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Antitumoral Zinc Oxide Composite Drugs

#A-1962


Development of Zinc Oxide Composites of Antitumor Drugs and Antitumor Compounds with High Antitumor Activity and Low Toxicity

Tech Area / Field

  • MAT-COM/Composites/Materials
  • 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
  • PHY-PLS/Plasma Physics/Physics

Status
8 Project completed

Registration date
17.08.2011

Completion date
08.10.2014

Senior Project Manager
Savinova N V

Leading Institute
State Engineering University of Armenia, Armenia, Yerevan

Supporting institutes

  • Scientific Technological Centre of Organic and Pharmaceutical Chemistry SNPO, Armenia, Yerevan\nNational Academy of Sciences of the Republic of Armenia / The Institute of Molecular Biology/Armenian National Academy of Sciences, Armenia, Yerevan

Collaborators

  • University of Oklahoma, USA, OK, Norman\nAlabama State University, USA, AL, Montgomery

Project summary

Recently in medicine wide acceptance have received the technologies, which use materials sized several tens of nanometers.

Ensembles of semiconductor nanoparticles attached to a polymeric capsule can be used to transport drugs in live organisms. As for luminescent properties of semiconductor nanoparticles, they allow to trace the delivery process and make sure that necessary molecules have got to the destination place.

In oncology, at the interface of fundamental sciences - physics, chemistry and biology, as well as medicine and nano-technology – a new direction, “cancer nanotechnology” has formed to develop the methods of molecular therapy of oncological diseases.

Metal oxides, in particular zinc oxide nanoparticles have received wide acceptance in medicine due to their specific opto- electrical properties in view of opportunity to control their resistance within very wide ranges (3·10-4÷ 2·1011 Ohm·cm)

as well as high photocatalytic, antibacterial, antioxidant and antitumor activity that they reveal when the particles size is approximately 20 nm and less. It is known that zinc oxide is not toxic and shows photocatalytic, antibacterial activity under the influence of UV-radiation, while ZnO nanoparticles reveal such properties without UV-radiation. However, photocatalytic activity of ZnO nanoparticles can have toxic effect on cells and tissues.

Today, one of the main problems of modern antitumor therapy is increase the efficiency and decreases the toxicity of treatment, i.e. selective delivery of antitumor drugs with minimum damage of normal organs and tissues.

When developing new approaches in oncology, along with development of new drugs it is expedient to modify the chemotherapeutic drugs which are widely used in antitumor therapy in order to reduce their general toxicity and side effects.

Recent investigations on deposition of oxide thin films by DC-magnetron sputtering of Zn target on amino acid salicylidene chelates (DL-tyrosine, DL-β-phenyl-α-alanine, ω-aminocaproic acid) with expressed antioxidant and antitumor properties have shown that zinc oxide composites in the form of coatings and composite films with polyvinyl alcohol (PVA) reveal higher (by a factor of 2 and 2.5) antitumor activity and considerable smaller toxicity in comparison with initial compounds. Preliminary results on antitumor activity of ethyl ether salycilidene DL- β -phenyl- β -alanine Cu (II) chelate have shown not only higher activity (60%) but also higher toxicity in comparison with earlier studied ethyl ether salycilidene DL--phenyl--alanine Cu (II) chelate. Of a certain interest is obtaining of zinc oxide compositions of ethyl ether salycilidene -phenyl-β -alanine Cu (II) chelate in the form of coatings and composite films with PVA aimed at decrease in toxicity and increase in antitumor activity in comparison with the initial antitumor compositions.

Also, preliminary results on increase of antitumor activity and decrease of toxicity of zinc oxide compositions of widely used in oncology antitumor drug cisplatin (97%) in comparison with cisplatin itself (85%) have been obtained.

These results confirm earlier investigations where it was shown that decomposition of hydrogen peroxide on the surface of zinc oxide is accompanied by formation of a Zn-containing complex that transforms to gas phase and decomposes on the surface of a solid substrate with precipitation of initial compound ZnO. It is a chemical transport reaction (CTR), various modifications of which can receive wide acceptance in various areas of science and engineering. They are effective methods for transport of substances – just that determines their important role in both processes of formation of films, coatings and transport of drugs.

Earlier a method of ZnO thin film deposition on the surface of silicon substrate coatings, copper complex of ethyl ether salycilidene DL-tyrosine (biologically active compound) was also worked out.

ZnO thin films were deposited on quartz substrates covered by copper complex of ethyl ether salycilidene DL-tyrosine by means of interaction of the mixture of Н2О2 and peracetic acid vapors with polycrystalline ZnO target preliminary treated by ultraviolet irradiation, with formation of a volatile Zn-containing complex and its subsequent decomposition on the substrate surface.

Thus, it was shown opportunity of chemical transport of zinc oxide composites to a substrate, tumor cell, due to their interaction with peroxide radicals. It seems that zinc oxide plays the role of a carrier of the biologically active compound taking into account its active role in oxidation-reduction reactions, interaction with peroxide radicals.

This project proposes modification of the surface of widely used antitumor drugs by deposition of ZnO thin films on their surface by DC-magnetron sputtering of a zinc target. The specified method stand out favorably by your vide opportunities of controlling the process of formation of the compositions at lower deposition temperature (-30˚C≤T≤30C) and simplified techniques of controlling thickness of the ZnO film deposited on the surface of antitumor drugs and compounds, layer-by-layer deposition of coatings and films, which allows growing of the composites with preset technological characteristics.

Of prime importance is that the offered approach to modification of surfaces of antitumor drugs enables decrease the toxicity depending on the ZnO film deposition rate and average size of particles in the film, as well as low temperature (within the range of-30˚C≤T≤30C) of deposition of zinc oxide compounds, when there are no undesirable side reactions.

The objective of the presented work is the formation of zinc oxide composites of antitumor drugs in the form of coatings, composite films and gels possessing high antitumor activity and low toxicity using DC-magnetron sputtering of zinc targets by deposition of ZnO thin films on their surfaces.

The Project supposes solution of the following problems:

  1. Formation of composite materials on the basis of antitumor drugs (cisplatin, doxorubicin, 5-fluorouracil) and antitumor compound: Cu (II) chelate of salicylidene DL- β-phenyl- β -alanine in the form of coatings, composite films, gels and ointments in a matrix of water-soluble polymers (polyvinyl alcohol, polyoxyethylene, polyvinylpyrrolidone, etc.) of prolonged action.
  2. Determination of optimum kinetic and dynamic parameters (temperature T, pressure P, Ar and O2 gas flow rate) of the process of formation of zinc oxide composites of antitumor drugs (cisplatin, doxorubicin, 5-fluorouracil) and antitumor compound (Cu (II) chelate of salicylidene DL- β-phenyl- β -alanine) with high antitumor activity and low toxicity by DC-magnetron modification of their surfaces.
  3. Research of acute toxicity, cytotoxicity, antitumor activity of zinc oxide composite antitumor drugs and antitumor compounds in the form of coatings, composite films, gels and ointments in a matrix of water-soluble polymers (polyvinyl alcohol, polyoxyethylene, polyvinylpyrrolidone, etc.).
  4. Development of technology of obtaining of zinc oxide antitumor composite drugs with high antitumor activity and low toxicity.

To obtain zinc oxide antitumor composite drugs the following scientific and technical approaches will be used:
  • Use of physical methods of deposition and dispersing of zinc oxide compositions of antitumor drugs and antitumor compositions (DC-magnetron sputtering, ultrasonic method).
  • Use of chemical, spectral and structural methods of the analysis to study zinc oxide compositions of antitumor drugs and new antitumor compositions.
  • Use of X-ray diffraction technique, electronic microscopy, microanalysis, ellipsometry, electron-tunnel and capacitance-tunnel spectroscopy to study zinc oxide compositions of antitumor drugs and new antitumor compositions.
  • Calculation of optimum parameters of physical methods of deposition of zinc oxide thin film, sizes of nano-particles in ZnO films to model their formation methods.
  • Mathematical treatment of experimental data on the formation mechanism of zinc oxide compositions of antitumor drugs.
  • Use of optimum kinetic and dynamic parameters (T, P, V) of the ZnO composite formation process as well as structural characteristics of substrate material for modeling formation of composite systems.

As a result of the carried out scientific research and technological developments the following results are expected to obtain:
  • Determination of optimum kinetic and dynamic parameters of formation of zinc oxide compositions of antitumor drugs and antitumor compounds. Controlling thickness of ZnO film and its content in zinc oxide composites as well as target properties of composite on the basis of the determined kinetic and dynamic characteristics of the formation of composite systems;
  • Development of technology of obtaining zinc oxide compositions by the example of chemotherapeutic drugs: cisplatin, doxorubicin, 5-fluorouracil and antitumor compound: Cu (II) chelate of salicylidene DL- β-phenyl- β -alanine;
  • Obtaining of zinc oxide compositions of antitumor drugs with high antitumor activity, low toxicity and adjustable technical characteristics;
  • Modification of the developed method of obtaining of zinc oxide compositions for composite systems of various antitumor drugs;
  • Creation of highly effective, ecologically clean, economically cheap, technologically reproducible process of obtaining of zinc oxide compositions of antitumor drugs with high antitumor activity and low toxicity.
  • Development of technological schemes for modeling high antitumor active zinc oxide as well as different metal oxide composite antitumor drugs systems on the basis of the obtained results of scientific researches and technological investigations.
  • Involve in the work program highly qualified specialists, scientists earlier engaged in the development and production of weapon;
  • Participation of Armenian scientists in joint scientific investigations, workshops with collaborators, international conferences will assist their integration in international scientific community.
  • It is assumed to organize – on the basis of scientific investigations and technological developments – a flow diagram for the modeling of anticancer drugs with high antitumor activity, low toxicity and marketing research in the field of medicine and electronics aimed at creation of marketing outlets.


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