Laboratory: BIOPOLYMERS AND NEW MATERIALS

PERIMED

Head: Prof. Temenujka Yovcheva, PhD

The work package is consistent within the scope of priority axis 3 “Industry for a healthy life and Biotechnology” with direct relevance to priority areas “Nano-technologies at the service of medicine” and “Formulations substances and products” by ISIS of the Republic of Bulgaria from 2014 to 2020.

The development of the planned research will lead to the formulation of new innovative nano-structured polymer materials, which applied as drug carriers, will have the potential to reduce the side effects of medicines, to prevent overdose and to facilitate the drug intake. Thus, improvement of the treatment quality and improving patient comfort is expected.

Built-up of new functional polyelectrolyte biopolymer structures with controlled features in micro – and nanodimensional scale, which have the capacity of immobilization and prolong release of bioactive compounds are of an essential interest, both from a sciеntific and practical point of view, because of their usage in biotechnology, tissue engineering, pharmacy, and food technologies.

In the recent decades, intensive research related to the polyelectrolyte interactions and opportunities to create nanostructured polyelectrolyte complexes is carried on. The main objective of these studies is to establish the relation between method and conditions of formulation – structure – properties – applications. The polyelectrolyte complexes form as a result of electrostatic interactions between oppositely charged polyelectrolytes. Essential for the complexation nonelectrostatic physical interactions are hydrogen bonds and hydrophobic interactions. The most important factors effecting the complexation are: pH and ionic strength of the medium, polyelectrolyte concentration, charge density and distribution onto the macromolecular chain and a stoichiometric ratio of complexing partners. Depending on the molecular weight, the linear charge density and the concentration of the partners, the resulting complexes may be in the form of precipitates (insoluble complexes), coacervates (dense liquid phase) and gels (soluble complexes). The insoluble complexes form by complete charge compensation – so-called stoichiometric complexes. The soluble complexes are formed by partial charge compensation. The resulting charge on the complex allows its dissolution as a result of interaction with the solvent molecules.

The wide variety of structures and properties of nano-sized biocompatible and biodegradable polyelectrolyte complexes from natural polyelectrolyte determines their application as carriers of various drugs. The immobilization of the drugs in polyelectrolyte complex increases their efficiency, specificity and opportunities for targeted action. The nano-carriers protect the drugs from premature degradation in biological environment, increase bioavailability and extend their presence in the blood and into the cell.

Specific form of polyelectrolyte complexes are planar polyelectrolyte multilayer structures. Typically, they are prepared by the Layer-by-Layer (LbL) deposition method, which is widely used for developing nano-films with controlled structure and composition. Due to the high level of control over the film properties, flexible choice of the polyelectrolytes used to obtain them and their easy and environmentally friendly production, polyelectrolyte multilayer structures find different applications ranging from optical and electrochemical materials to biomedical devices.

In the recent years, an increasing interest is observed in developing of drug carriers based on polyelectrolyte multilayer structures with applications in biomedicine, offering opportunities for very fine control of the structure and concentration of the involved drugs. The multilayer surfaces possess a good ability to immobilize biomolecules which are in a good preserved activity because of: 1) layer by layer deposition of polyelectrolytes does not need drastic conditions in order to build the structures and the process is very often done in water; 2) layer by layer deposition of polyelectrolytes enables different environmental conditions (pH and ionic strength), which ensure the construction of PEMS with loose structure and functional groups capable of binding molecules; 3. the component release rate can be controlled in a very wide range through а change of the electrolytes partners in the structures, through a depth of immobilization in the volume of the film or through an environmental change in which releasing takes place – pH, temperature, ionic strength.

The formulated by layer-by-layer deposition polyelectrolyte structures represent an outstanding and successful solution of the demanded from the pharmaceutical science opportunities to improve the effectiveness of well-known medical substances (MS) by including those in innovative therapeutic systems that provide sustained release in a specific target area.

One of the main problems concerning the most methods for functionalization of polyelectrolyte multilayer structures is the low loading capacitance of a single layer. For the immobilization of larger quantities of medicinal substances, it is necessary to obtain a large number of layers. Therefore, it is of interest to study the possibilities for immobilization of larger reservoirs of drug substances, such as nano-sized polyelectrolyte complexes. Thus, it is expected a significant increase of the loading capacity of the multi-layer films.

The described factors make the basic idea of the work package to immobilize drug pre-loaded polyelectrolyte complexes in polyelectrolyte multilayer structures particularly relevant and innovative.

The main objective of this project is the development of planar nano-structured polymer composite materials containing nano-sized polyelectrolyte complexes with application for drug carriers.

The tasks to solve with the realization of this work package are the following:

  • Development of appropriate protocols for the formulation of polyelectrolyte complexes in respect to their use as drug carriers.
  • Characterization of the formulated polyelectrolyte complexes in terms of their physical, physico-chemical and operating properties.
  • Establishing optimal chemical composition and structure of polymer composite materials including polyelectrolyte complexes to immobilize drugs.
  • Characterization of Polymer composite materials included polyelectrolyte complexes in terms of their physical, physico-chemical and operating properties.

The planned research is focused on formulation of innovative structures based on nano-structured polyelectrolyte complexes with improved ability to immobilize bioactive substances.

The planned research will be carried on by modification of the layer-by-layer self-assembly method, which is used for polyelectrolyte layer deposition. It is planned the deposition to be realized onto prior charged in corona discharge system polymer substrates. There are no literature reviews that such pretreatment of the substrate before the multilayer deposition has been used elsewhere and therefore we believe that this is an innovation of high international level. The project activities provide deep study on the conditions of the surface electrostatic charge on the deposition and properties of multilayer films. It is expected that the pre-charging of the substrate will contribute to improved adhesion and stability of the deposited polyelectrolyte layers, and thus will improve the existing technology of electrostatic deposition of polyelectrolyte layers.

The second modification relates to the traditional techniques for drug immobilizing the. In the planned study the drug substances will be initially embedded in the polyelectrolyte complexes, which subsequently will be immobilized in multilayer films. Thus, it is expected to increase the loading capacity of the film and more accurately controlling the rate of the drug substances release. This is a prerequisite to modify the technology for immobilization of biologically active substances at high international level.

The objective criteria to measure the expected level of planned scientific products and results over 10 years period are:

  • Publications in journals with impact factor – 10.
  • Publications in the top 10 journals in their field – 2.
  • The developed polymer composite materials containing nano-sized polyelectrolyte complexes including drugs will be registered as a patents or utility models– 2.
  • International interest – ensuring the specialization of two researchers at a leading scientific organization in the EU to training and acquisition of new competencies; participation in international scientific forums in the field – 3.

The following methods and approaches will be used in the scientific investigations:

  1. In order to formulate the polyelectrolyte complexes the following methods will be utilized: polyelectrolyte titration, polyelectrolyte solution mixing under pressure, ionic gelation and others;
  2. Their size and its distribution, rheology, mobility, and z-potential;
  3. The polymer composite materials will be designed by the layer-by-layer deposition technique onto a substrate made of biodegradable polymers treated in advance in electric corona discharge;
  4. The kinetics of layer deposition will be monitored by quartz crystal microbalance (QCM) and surface plasmon resonance methods (SPR);
  5. The polymer composite materials containing polyelectrolyte complexes with drugs will be characterized by means of the following methods: Furrier-transform infrared spectroscopy (FT-IR); (AFM); scanning electron microscopy (SEM); X-ray diffraction and scattering methods; static mechanical tests; differential scanning calorimetry (DSC).
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