Joint research project

Encapsulation of L-thyroxine onto the N-trimethyl iodine derivative of chitosan and biological investigation on its long-term controlled release in vivo. (BIOTEC)

Project leaders
Mariagrazia Raucci, Nizami Zeynalov
AZERBAIJAN - ANAS - Azerbaijan National Academy of Sciences
CNR/ANAS biennio 2018-2019 2018-2019
Chemical sciences and materials technology
Thematic area
Chemical sciences and materials technology
Status of the project

Research proposal

The scientific aim of the present proposal concerns the development of amphiphilic chitosan-based polymers able to incorporate and release a levothyroxin, increasing its therapeutic effect. The modified biopolymer will contribute to increase the drugs daily dose and reduce receiving frequency. It known, that thyroid gland has an important role in the normal functioning of the human body. However, thyroid gland diseases are an actual problem for our population. According to World Health Organizations data 300 million of world population are registered as sick from goiter and hypothyroidism and there no tendency to reduce this number.
Most of the patients under our observation are suffered from chronic inflammation of thyroid glands- chronic thyreoiditis (Hashimotos thyreoidit). Changes in the environment and the composition of the food, stress are important factors in the developing this disease. The diagnosis is based on patient complaints, laboratory tests and ultrasound examination.
Polymers are extensively used for the delivery of an active pharmaceutical ingredient. They can form a matrix or membrane that can control the release of a drug over a prolonged period, thus avoiding repetitive dosing. They can also be used to form (nano)carriers to deliver drugs, in particular poorly soluble drugs or biotechnology-based drugs. Both systems can protect the drug from degradation.
Several polymeric drug delivery systems such as nanoparticles, micelles, hydrogels, or matrices are being studied worldwide. The release of the drug usually occurs by diffusion through the polymer, by degradation of the polymer, or by disorganization of the supramolecular structure of the carrier.
Among all the polymers available to be used for drug delivery systems, (bio) degradable and biocompatible polymers are highly recommended. For all of these reasons, natural polymers such as polysaccharides(i.e. chitosan), polypeptides, or phospholipids are generally used as building blocks for the formulations. One of natural and biodegradable polymer is Chitosan that is a nontoxic, semicrystalline, biodegradable, and biocompatible linear polysaccharide of randomly distributed N-acetyl glucosamine and glucosamine units. It is possible to use amphiphilic copolymers for their double affinity for both hydrophilic and hydrophobic environments and are able to self-organize in water to form, in most cases, specific architectures such as micelles or vesicles, which can be used as carrier in drug delivery systems. Micelles as drug carriers provide a set of advantages, i.e., increase water solubility of sparingly soluble drug, improvement of bioavailability, reduction of toxicity, enhancement of permeability across the physiological barriers, and changes in drug biodistribution. Because intravenous injection of a micellar solution induces extreme dilution by blood, polymer micelles could disassemble and release the loaded drug. However, their critical micellar concentration and kinetic stability was usually higher than those of surfactant micelles. Hydrophobically modified chitosan derivatives have been designed to increase the solubility of poorly soluble drugs. However, chitosan is not optimal as the hydrophilic part of an amphiphilic self-assembling polymer because it is only soluble in acidic aqueous solutions with pH values lower than its pKa value (6.5). Hence, glycol chitosan has been used to synthesize new amphiphilic chitosan-based polymers. These amphiphilic glycol chitosan derivatives are expected to self-aggregate and to ensure the solubility of poorly soluble drugs with a better stability in physiological conditions than chitosan derivatives.
Structure of synthesized N-trimethyl chitosan iodide will be characterized by morphological (SEM, TEM) and physico-chemical (FTIR, XRD, DLS) analyses.
The biological studies, will be performed by using Nthy-ori 3-1 cells, a follicular epithelial Cell Line derived from human Thyroid, in order to evaluate the effect of levothyroxin released from N-trimethyl chitosan iodide on cellular behaviour in terms of vitality and production of T3 and T4 which are major thyroid hormone and its prohormone thyroxine, respectively.
The proposed project is particularly important to foster scientific collaboration between the two involved institutes whose expertise are exceedingly complementary. The team at Institute Catalysis and Inorganic Chemistry (ICIC, Baku-Azerbaijan) will offer its expertise and use of equipments for the synthesis and investigations of amphiphilic polymer. The team at Institute of Polymers, Composites and Biomaterials (IPCB-CNR Naples, Italy) will offer its expertise and use of equipments for the investigation of physico-chemical and release kinetics of levothyroxin as well as a Tissue Engineering&Cell Cultures laboratory for the evaluation of biological properties of biomaterials in terms of cytotoxicity, biocompatibility and bioactivity. This proposal in the biomedical field, improves health and quality of life, in particular reducing hospitalization and drug assumption, and will radically reduce health costs associated to thyroid diseases. BIOTEC will have major socio-economic potential benefits, particularly in terms of prolonging life and reducing the level of pain and suffering inflicted on patients. These aspects are due to development of biocompatible and biodegrable micelles able to increase the therapeutic effect of levothyroxine and to obtain a controlled release in human body. From a general point of view, the proposed challenging research activities represent the first important step for the establishment of a more comprehensive cooperation between the two institutions, which in the middle-term could allow the dissemination of the findings via the publication of the obtained results in high-impact internationally peer-reviewed journals as well as prestigious international conferences.

Research goals

The overall objective of BIOTEC is the development of the fundamental and technological knowledge for the rational designing, preparation and validation of glycol chitosan based-biopolymers able to self-aggregate and encapsulate the levothyroxine for the treatment of thyroid disease. In this way, it is possible an increasing of therapeutic effect of levothyroxine which will contribute to increase the drugs daily dose and reduce receiving frequency.
The main scientific objectives are the following:
- Synthesis and investigation of N-trimethyl chitosan iodide with levothyroxine able to obtain a right concentration in the blood;
- In vitro biocompatibility by using Nthy-ori 3-1 cells, a follicular epithelial Cell Line derived from human Thyroid
- Pharmacokinetic study of new forms of levothyroxin in blood prepared with biopolymer according to the level of TSH in the thyroidectomy rabbits.
From a strategic point of view, the BIOTEC is also aimed to:
- promote the exchange of permanent and young researchers involved in the project and make synergistic assistance in raising their scientific qualification;
- integrate complementary research facilities;
- co-publish papers in the top-impact Journals of chemistry, material science and Pharmacy;
- jointly apply for international research projects in the field of Health and Advanced Materials.

Last update: 27/11/2021