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Addressed Liposomes in New Drugs

#1781


Design and Studies of New Anti-Virus and Anti-Tumour Agents Based on Stable Addressed Liposomes Carrying Lipophilic Drug Derivatives

Tech Area / Field

  • BIO-CHM/Biochemistry/Biotechnology
  • MED-DRG/Drug Discovery/Medicine
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry

Status
8 Project completed

Registration date
09.02.2000

Completion date
21.12.2005

Senior Project Manager
Melnikov V G

Leading Institute
Lomonosov Academy of Fine Chemical Technologies, Russia, Moscow

Supporting institutes

  • Ivanovsky Institute of Virology, Russia, Moscow\nInstitute of Bioorganic Chemistry, Russia, Moscow

Collaborators

  • Sib Tech, Inc., USA, CT, Newington

Project summary

The increasing needs of clinical medicine in the widening of effective drugs using for the treatment of virus infected and oncology patients are connected with tendency of expansion of these severe diseases among more and more groups of population everywhere in the world. Such situation in the sphere of human health care determines the particular actuality of fundamental and applied researches directed to design of next generation of anti-virus and anti-tumour medicines. The solution of the problem is seen not only on traditional pathways of synthesis and following pharmacological screening of new organic substances - the important task is the searching for the reliable methods of addressed drugs delivery to the cell-targets with subsequent penetration of medicine into intracellular space.

Among several perspective methods for enhance the therapeutic efficiency of various medicines recently was found an attractive approach and which one used liposomal formulations for the directed drug delivery to chosen type of cell-targets. The use of liposomes increases substantially the possibilities of chemotherapy against the virus and tumour diseases due to combined action of different factors: reduction of toxic influence and increasing of bioaccess of the drug; preservation of untimely degradation of medicines under the enzymes action; prolongation of a life time while the drug circulates in organism; passive targeting of liposomes inti tumour tissues(liposomes could give an effective result in the treatment of tumours by virtue of the accumulation of large concentrations in tissues and organs where the tumour is located).


The development of this approach is needed the further systematic studies which could be of help in resolving of the remaining unsolved problems:
– formation of stable liposomal forms of the known drugs or newly synthesised biologically active compounds;
– overcoming the problem of negative influence of different barriers and protective systems in living organism;
– increasing the efficiency of liposomes targeting to affective cells by means of molecular addressing.

At present time quite a limited set of medicines are in disposal of physicians for medical treatment of millions unhappy patients suffering from virus and tumour caused diseases. For example, now there are no radical remedies against HIVs while just few drugs have been introduced in clinical practice only for supporting therapy of the AIDS. The anti–AIDS drugs with supporting action were obtained by synthetic methods starting from nucleosides and their derivatives or as alternative way on the base of other types of organic compounds. These substances terminate the chain elongation of virus's DNA or block certain other critical enzyme steps during the virus's life cycle. It was found that such drugs usually show substantial destructive action on vital systems and organs in human organism.

As concerning for most common used anti-tumour medicines they were developed on the base of highly cytotoxic natural or similar synthetic compounds and so generally they have quite dangerous toxicity for man. In many cases the side effects and general toxicity of the drugs are the reasons of untimely deaths of patients.

The objective of the project consists in searching of rational approaches for design and preparation of the new effective anti-virus and anti-tumour medicines by means of substantial increasing of therapeutic index of known as well as newly synthesized medical preparations. In practice the traditional forms of medicines pass through the cell membrane barrier relatively slowly and in limited quantities. The desired increasing of effectiveness will be obtained by hydrophobization of the drug molecules after coupling with suitable hydrophobic structural fragments and the latter could be removed easily under mild hydrolysis in given time. The modified compounds will be introduced into liposomes in order to increase their water-solubility. The structures of these liposomes will include specific sites with steric stabilizators and molecular addresses what could give an opportunity for more long circulation of liposomal particles in the bloodstream as well as for the directed transportation of preparations to cell-targets. The genetic mechanisms of virus cells affection and tumour cells proliferation are very close related to each other and so the tests for anti-tumour activity usually are included in programs for synthesis and screening of anti-virus preparations. This is the reason why in the project two therapeutic groups of substances are combined for one study.

Authors of the project have the proven many years experience in design, synthesis, screening and development of new medicines for human health care (for example, the authors have took part in studies and development of the following preparations: azidothymidine, acyclovir, anti-virus nucleoside derivatives, aminophosphatide, cardiolipin antigene, highly purified phospholipids and glycolipids, immunomodulators, liposomal preparations of anti-tumour antibiotics) as well as necessary professional knowledge in molecular biology of viruses, HIV’s and tumour diseases.

For the realization of the project goals will be used the novel approach in designing of biomedical preparations. The approach is based on the phenomenon of ligand-receptor interactions and this is providing the directed delivery of biologically active substances into intracellular space. It is clear that in the frames of the project modification of drugs with known action as well as newly synthesized bioactive compounds will lead to rather complex molecular structures due to adding of new functionalities. Such needed change will allow to make more effective the process of drug penetrating through the membrane barrier. The above mentioned properties will appear in molecules after introducing of specific linking and recognizing sites.

The project will deal with the complex studies on fine organic synthesis, screening of biological properties and preparing of stable forms of compounds having anti-virus and anti-tumour activity. The formation of desired molecular structures will be provided in according with following general principles: The researched substances shall include specific structural fragments which are very similar to the structures of superficial cell recognizing and linking ligands. For the structures of tested compounds it is necessary to have the special molecular fragment which displays the chosen biologic activity. Compounds shall bear some specific groups which posses the substrate’s properties for enzymes which liberate the pharmacologically active sites nearly of cell-targets or inside thereof. The following types of compounds are planned for synthesis and /or modification in order to select and develop new preparations with anti-virus and anti-tumour activities: structurally modified nucleosides; lipophilic derivatives of some cytostatics (sarcolysine, methotrecsat, rubomycin etc.); hydrophobic derivatives of glycyrrhetinic and betulinic acids; olygopeptide fragments of chemokines or their non-peptide analogs.

As a result of researches in the frames of the project the advanced methodology of design and preparation of more effective anti-virus and anti-tumour medicines will be developed.

The technology of forming stable liposomal formulations for series of new anti-virus and anti-tumour compounds as well as the study of pharmacological and specific activity of novel medicines will be performed in vitro and in vivo.

The Leading Institution (M.V.Lomonosov’s Moscow State Academy of Fine Chemical Technology) will carry on the woks on the synthesis of new biologically active substances based on the modification of nucleosides, heliomycine, synthetic analogues of chemokin’s receptors and lipophilic derivatives of these compounds. In close cooperation with other Participating Institutions the biological tests of original substances as well its liposomal preparations will be performed.

Participants from the Institution 1 (M.M.Shemyakin’s and Y.A.Ovchinnikov’s Institute of Bioorganic Chemistry) will take part in synthesis and studies of anti-virus and anti-tumour activity of new lipid derivatives of rubomycin, methotrexate, glycyrrhetinic acid, sarcolysin, 5-fluorouridine. After synthetic work the liposomal preparations of these compounds will be formed for subsequent biological tests in vivo.

Participants from the Laboratory of Virus Leucosis (Participarting Institution 2 – D.I.Ivanovsky’s Institute of Virology) will develop the protocols for model system “virus-cell”. The series of organic compounds and liposomal preparations made by Leading Institution and Institution 1 will be tested for anti-AIDS and other types of anti-virus activity in this Laboratory.


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