Projects / Programmes
Synthesis of Dendronized Polypeptides for Biomedical Application
| Code |
Science |
Field |
Subfield |
| 2.04.03 |
Engineering sciences and technologies |
Materials science and technology |
Polymer materials |
| Code |
Science |
Field |
| T390 |
Technological sciences |
Polymer technology, biopolymers |
| Code |
Science |
Field |
| 2.05 |
Engineering and Technology |
Materials engineering |
drug delivery, dendronized polymers, chitosan, polypeptides
Researchers (21)
Organisations (3)
Abstract
In practice the delivery systems, in which an active ingredient is bound to a polymeric carrier, have already demonstrated improved efficiency of drug treatment with simultaneously reduced negative side effects. Many natural and synthetic linear (co)polymers have been used for this purpose, which disadvantage is mainly in that they show too broad molar mass distribution and/or their structure consists of a limited number of functional groups. For this reason, the research in the field of biomedicine and pharmacy has been focused into the development of novel, more efficient drug delivery carriers, the properties of which can be tuned to the desirable by exact adjustment of the polymer chemical composition, architecture and molar mass. Novel drug formulations have been designed to improve efficiency of drug therapy as compared to conventional pharmaceutical dosage forms. For this purpose, a wide range of materials, such as natural and synthetic polymers, lipids, surfactants and dendritic polymers, have been tested as drug carriers. Among these, the dendritic polymers (dendrimers, hyperbranched polymers, dendronized polymers) and polysaccharides (chitosan, hyaluronan, alginates, etc.) have gained increasing attention because of their outstanding properties. The latest research in the field of drug delivery systems is focused on the synthesis of linear-dendritic block copolymers since they exhibit a multivalent character, a branched structure and a possibility of tailoring the structure with the purpose to adjust the polymer’s properties to the desirous.
The goal of this research project is to prepare novel, non-toxic, biodegradable and biocompatible polymeric drug carriers, which will be potentially applicable for delivery of poorly water-soluble, low molar-mass active substances as well as for oral delivery of high molar-mass proteins/peptides drugs. In the proposal of this research project we represent various synthetic routs for preparation of linear-dendritic block copolymers, i.e., dendronized polymers based on polypeptide and polysaccharide backbone (dendronized polypeptides, dendronized chitosan), which will differ in chemical composition and functionality with respect to the intended use. The topic of the synthesis of linear-dendritic hybrids for use in biomedical applications is new and state of the art.
The dendronized polypeptides based poly(lysine) and poly(cysteine) with neutral, hydroxyl functional groups, which have proved to be the least toxic, will be synthesized with the purpose to prepare polymeric carriers with a high loading capacity for low-molar mass active substances. By the preparation of solid dispersions of low-molar mass active substances and the polymeric carrier we intend to increase the poor water-solubility of active ingredients and to prolong the residence time in the bloodstream.
The delivery systems of nano-dimensions based on anionic polymeric carriers will be synthesized in order to apply them for oral delivery of high molar-mass protein/peptide drugs. For this purpose, we will build carboxylic functional groups into the chitosan’s structure using different modification procedures of chitosan, which will result in the preparation of dendronized chitosan and grafted chitosan with polypeptide chains. From such polymers we will prepare anionic hydrogels in the presence of two-valent ions, which will in acidic conditions of the stomach, due to physical crosslinking of the polymer, allow the retention of protein drugs in the polymer matrix and their release into the intestine (neutral pH). One of the objectives of the project is also the synthesis of the partially PEGylated chitosan, which will be used for coating the nano-particles to improve their stability in the harsh conditions of the stomach.
Significance for science
Protein drugs or biopharmaceuticals are becoming the key drugs of the future. Their major drawback is their labile structure, which can be solved by employing suitable delivery system. One of interesting and technologically the simplest approaches to overcome this issue is the preparation of nanoparticles formed by spontaneous complexation of the protein and the polymer carrier. Since no organic solvents are used in this procedure, there is no fear of losing protein activity due to denaturation. The most important part is to select an appropriate “smart” polymer designed for a specific protein, which enables efficient complexation and, in addition, is responsive to external stimuli. We synthesized novel polymers which proved to be highly efficient for association with selected protein and resulted in formation of stable nanoparticle systems. The protein loading in nanoparticles was high and even exceeded the values reported so far in the literature. The results were protected in international patent application: »Polymer selection for preparation of nanoparticles with high protein loading«, and published in several articles. The topic of polymer carrier development for active pharmaceutical ingredients is state of the art and in accordance with the development policy of the country, since the scope: "Health and life sciences" is one of the priority topics. The products of research project are beneficial for the development of basic and applied knowledge in extremely attractive and rapidly developing field of modern biomedicine and pharmacy as well as in the area of polymer material science. Namely, the application of properly designed drug delivery systems results in improved drug bioavailability, enhanced therapeutic efficiency with simultaneously reduced unwanted side effects of drug treatment, a reduced number of doses and, at the same time, targeted drug delivery to the specific cells or organs in the body.
Significance for the country
The content and goals of the project were in line with the global scientific directions and are closely connected to Slovenian pharmaceutical industry, which creates a substantial part of the national income. Research was conducted in accordance with the interests of the Slovenian pharmaceutical company on the issue of improving the efficacy and safety of treatment with biopharmaceuticals. Thus, the results of the research have a great applicative potential for the development of technologically promising, new delivery systems, which are important for the pharmaceutical industry that represents an important financial element in Slovenia, is already involved in the development of biopharmaceuticals and is characterized by a large number of products with high added value. In addition to the direct impact of the project results on the pharmaceutical company that was involved in this applicative project, the successful realization of the project aims represents broader benefits through new scientific achievements on the development of new generation of drugs by gaining a detailed knowledge of the impact of the architecture and chemical composition of polymeric carriers on the ability of formation of drug delivery systems in the form of nanoparticles. The newly acquired knowledge in a very competitive field of biomedical applications will enable further steps in the development of high-tech products. The acquired knowledge on the role of polymer carriers in preparation of drug delivery systems in the form of nanoparticles was spread among participating researchers of the project team, especially among the involved students and young researchers who will be able to use the important practical and theoretical experiences in their future employments. By this means, the project has multiplied effect over a longer period.
Most important scientific results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2011,
2012,
2013,
final report,
complete report on dLib.si
