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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - VAHVISTUS (Integrative development of smart drug-vector nanostructures for adaptive delivery to target cells)

Teaser

Summary

International and multidisciplinary VAHVISTUS project addresses research and innovation staff mobility, knowledge sharing, new skills acquisition, and career development. The Project focuses 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 integrative development includes computer modelling, synthesis, nanoformulation, in vitro and in vivo testing, bioassays feedback, and optimisation. Intersectoral collaboration will bring those materials and ideas closer to applications and to the market. The ambitious scientific objectives will be 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 PhACs, control their release and provide a possibility to target cells. However, the nanomedicine is still in the early state. The above possibilities will be extended to the development of adaptive delivery to target cells, to subsequent interaction with the secretory pathway (SP) involving pH or red/ox triggered release. Thus, a suppression of parasitophorous vacuoles (PV) formed by a protozoan parasite inside the infected cell will be activated. Influence on a tumour cell SP will activate the cell demise mechanism. The Project will challenge and resolve 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 will strengthen already established international collaborations within FP7-PEOPLE-IRSES VAIKUTUS project. VAHVISTUS will also build a new network of international cooperation with the academic partners from the USA and Morocco, as well as will establish intersectoral cooperation with industrial partner Farmak (UA).
VAHVISTUS will develop joint research and innovation activities, accompanied by knowledge sharing during well-balanced international and intersectoral mobility. The Consortium has experience in synthesis of biologically active substances and nanoparticles (IOC, EOK, Farmak); in the development of stimuli-responsive nanocarriers (EOK, ICTP); in quantum-chemical modelling of the active compounds and nanoparticles (IOC, UIT); in comprehensive biological testing (INPA, UFL); in scaling up and validation of proposed technologies (Farmak). All the above will take place during international and intersec

Work performed

From the library of 1800 structures 50 top-scored compounds were selected for the synthesis by means of molecular docking. The interactions of Sb2O5 nanoparticle with bioimportant organic molecules were modeled at the DFT level of theory using a medium-sized cluster involving 16 Sb atoms. The water soluble and previously unknown derivatives of ellipticine and zerumbone, novel pentamidine analogues were prepared and their biological activity was tested. 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 â€œhitâ€ 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.
A reliable synthetic platform was developed and validated in the lab for obtaining of different INMs, based on original controlled hydrolysis and co-precipitation procedures. The INMs obtained were treated with above mentioned PhACs and were successfully tested in vitro and in vivo against L.guayanensis and L.amazonensis.
A series of amphiphilic thermoresponsive polymers capable to thermally-triggered self-assembly behavior were obtained. PhAC Retro-2cycl (R2) and Nile Red (NR) dye were encapsulated to evaluate biomedical applications. Raw264.7 murine macrophages infected with L.donovani were sucessfully treated.

Final results

Development of new drugs against NTDs is currently of great importance. Several prospective hits will be proposed as potential anti-malarial and anti-leishmanial drugs. Lead structures will be looked for using molecular docking. In stimuli-responsive loading and release of PhACs from nano-carriers, the encapsulation efficiency of the PFG copolymers turned out to be 96.8%, which is higher than the values reported until now. Further activity will be addressed on the assessment of the maximum loading capacity of the polymers and INMs. The DVN made of PFG30 containing retro-2cycl (R2) significantly reduced the EC50, when compared to the conventional drug.
There are no analogues in the art for pH-responsive INMs, a new class of stable nano-carriers that can be used both for topical and systemic treatment of parasitoses and tumours. The Consortiumâ€™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 above will have a huge socio-economic impact,since 1/6 of the world population is affected by the NTDs.