intensive continuous knowledge sharing between the participants.Nanostructures for targeted drug delivery have attracted increasing attention owing to their ability to improve the efficacy and enhance bioavailability of pharmacetically active compounds (PhACs), control their release and provide a possibility to target cells. The Project challenged and resolved many technical problems associated with the synthesis and composition of the nano-assemblies, their uptake into the target cell and efficient adaptive payload release.Project objectives- The principal objective of VAHVISTUS is to strengthen the existing international collaborations between the Consortium Partners and to establish new long-lasting international and intersectoral ones, to provide knowledge sharing, to enable exchanges of research and innovation staff, and to create an intercontinental network in the area of smart DVNs for adaptive delivery to target cells;- The main scientific objective consists in the integrative development of drug-vector nanostructures for adaptive delivery into the target cells to influence the SP compartments, to monitor the DVN behaviour inside the cell. Thus, the DVN will suppress the PV formed by protozoan parasites inside the infected mammalian cell or to affect the SP in order to initiate the cell demise in tumour cells.- The key innovation objective of Project is to establish a creative multicultural interdisciplinary environment for the development of smart DVNs for adaptive delivery through shared culture of research and innovation, cross-fertilisation of ideas, international and intersectoral staff exchanges and transfer of knowledge and ideas from research to market.VAHVISTUS project is highly relevant to the society, it is devoted to the development of new treatments for neglected tropical diseases (NTDs) and cancer.The Project strengthened already established international collaborations and built a new network with the academic partners from the USA and Morocco as well as industrial partner Farmak (UA).VAHVISTUS developed joint research and innovation activities, accompanied by knowledge sharing during well-balanced international and intersectoral mobility. The researchers developed abilities to appreciate the value of good scientific practice and the role of science in preserving human dignity and life. VAHVISTUS opened possibilities for the ESRs to perform training, to develop competences, to become aware of socially relevant areas; to discover new cultures, habits and life-styles; to strengthen values like solidarity, democracy, and friendship. Communication and dissemination activities, as well as exploitation of results were crucial within the VAHVISTUS. The Project results will enhance the competitiveness of European pharmaceutical industry, health care, and higher education. Five project workshops were organised in Finland, Ukraine, Morocco, Brazil , and Italy. In June 2018, Summer School on Smart Nanomaterials for Drug Delivery was successfully organised on the island of Capri (NA), Italy. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Synthesis and characterisation of PhACs was planned to have several different approaches to the development of new synthetic and natural compounds. New 2-(1,3-benzoxazol-2-yl)-4-[(2-hydroxyphenyl)amino]-1,3-dimethyl-1H-imidazol-3-ium chloride was found to completely suppress L.amazonensis promastigotes and was considered as the “hit” for further structural modification and activity reinforcement. A series of previously unknown heterocycles with a spiroindolone fragment (3-indolin-2-one) have been prepared as the potential anti-parasite substances. The Consortium realised complete synthesis of water-soluble alkaloid ellipticine derivative and obtained water-soluble zerumbone compounds. Discovery, isolation, and characterisation of several natural PhACs of ethnomedical plant origin (alkaloid N-methymaitenine, polyphenolic extracts) possessing high anti-proliferation activity coupled with a range of other biological properties (immunomodulatory, enzyme inhibition, antibacterial, etc. activities) was an outstanding achievement.From the library of 1800 structures 50 top-scored compounds were selected for the synthesis by means of molecular docking. The interactions of Sb2O5 nanoparticles (model drug-vector nanostructure, DVN) with trypanothione (a peptide present in Leishmania cells) were modeled at the high level of theory using a medium-sized Sb cluster. The results provided a possible explanation of the Sb-DVN drug action mechanism.A reliable synthetic platform for obtaining of different drug-vector nanostructures (Sb5+, Bi3+, Nb5+, Ta5+) based on original controlled hydrolysis and co-precipitation procedures was developed and validated in the relevant environment. The Bi3+ DVN development was particularly valuable.A series of amphiphilic thermo- and pH-responsive PFG copolymers suitable for self-assembly, encapsulation, and triggered release of PhACs were obtained. Linear porphyrin-based RAFT homo-polymers and block copolymers were developed to prepare PEI-functionalized PHB nanoparticles as highly efficient miRNA delivery vectors for prostate cancer therapy. The copolymer manufacturing protocols were scaled-up, optimised, and validated in the relevant environment.Principal achievements of the Consortium relate to the establishment of high efficiency of Bi3+ and polymer DVNs in treatment of leishmaniasis and cancer as well as high anticancer activity of some synthetic and ethnomedical natural PhACs.Results were published in 19 open access scientific articles, presented at several conferences and workshops. Consortium has 2 patents (UA) and 1 patent application (BR). Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Development of new drugs against NTDs is currently of great importance. The encapsulation efficiency of stimuli-responsive PFG-DVNs turned out to be 96.8%, which is higher than the values reported until now. The DVN made of PFG30 containing retro-2cycl (R2) significantly reduced the EC50, when compared to the conventional drug. Sb5+ and Bi3+ -based DVNs have no analogues in the art possessing a spectacular leishmanicidal activity of IC50 < 46.0 nM, which is several orders of magnitude lower than that of commercially available drugs.For the first time, high antileukemic activity was discovered in ethnomedical PhACs, the alkaloids on A.panurensis and polyphenolic extracts from Mediterranean plants.The Consortium’s innovation is protected by 2 Brazilian patents. Innovative treatment of the NTDs with INMs would significantly reduce the dose and side effects of toxic drugs, will improve their administration. The project results will have a huge socio-economic impact, bearing in mind that both cancer and neglected tropical diseases affect millions of people all over the world.The VAHVISTUS project was a perfect bridge between academic science and industry, which has invaluable practical benefit for the future use of its results. VAHVISTUS Consortium logo
