Projects / Programmes
Synthesis of multifunctional polypeptides for delivery of biopharmaceuticals
| Code |
Science |
Field |
Subfield |
| 2.04.00 |
Engineering sciences and technologies |
Materials science and technology |
|
| Code |
Science |
Field |
| P370 |
Natural sciences and mathematics |
Macromolecular chemistry |
| Code |
Science |
Field |
| 2.05 |
Engineering and Technology |
Materials engineering |
Polypeptides, N-Carboxyanhydrides, Ring-Opening Polymerization, Polyelectrolytes, Nanoparticles, Drug Delivery Systems
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
29613 |
PhD David Pahovnik |
Materials science and technology |
Head |
2014 - 2016 |
189 |
Organisations (1)
| no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
| 1. |
0104 |
National Institute of Chemistry |
Ljubljana |
5051592000 |
20,997 |
Abstract
The aim of drug delivery systems, consisting of a drug and a polymeric carrier, is to improve therapeutic efficiency of the drug. With the development of protein/peptide drugs (biopharmaceuticals) the new delivery systems have to be designed as well. Recently, nano-sized delivery systems are becoming highly promising since they deliver the drug into the body by noninvasive paths through the mucus membranes (oral, nasal, etc.). Due to small size of nanoparticles they exhibit mucoadhesive properties which enable the drug to penetrate through the mucus. The nanoparticles of biopharmaceuticals are preferred to be prepared in water medium under mild experimental conditions in order to leave the protein tertiary structure intact and thus not affect the protein activity. Nanoparticles can be prepared by spontaneous complexation of the polymeric carrier and the protein/peptide drug. A mechanism of nanoparticles formation depends on the chemical composition and structural properties of both constituents since these parameters determine the type of interaction between them, the conformation of polymer chains in solution and the polymer ability to self-organize in supramolecular structures. In most cases only one type of physical interaction is not enough for preparation of efficient drug delivery system since the protein drugs have highly diverse chemical structure. Therefore, targeted and careful design of new polymeric carriers is essential to enhance mutual interaction between the polymer carrier and the drug and thus to prepare drug delivery systems with high loading capacity. The development of new carriers based on synthetic polypeptides, which are distinguished by well-defined chemical composition, architecture, narrow molar mass distribution, desired functionality and ability to self-organize into secondary and tertiary structures, will be a step further to prepare efficient delivery systems for peroral protein/peptide drug administration.
The proposed postdoctoral research project aims to prepare the synthetic polypeptides of different chemical composition with overall negative or positive charge. Synthetic polypeptides will be synthesized by ring-opening polymerization (ROP) of N-carboxyanhydrides of α-amino acids (NCA) since this polymerization mechanism enables the preparation of polypeptides with well-defined structure, molecular weight and functionality. In order to enhance the association efficiency of synthetic polypeptides with the therapeutic proteins by multiple types of interactions between them, the polypeptide backbone will consist of various hydrophobic as well as hydrophilic repeating units. Different functionalities will be introduced into the polypeptide chains by copolymerization of the NCA monomers prepared from different amino acids and/or the NCA monomers prepared from appropriately modified amino acids. Another proposed methodology for tuning the polypeptide properties is the post-polymerization modification of its pendant functional groups. In further research work the nanoparticles of biopharmaceuticals (insulin used for diabetes treatment, GCSF protein used for stimulating the production of white blood cells called granulocytes, and EPO used for treating the anemia) and the synthesized polypeptides will be prepared by polyelectrolyte complexation method. The goal will be to prepare the polypeptide carriers of such chemical composition that will allow the preparation of nanoparticles with high loading capacity for specific therapeutic protein. Since the microstructure also affects the polypeptide ability to spontaneously associate with the therapeutic protein, a series of anionic, water-soluble copolypeptides based on partially alkyl modified polyglutamic acid with different microstructure (block, random, gradient) will be synthesized to study the effect of microstructure on the polymer self-assembly in solution and, consequently, on the association ability with the GCSF therapeutic protein.
Significance for science
The results of the postdoctoral research project are important for the continuous development of basic and applicative knowledge in the area of synthesis and characterization of synthetic polypeptides for application in various biomedical fields. The synthetic polypeptides show a lot of promise in medical application since they are biocompatible, biodegradable and can be highly functionalized, which in combination with various possible modifications enables the preparation of polymers with the desired properties such as polarity, solubility, permeability and ability to respond to external stimuli (pH, temperature, etc.). Our results show that by employing ring-opening polymerization of N-carboxyanhydrides in combination with post-polymerization modifications we are able to prepare well-defined multifunctional synthetic polypeptides with desired properties for a broad range of biomedical applications. The results of the project thus contributed to the database of knowledge on the synthesis of polypeptides with various molecular architectures and functionalities, their detailed characterizations and understanding the type of interaction between the polymeric carrier and the drug, which is important for potential use of synthetic polypeptides in peroral drug delivery. The acquired knowledge is also important for application of synthetic polypeptides in biomedical applications and is original contribution to science.
Significance for the country
The project results have beside their basic relevance also a high applicable potential for development of technologically promising new drug carriers. This topic is of significant interest for pharmaceutical industry, an important financial element in Slovenia which is distinguished by a large number of products with high added value and is already involved in the development of biopharmaceutical drugs. The results of our project can thus help to the development of the pharmaceutical industry in Slovenia which is an important factor for the industrial advancement of Slovenia as well. Due to increasing importance of biopharmaceuticals, which are expected to take over the large market share, the development of new drug carriers is extremely important. To be competitive on the market, new innovative and intellectually protected solutions have to be found. Since the scientific concept of peroral drug delivery of biopharmaceuticals is rather new, it is intellectually protected and therefore our own intellectual protected technologies are needed to stay on the market. By acquiring and expansion of basic knowledge on polypeptide synthesis and characterization as well as on preparation of drug delivery systems in the form of nanoparticles for peroral delivery of biopharmaceuticals, our laboratory become internationally recognized in this field of research. During the project we have also gained new knowledge, know-how and skills, all of which support the development of new technologies and in which we have also integrated education of new generation of students and researchers. International recognition in this field of polymer chemistry gives us the opportunity to cooperate with foreign research groups, which can already be seen in bilateral cooperation.
Most important scientific results
Annual report
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
