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Antibiotic Metal Oxide Composites Drugs

#A-2205


Development of nanosize metal oxide (ZnO, ZnO/Ag) composite antibiotic drugs with high antibacterial activity and efficiency to bacteria associated infections.

Tech Area / Field

  • MAT-COM/Composites/Materials
  • PHY-PLS/Plasma Physics/Physics
  • BIO-CGM/Cytology, Genetics and Molecular Biology/Biotechnology
  • CHE-POL/Polymer Chemistry/Chemistry
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry
  • MAT-SYN/Materials Synthesis and Processing/Materials
  • MED-DRG/Drug Discovery/Medicine

Status
3 Approved without Funding

Registration date
28.07.2015

Leading Institute
National Polytechnical University of Armenia, Armenia, Yerevan

Supporting institutes

  • Scientific Technological Center of Organic and Pharmaceutical Chemistry, Armenia, Yerevan\nScientific and Production Center "Armbiotechnology" NAS RA, Armenia, Yerevan

Collaborators

  • University of Maryland / Department of Physics, USA, MD, College Park\nImperial College of Science, Technology and Medicine / National Heart and Lung Institute, UK, London\nHelmholtz Center for Infection, Germany, Braunschweig\nHarvard Medical School / Wellman Center for Photomedicine, USA, MA, Boston\nWestern Michigan University, USA, MI, Kalamazoo\nYonsey University College of Microbiology, Korea, Seoul\nUniversity of North Carolina Greensboro, USA, NC, Greensboro\nRamon and Cajal University Hospital, Spain, Madrid\nUniversidade da Madeira, Portugal, Funchal\nAlabama State University, USA, AL, Montgomery\nLawrence Livermore National Laboratory, USA, CA, Livermore\nDepartment of the Navy / Naval Research Laboratory, USA, DC, Washington\nUniversity of Santiago de Compostela, Spain, Santiago de Compostela\nUniversität Siegen, Germany, Siegen\nUniversity of Tsukuba, Japan, Tsukuba\nTokyo Medical and Dental University, Institute of Biomaterials and Bioengineering, Japan, Tokyo\nUniversity of Tokyo / School of Engineering, Japan, Tokyo

Project summary

Modern antibiotic therapy occupies a prominent place in treatment of bacterial infections. The list of antimicrobial drugs is continuously expanded by introduction of new generations of antibiotics due to wide spread antibiotic resistance and, as a consequence-reducing the effectiveness of antibiotic therapy. Over the last few decades, the applications of nanotechnology in medicine have been extensively explored in many medical areas, especially in antimicrobial drug system. By loading drugs into the targeted nanoparticles through physical encapsulation, adsorption, or chemical conjugation, the pharmacokinetics and therapeutic index of the drugs can be significantly improved in contrast to the free drug counterparts. Many advantages of nanoparticle-based drug have been recognized, including improving solubility of the drugs, prolonging the systemic circulation life time, releasing drugs at a sustained and controlled manner, targeting drugs delivery to the tissues and cells.

The Project proposes solutions to the following problems:
1. Formation of composite materials on the basis of antibiotic drugs (doxycycline, amoxicillin, clarithromycin) and new antibiotic conpound (salicylidene DL-triptophan) of prolonged action in the form of coatings, composite films, gels and ointments in a matrix of water-soluble polymers (polyvinyl alcohol (PVA), polyethylene oxide (PEO), starch - sodium carboxymethylcellulose (Starch+Na-CMC), 2-hydroxyethyl cellulose (HEC)).

2. Determination of optimum kinetic and dynamic parameters (temperature (T), pressure (P), Ar and O2 gases flow rate, (V)) of the process of formation of ZnO, ZnO/Ag composite antibiotic drugs (doxycycline, amoxicillin, clarithromycin) and antibiotic compound (salicylidene DL-tryptophan) with high antibacterial activity, low toxicity and low resistance of pathogenic bacteria to them by DC-magnetron modification of their surfaces.

3. Study of antibacterial activity (in vitro and in vivo), toxicology, hematology, morphology of antibiotic drugs (doxycycline, amoxicillin, clarithromycin), antibiotic compound (salicylidene DL-tryptophan) and their ZnO, ZnO/Ag composites in the form of coatings, composite films, gels and ointments in a matrix of water-soluble polymers (PVA, PEO, Starch+Na-CMC, HEC) to gram-positive and gram-negative microbial strains, as well as yeasts and some other methicillin resistant strains.

4. Development of a technology for obtaining of ZnO, ZnO/Ag composites of antibiotic drugs (doxycycline, amoxicillin, clarithromycin) and antibiotic compound (salicylidene DL-tryptophan) with high antibacterial activity, low toxicity and low resistance of pathogenic bacteria to them.

Metal oxide nanoparticles represent a new class of important materials that are increasingly being developed for the use in research and health-related applications. Hybrid materials, metal-modified oxide semiconductors, especially, materials that combine silver and zinc oxide, have attracted attention because they were successfully used in chemical and biological sensors, electronics and photoelectronic devices and have considerable antimicrobial activity as well.
The strong antibacterial effects of both metallic Ag and Ag+ ions have been known for a long time. Silver, as proposed by a new study conducted at the Howard Hughes Medical (HHMI, USA) Institute, alters cellular processes that keep the bacteria alive, such as its metabolism, internal silver levels, and its ability to form bonds between vital proteins.

It has been shown that small amounts of silver in Ag/ ZnO nanoparticle have considerably increased the antimicrobial activity. Metal oxides, in particular, zinc oxide are non- toxic and show photocatalytic, antitumor, antibacterial activity under the influence of UV-radiation, while ZnO nanoparticles reveal such properties without UV irradiation. These results confirm our earlier investigations, where it was shown that decomposition of hydrogen peroxide on the surface of zinc oxide target was accompanied by the formation of a ZnO -containing complex, which was increased by two orders of magnitude when the target surface was photoactivated using ultraviolet irradiation. A method of ZnO- composite formation by deposition of nanosize ZnO thin films on newly synthesized biologically active compounds-amino acid salicylidene copper chelates, was proposed. The results of our investigations on deposition of zinc oxide thin films by DC-magnetron sputtering of Zn targets on amino acid salicylidene chelates (L-tyrosine, â-phenyl-á-alanine, -aminocapronic acid and its ethyl ether) with expressed antioxidant and antitumor properties synthesized by our researchers have shown in vivo (model Sarcoma180) that zinc oxide composites in the form of coatings and composite films with polyvinyl alcohol reveal higher (by a factor of 2-2.5) antitumor activity and considerable smaller toxicity in comparison with initial compounds.

The results of these researches have been used by our team to obtain zinc oxide compositions of well known antitumor drugs with high antitumor activity and low toxicity. Our recent results also testify to the increase in antitumor activity and decrease in toxicity when using zinc oxide compositions of widely used antitumor drugs: 5-fluorouracyl on the model of Crocer`s Sarcoma and doxorubicin on the model of ascitic Ehrlich's carcinoma. Chemotherapeutic investigations of 5-fluorouracyl (FU) zinc oxide composites on the model of Crocer`s Sarcoma have shown considerable increase in antitumor activity at the lower FU doses of 15.0 mg/mouse and 17.5 mg/mouse in the form of coating (50.8%, 68.2%) in comparison with FU at the therapeutic dose 20 mg/kg (37.8%) . The lifespan reached 332.3% for zinc oxide composite of doxorubicin in the form of coatings, 384.1% for hydrogels on the basis of sodium carboxymethyl cellulose-starch and 391.5% for composite films with polyvinyl alcohol at lower doses (3 mg/kg) in comparison with doxorubicin (168.9%) at therapeutic dose (5 mg/kg).

Recently, our preliminary results of in vitro and in vivo studies on zinc oxide compositions of antibiotic drug-doxycycline have been obtained and it was demonstrated to increase antibacterial activity by a factor of 2 in comparison with the initial drug. At present, the main problems of modern antibacterial therapy are increasing the efficiency, reducing the toxicity of treatment and decreasing resistance of bacterial infections to drugs. At present, actual tasks are the methods development for modification of known antibacterial substances.

Some preliminary results were obtained of in vitro study of antibacterial action of doxycycline zinc oxide compositions using the method of two-fold serial dilution in beef-extract broth (рН 7.2-7.4) on Staphylococcus aureus 5 and Shigella Flexneri 6858 strains. It was shown that doxycycline zinc oxide compositions in the form of composite films with polyvinyl alcohol (PVA) reveal activity at lower concentration (by a factor of 2) in comparison with the pharmaceutical preparation and doxycycline-PVA composite film. In vivo study of doxycycline zinc oxide compositions on the model of white mice generalized staphylococcal and dysenteric infections using St. aureus 5 and Sh.Flexneri 6858 strains has revealed an essential therapeutic action at all examined doses: 100, 50 and 25 mg/kg for both strains. It was shown that activity of zinc oxide compositions at the doses of 100 mg/kg for St. aureus 5 strain makes up 94% in comparison with 76% for the initial preparation, whereas at lower concentrations (50 and 25 mg/kg) a significant increase in activity of doxycycline zinc oxide compositions was observed: 90% and 72% correspondingly in comparison with the initial preparations at the same concentrations (68% and 40% correspondingly). Much the same difference was observed for Sh Flexneri 6858 strain.

Previously our team of in vitro investigations showed that the antibacterial activity of salicylidene -DL-tryptophan (synthesized in STCOPC) was two times higher in comparison with the known antibiotic furazolidone against gram-negative (Sh. Flexneri 6858, E.coli 0-55), and gram-positive (St. aureus 209p,1) microbes with the same effect.

Of a certain interest is obtaining of ZnO, ZnO/Ag compositions of salicylidene DL-triptophan with high antibacterial activity, low toxicity and low bacterial resistance to them in comparison with the initial antibiotic compositions.

The objective of the presented work is formation of metal oxide (ZnO, ZnO/Ag) composites of known antibiotic drugs (doxycycline, amoxicillin, clarithromycin ) and antibiotic compound (salicylidene DL-triptophan) in the form of coatings, composite films and gels with high antibacterial activity, low toxicity and reduced resistance of pathogenic bacteria to antibiotics, by modification of surfaces of initial preparations through the deposition of ZnO and ZnO/Ag thin films using DC magnetron sputtering of Zn, Zn/Ag targets in Ar:O2 medium.

The specified methods stand out favorably by their wide opportunities of controlling the process of formation of the compositions at lower deposition temperature (-30C T 30C) and simplified techniques of controlling thickness of the ZnO, ZnO/Ag films deposited on the surface of antibiotic drugs and antibiotic compounds layer-by-layer deposition of coatings and films, which allows growing of the composites with preset technological characteristics.


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