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Description
Hearing impairment can be caused by different factors which induce an irreversible hearing loss. Several administration routes for the inner ear treatment are possible, but injection through the tympan directly into the inner ear can bypass the blood labyrinth barrier and lead to higher drug concentration in the inner ear fluids. Unfortunately, large amounts of drugs are eliminated by the internal components of the inner ear. The main objective of this project is the preparation of drug-loaded systems with very low sizes capable of dual active targeting: (i) under the action of a magnetic external field, and (ii) internalizing in the inner ear specific cells. Specific objectives of the project are: (i) Synthesis of both natural polymer with a low molecular weight and magnetic nanoparticles, modification of the natural polymer with some peptides; (ii) Preparation of vesicles from fats which are protected at the exterior by a layer of natural polymer; the same natural polymer will be used for the preparation of other type of vesicles with magnetic nanoparticles included in their core; (iii) In vitro testing of these vesicles. The obtained results will be disseminated in 6 ISI articles, 12 participations at international conferences and 4 bilateral workshops. The project intends not only to achieve scientific results but also to allow the development of a technology capable of producing drug delivery systems for hear deficiency at a large scale and accessible at a reasonable cost. The results are of a great interest to the medical doctors and to patients as a viable alternative for the treatment of the hearing deficiency. Moreover, we anticipate that these results will contribute to the development of the biotechnology field and will have an important practical potential as the elaborated technology will be able to be translated to a pilot and even industrial level. This project will enhance the scientific visibility of the three partners at European level.
Summary of project results
Irreversible hearing loss is due to various factors, such as: genetic defects, environmental factors or a combination of both. The classic treatment of these ear diseases involves the administration of the drug, either systemically or locally by intratympanic injection or even directly into the cochlea. Targeted drug delivery has recently been introduced to treat sensorineural hearing impairments associated with hair cell pathology. In recent years, two possibilities for targeting these inner ear-specific cells have been studied: directing the magnetizable drug carrier and concentrating it to the target site with the help of an external magnetic field, or functionalizing the drug carrier with specific ligands capable of being recognized by ear specific cell receptors. The main objective of this project consisted in the preparation of magnetic nanocarriers functionalized with drug-loaded peptides, capable of dual active targeting: under the action of an external magnetic field and internalization in the inner ear of specific cells due to peptide ligands. Two new types of nanocarriers were studied in this project, such as oligochitosan-based nanocapsules and oligochitosan-coated liposomes. The in vitro tests proved the validity of the starting idea and their applicative potential, which must be validated by in vivo tests in a future project.
The main activities implemented within the project are the following:
1.The synthesis of precursors necessary for the preparation of nanocarriers : [poly(N-vinylpyrrolidone-alt-itaconic anhydride) (poly(NVPAI), chitosan functionalized with Tet1 and TAT peptides and magnetic nanoparticles. Poly(NVPAI) copolymer was synthesized by classical solution/suspension radical copolymerization method. To ensure the targeting of inner ear cells, oligochitosan was functionalized with ligands capable of being recognized by inner ear cells (through the existence of specific receptors located in their membrane).
2. Synthesis and characterization of peptide-functionalized magnetic nanocarriers loaded with dexamethasone;
3. Evaluation of in vitro behaviour of peptide-functionalized magnetic nanocarriers loaded with dexamethasone;
The results show that the release efficiency of dexamethasone from the capsules was between 74% and 99.8% and from the liposomes was between 13% and 40%, after 24 hours. All analyzed nanoparticles showed hemolysis degrees lower than 3%, which demonstrated their non-hemolytic character. The viability and morphology tests on different cell lines depended on the administered dose and after a 48-hour treatment, all analyzed nanoparticles showed a non-toxic, weak or moderately cytotoxic effect. The results of the research were promising and allowed the conclusion that the designed system can be an important alternative to the traditional treatment of inner ear diseases.
The researches carried out have led to important results, first of all in scientific terms, contributing to the development of the field of nanomedicine by publishing 5 papers and presenting 15 scientific communications at internal and especially international events, which were well appreciated by the international scientific community. In terms of application, although the research must be continued with in vivo tests and later on human patients, we estimate that the results are important from two points of view. A new way of formulating medicines for the treatment of inner ear diseases is proposed, which could be taken over for industrial production by interested pharmaceutical companies. Secondly, an alternative treatment to the classical one is proposed to prevent and treat the problems of infection and damage to the cells of the inner ear that eventually lead to deafness, the main beneficiaries being the patients with such problems. The application of the systems developed in the framework of our research could reduce the costs and duration of the treatment, increase its effectiveness and the compliance of the patients, with obvious beneficial effects on the social level.
Summary of bilateral results
The partnership that contributed to solving this topic was conceived from the very beginning based on the complementarity of the two research teams. The collaboration was based on mutual respect, the bilateral information continues throughout the duration of the project, the presentation of the results obtained at different stages either through periodic "online" meetings or through the 4 workshops in which the balance of the results obtained was usually made on over the course of a year, the difficulties that arose over time were discussed and measures were proposed that proved beneficial for solving them. This partnership was established in a model of bilateral collaboration between specialists coming from two friendly countries, and it indisputably contributed to its strengthening.