The overall objective of the project consists of obtaining micro/nanoparticles of covalently crosslinked hydrogels based on polyethylene glycol and aliphatic polyamines (injectable micro/nanogels) having embedded both natural nanozeolites but also of natural bioactive substances in their polymer structure, with potential pharmaceutical applications. These new micro/nanogel composite structures are of great interest as they are aimed at being used as devices for subcutaneous or intravenous injection, ensuring the release of bioactive substances in hard-to-reach areas (by macroscopic hydrogels). The role of natural nanozeolites incorporation is to allow for a much slower and controlled release of the embedded active substances and to improve the viscoelastic features of hydrogels. Nowadays bioactive substances play an important role in the development of controlled release systems in medicinal chemistry for the production of new drugs with fewer side effects. The use of phytoextracts as bioactive substances is a big challenge of the project proposal. These new micro/nanodevices with controlled release will have significant influence, both nationally and internationally on the scientific, social and economic field. The results will be disseminated as follows: three articles published in ISI journals; three scientific communications at international conferences, and patenting of any original aspect.

Novelty and originality of the proposal consist of the obtaining of covalently crosslinked micro/nanogels based on polyethylene glycol and aliphatic polyamines that will contain nanoparticles of natural zeolite and natural bioactive substances from phytoextracts in their polymer structure. Natural zeolites exhibit various biological activities, being successfully used as compounds which activate the action of a drug (anti-cancer therapy, vaccine, etc.). The role of natural nanozeolites incorporation is to allow for a much slower and controlled release of the embedded active substances and improving the viscoelastic properties of hydrogels. It is also well known that zeolites play also a surfactant role. By placing them in the inverse emulsion polymerization, zeolites can act as a surfactant or co-surfactant making it possible to obtain nanoparticles. Bioactive substances from medicinal herbs have a significant role in the treatment of acute and chronic diseases, such as cancer, AIDS, hepatitis and acute kidney diseases. Nowadays bioactive substances play an important role in the development of controlled release systems in medicinal chemistry for the production of new drugs with fewer side effects. Limitations of this project consist of the fact that these controlled release systems will be tested only in simulated environments. In vivo tests will be carried out within forthcoming innovation type projects.

The specific objectives of the project BIOGELFARM are the following:

The synthesis and characterization of new structures of composite micro/nanogels able to transport and controllably release the embedded bioactive natural substances. The aim of obtaining these new composite nanogel structures is to use them as devices for subcutaneous or intravenous injection, thus achieving the release of bioactive substances in hard-to-reach areas, or directly to the affected area. The results of the project are aimed at achieving the following objectives:

• O1. The first specific objective consists of the synthesis of new structures of composite micro/nanogels and of the swelling of hydrogels of polyethylene glycol and natural nanozeolites by polymerization in inverse micro/nano-emulsion method. It is desirable that they exhibit enhanced properties in terms of slow and controlled release of incorporated active substances and also improved viscoelastic properties.
• O2. A new objective consists of the physico-chemical characterization of new structures of micro/nanogels. They will be characterized in terms of morphology, thermal stability, and mechanical properties and also of their capacity to controllably release the embedded natural bioactive substances.
• O3. Another important specific objective is represented by the reproducibility of the results in order to establish the laboratory technology for the obtaining micro/nanogels used in controlled release, which will allow for a patent application in this direction.
• O4. Another important objective of the project, will consist of the dissemination of the obtained scientific results, namely: (i). obtaining prestigious scientific results reflected by an increase in the number of publications of high international impact; (ii). protection of intellectual property rights of authors by filing a patent application; (iii). participation in national and international conferences (at least three international conferences).

Getting new structures of micro/nanogels composite containing bioactive natural substances have significant potential in terms of research and development in chemistry and biomedicine. It is well known that the use of synthetic drugs has many side effects, thus the new systems of micro/nanogels for controlled release of bioactive natural substances; significantly reduce harmful effects on the human body. The main advantages of the controlled release of the active ingredient, compared to the conventional administration, consist of a sustained release of active ingredient over a longer period of time and in a concentration in the desired range so as to be used efficiently. This leads also to savings in active principle. Therefore, scientific impact, along with finally getting new controlled release of nanodevices will have significant influence, both nationally and internationally on the scientific, social and economic domain. Social effects consist of attracting PhD students and doctors in research alongside with experienced researchers in the field who will be part of this project team. Developing innovative technology for obtaining and implementing of new nanosystems for controlled release of bioactive natural substances will provide: (i). new devices with improved controlled release of the active substance; (ii). new devices that may have a strong social impact (health, economy and quality of life). Therefore, by financing this project, it is desired to establish synergy between research, biomedicine and medicinal plant processing companies.

Phases 1. Preliminary studies on the synthesis and characterization of simple micro/nanogels based on polyethylene glycol and aliphatic amines.

Phase period: 01.10.2015 – 30.12.2015

Phases 2. Synthesis and characterization of injectable composite micro/nanogels based on polyethylene glycol, aliphatic amines and encapsulated nanozeolites

Phase period: 31.12.2015-30.12.2016

Summary of phase 2: In this phase, novel micro/nanogel composites were obtained. The synthesis protocol of the micro/nanogels was optimized for parameters such as hydrophilic to lypophilic balance, solvent to aqueous phase ratio, emulsifier system to aqueous phase ratio and starting macromonomer. Furthermore, in case of the composites, the weight percentage of the nanozeolite was also varied, following that in the next stage the effects of this variation would reflect on the incorporation and release properties of the compounds.

The compounds were characterized in terms of particle size and size-distribution by means of dynamic light scattering technique in emulsion, their morphology was studied by transmission electronic microscopy and structurally they were analyzed by infrared spectroscopy.

A laboratory technology for the obtaining of micro/nanogel composites for slow release of bioactive compounds was formulated and proposed, detailing step-by-step the synthesis, work-up and storage recommendations of the products.

Phases 3.

The results of stage 2 were presented by team members within the framework of several scientific manifestations (participation at different national and international conferences), such as:

1. “Hydrogels for controlled delivery of biologically active substances”, Catalina-Paula Spatarelu, Anamaria Zaharia, Anita-Laura Radu, Tanta-Verona Iordache, Ana-Mihaela Florea, Teodor Sandu, Andrei Sarbu, Mircea Teodorescu, Conferinta 5th Portuguese Young Chemists Meeting (5th PYCheM) and 1st European Young Chemists Meeting (1st EYCheM), 26-29 Aprilie 2016, Guimaraes, Portugalia
2. “Synthesis paths for micro-hydrogels containing polyethylene glycol and aliphatic amines”, Anita-Laura Radu, Anamaria Zaharia, Bogdan Cursaru, Catalina-Paula Spatarelu, Tanta-Verona Iordache, Ana-Mihaela Florea, Raluca Ianchis, Teodor Sandu, Andrei Sarbu, Mircea Teodorescu, Conferinta 5th Portuguese Young Chemists Meeting (5th PYCheM) and 1st European Young Chemists Meeting (1st EYCheM), 26-29 Aprilie 2016, Guimaraes, Portugalia
3. "L'obtention des hydrogels pour des systèmes a libération contrôlée", Catalina Paula Spatarelu, Anita-Laura Radu, Anamaria Zaharia, Bogdan Cursaru, Tanta-Verona Iordache, Ana Mihaela Florea, Raluca Ianchis, Teodor Sandu, Andrei Sarbu, Mircea Teodorescu, Le Neuvieme Colloque Franco-Roumain de Chimie Appliquee, 29 Iunie-2 Iulie 2016, Clermond-Ferrand, Franta
4. "Hydrogels composites innovatrices pour la liberation controlee des engrais chimiques", Anita-Laura Radu, Anamaria Zaharia, Catalina Paula Spatarelu, Andrei Sarbu, Tanta-Verona Iordache, Ana Mihaela Florea, Teodor Sandu, Stela Iancu, Anicuta Stoica, Marta Stroescu, Le Neuvieme Colloque Franco-Roumain de Chimie Appliquee, 29 Iunie-2 Iulie 2016, Clermond-Ferrand, Franta
5. « Modelling the separation of algae extracts by a coupled ultrafiltration/pervaporation process », Bogdan Trica, Tanase Dobre, Gholamreza Djelveh, Raluca Somoghi,Le Neuvieme Colloque Franco-Roumain de Chimie Appliquee, 29 Iunie-2 Iulie 2016, Clermond-Ferrand, Franta
6. "Influence of synthesis parameters on the obtaining of PEG covalently cross-linked nanogels", Catalina-Paula Spatarelu, Anita-Laura Radu, Anamaria Zaharia, Bogdan Cursaru, Andrei Sarbu, Tanta-Verona Iordache, Ana-Mihaela Florea, Bogdan Trica, Teodor Sandu, 14th Young Chemists’ Congress (YOUNGCHEM), 5-9 Octombrie 2016, Czestochowa, Polonia
7. ”Hybrid hydrogels based on bio and synthetic polymers with applications in agriculture”, Anita-Laura Radu, Anamaria Zaharia, Catalina Paula Spatarelu, Andrei Sarbu, Tanta-Verona Iordache, Ana Mihaela Florea, Teodor Sandu, Stela Iancu, 14th Young Chemists’ Congress (YOUNGCHEM), 5-9 Octombrie 2016, Czestochowa, Polonia
8. “Obtaining of new nanogels for controlled delivery of biologically active substances”, Bogdan Cursaru, Catalina-Paula Spatarelu, Anita-Laura Radu, Anamaria Zaharia, Andrei Sarbu, Tanta-Verona Iordache, Ana-Mihaela Florea, Bogdan Trica, Teodor Sandu, Mircea Teodorescu, XXXIX-th Romanian Chemistry Conference, 4-7 Octombrie 2016, Caciulata, Romania

Moreover, a patent application was filed, entitled “Nanohydrogels for the slow release of drugs and their synthesis procedure”,Authors: Anamaria Zaharia, Anita-Laura Radu, Andrei Sarbu, Mircea Teodorescu, Bogdan Cursaru, Paula Catalina Spatarelu, Tanta- Verona Iordache, Sandu Teodor, Ana Mihaela Florea;  OSIM Request:  A 2016 -00620 / 07.09.2016.

Also the paper entitled “Advanced poly(ethylene glycol) diacrylate-nanogels designed for drug release of bioactive substances”, Anita-Laura Radu,Catalina Paula Spatarelu, Bogdan Cursaru, Tanta-Verona Iordache,Ana-Mihaela Florea, Raluca Ianchis, Bogdan Trica, Teodor Sandu, Andrei Sarbu,Mircea Teodorescu, Anamaria Zaharia^*, was submitted for evaluation and possible publication in Reactive and Functional Polymers Journal, IF : 2.7