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Anti-Tuberculosis Drugs and Drug Delivery System

#3326


Development of the New Generation of the Anti-Tuberculosis Drugs and Drug Delivery Systems

Tech Area / Field

  • MED-DRG/Drug Discovery/Medicine
  • BIO-MIB/Microbiology/Biotechnology
  • BIO-SFS/Biosafety and BioSecurity/Biotechnology
  • CHE-SYN/Basic and Synthetic Chemistry/Chemistry

Status
3 Approved without Funding

Registration date
21.07.2005

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

Supporting institutes

  • Research Center of Molecular Diagnostics and Theraphy, Russia, Moscow

Collaborators

  • Virginia Commonwealth University / High Technology Materials Center, USA, VA, Richmond\nNational Jewish Medical and Research Center, USA, CO, Denver\nJohann Wolfgang Goethe-Universität / Institut für Pharmazeutische Technologie, Germany, Frankfurt am Main\nLaurentian University, Canada, ON, Sudbury\nAlphaRx Ltd., Canada, ON, Markham

Project summary

The overall objective of the present Project is the development and investigation of the novel-generation anti-TB drugs based on isoniazid (INH) and its derivatives and targeted colloidal drug delivery systems with enhanced activity.

Background and Justification for Undertaking the Project. The primary goal proposed herein is the development of novel anti-TB drug formulations with the improved efficacy against Mycobacterium tuberculosis. The urgency of this research is indubitable in view of insufficient efficacy of existing anti-TB agents that is due to a number of reasons, e.g., global spreading of M.tuberculosis strains resistant against major anti-TB drugs, such as isoniazid, rifampicin, streptomycin, and pyrazinamide. Moreover, currently available tuberculostatic agents, e.g., isoniazid, display serious adverse side effects that often become a limiting factor for successful chemotherapy. In this context, development of novel potent low-toxic anti-TB drugs and drug delivery systems appears to be an urgent problem.

One strategy to solve this problem is the development of a new generation of the anti TB drugs based on isoniazid (INH) as a matrix structure with high antimycobacterial activity. Development of the colloidal delivery systems based on liposomes or nanoparticles will further increase the potential of the new drugs against TB due to the enhanced penetration in the infected cells and inflammatory foci. These two strategies constitute the subject matter of this Project.

Basing on their original concept of drug design, the authors of the Project propose the following strategies:

  • search for potential anti-TB drugs by «functional» screening based on the use of matrix molecules specifically directed against M.tuberculosis (e.g., isoniazid). The latter employs novel strategies based on the use of matrix isoniazid molecules and its derivatization using a vast array of aldehydes and ketones as well as carbofunctional organosilicon and organogermanic compounds.
  • development of colloidal liposome- and nanoparticle-based systems for targeted delivery of the most promising anti-TB drug components.

For this purpose, a series of novel drug components of the general structure I – III will be synthesized using various chemical methods based on pyridinecarboxylic acid hydrazide and aldehydes of С- and N-substituted pyrazoles; nitrogen-, oxygen-, sulfur- and halogen-containing carboxylic acids, as well as dimethylchloromethylchlorosilane (dimethylchloromethylchlorogermanium):

,

Structure I: R = C- or N-substituted pyrazoles;

Structure II: X = SiOSi or GeOGe;

Structure III: R and R = linear or heterocyclic nitrogen- or sulfur-containing radicals.

The novel colloidal formulations of the anti-TB drugs developed in the frame of the Project will be thoroughly characterized; the main parameters are size, drug loading and drug release. These factors are crucial for the therapeutic efficacy of colloidal formulations.

To meet the overall objective of the Project, researchers at two leading Russian scientific institutions will combine their efforts in an endeavor to apply their creative potentials, high professional skills and practical experience (including those gained during the implementation of the previous and on-going projects supported by the ISTC grants) in order to solve various chemical, biomedical, pharmacological, etc., problems. Most of the Project participants have mastered advanced methods for the synthesis of drugs and various organic and heterorganic compounds used as starting or intermediate products in the pharmaceutical industry. For a detailed description of the development and manufacturing of liposomal formulation at the “Biolek” plant (Patents of Ukraine 1997, 14596; 1994, 6700; 1994, and 5654).

* The originality of the Project is in the following:

  • synthesis of the novel-generation anti-TB drugs by derivatization of isoniazid using linear and heterocyclic organosilicon and organogermanium compounds;
  • development of a novel synthetic approach (one-pot synthesis) for the design of effective anti-TB drugs;
  • development of the drug delivery systems for the enhanced delivery of the anti-TB drugs to the infected cells/organs. These delivery systems will be engineered using various colloidal carriers, such as the nanoparticles and liposomes.
  • the potential of drug candidates and drug delivery systems will be evaluated using the comprehensive methodology including:
  • in vitro tests for evaluation of activity against mycobacteria sp.
  • tests for evaluation of activity against mycobacteria localized in macrophages
  • in vivo tests of drug efficacy in mice infected with TB
  • biodistribution studies
  • study of the mechanism of the interaction of the drugs with liposomes as model membranes.

The overall result of the Project will be presented as a well documented methodology, including:
  1. the advanced laboratory protocols for the synthesis of the target products selected by preliminary screening,
  2. the advanced laboratory protocols for the preparation of the colloidal drug delivery systems for the target products selected by preliminary screening;
  3. the protocols of the in vivo/in vitro tests designed specifically for the purpose of the project;
  4. the data on activity, efficacy, and pharmacokinetics of the most promising preparations.

The authors expect that this project will result in the development of an industry-applicable technology allowing an introduction of relatively inexpensive and potent medications in the clinical practice (specifically, in the field of chemotherapy of infectious diseases).

* The successful accomplishment of the Project will require intensive integrated studies based on the interdisciplinary approach and methodology. The following studies will be accomplished:

  • development of methods for the synthesis of novel organic and organoelement isoniazid-derived drugs and their physico-chemical characterization;
  • development of colloidal drug delivery systems for the enhanced drug targeting to the infected cells and inflammatory foci;
  • optimization of the methods for the synthesis of candidate nanoparticle-based drugs and manufacturing of the experimental batches for in vivo testing;
  • studies of the antimicrobial activity and biodistribution of the novel anti-TB drugs and drug delivery systems in vitro and in vivo.

The original methodology employed in the Project will rely on the advanced hi-tech synthetic and formulation strategies, analytical methods of new substances and formulations and comprehensive in-vitro/in-vivo testing.

In this respect, the Project is unprecedented.

*Importantly, the Project proposed here-in suggests active participation of the foreign collaborators who have consented to render methodological assistance in all problems related to the design and biological testing of new substances and formulations. Consistent with the scope of activities of the Project, our collaborators will also provide informational support and an opportunity for the extended visits of Russian scientists to their research entities for training and standardization of the experimental protocols. We also plan the exchange of materials and samples for testing and joint publications of experimental results in leading peer-reviewed journals

A noteworthy feature of this Project is the willingness of the National Jewish Medical and Research Center (USA) to participate directly in some experiments stipulated by the Technical Work Schedule, namely: testing and validation of the technologies and products developed during implementation of the Project.

The mutuality of benefit. We expect that the outcomes of the Project will create a good basis for the development of the novel generation of the effective anti-TB drugs thus contributing to elimination of TB. Persistence and growth of the global TB epidemic implies the mutuality of benefit for all participants.

Moreover, the results of this study may contribute to the development of the new trend in the pharmaceutical technology aimed at the creation of the novel generation of drugs, which is also beneficial for all participants. No doubt that the results of this study will be of interest for pharmaceutical institutes and enterprises in Russia, USA, and Canada, and for health authorities of these countries and UN/WHO organizations. This Project will definitely promote further integration of Russian scientists into the international scientific community.


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The International Science and Technology Center (ISTC) is an intergovernmental organization connecting scientists from Kazakhstan, Armenia, Tajikistan, Kyrgyzstan, and Georgia with their peers and research organizations in the EU, Japan, Republic of Korea, Norway and the United States.

 

ISTC facilitates international science projects and assists the global scientific and business community to source and engage with CIS and Georgian institutes that develop or possess an excellence of scientific know-how.

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