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Biodegradable controlled drug delivery systems for the treatment of brain diseases

   
Project

QLK3-2001-02226

Cell factory area

3.1.3

EU Contribution

2 228 703 Euro

Duration

36 months

Type

Research project

Starting date

01-01-2002

Keywords
blood-brain barrier
central nervous system
intracranial implants
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ABSTRACT
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The major objective of the present project is to develop new therapeutic strategies for the treatment of brain diseases. The aim is to restore, maintain and improve cell, tissue and organ functions within the Central Nervous System (CNS). Emphasis is on two kinds of diseases: brain cancer and neurodegenerative disorders, namely Parkinson's and Huntington's Disease. The treatment of CNS diseases is very difficult due to the Blood Brain Barrier, which hinders most drugs from reaching the brain tissue.

Thus, target-specific delivery systems are required. Using a multi-disciplinary approach we will develop new biodegradable microparticles and implants releasing highly potent drugs in a controlled manner into the CNS. The whole range of innovation, from advanced research, through technological development up to in vivo evaluation in animal models will be covered. With an industrial company being part of the consortium, we foresee the economic exploitation of the outcoming scientific results.

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OBJECTIVES
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The major objective of this project is to develop new and improved therapeutic strategies for health care, in particular for the treatment of brain diseases. The aim is to restore, maintain and improve cell, tissue and organ functions in the Central Nervous System (CNS).

Emphasis is on the treatment of two kinds of diseases:

  • Brain cancer.
  • Neurodegenerative disorders, such as Parkinson's and Huntington's Diseases.

The treatment of CNS-diseases is extremely difficult because of the Blood-Brain-Barrier (BBB). Only low molecular mass lipid-soluble molecules, and a few peptides and nutrients can cross this barrier to a significant extent, either by passive diffusion or using specific transport mechanisms. Thus, for most drugs it is difficult to achieve therapeutic levels within the brain tissue. In addition, highly potent drugs (e.g., anticancer drugs and neurotrophic factors) that may be necessary to be delivered to the CNS, often cause serious toxic side effects when administered systemically. Thus, target-specific delivery systems, providing the transport of the drugs exclusively to the brain tissue are highly desireable.

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DESCRIPTION OF THE WORK
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The workplan will be broken down into four individual, multi-disciplinary work packages (WPs):

  • Understanding the mechanisms involved in target-specific drug delivery to cns cells.
  • Development of new biodegradable microparticles for intracranial implantation.
  • Development of new pre-programmemable biodegradable intracranial implants.
  • In vivo testing of the newly developed therapeutic strategies.

WP1 aims at gaining new scientific knowledge about the transport mechanisms involved in drug release from controlled drug delivery systems into the brain tissue. This information is essential for an intelligent design of both types of new intracranial systems: new biodegradable microparticles and new pre-programmemable implants. Various physico-chemical methods will be used to characterise the newly developed pharmaceutical devices.

WPs2 and 3 encompass both, the optimisation of the design parameters and the development of suitable experimental methods to manufacture these systems in a laboratory and industrial scale. Particular attention will be paid to the biological activity of the incorporated drugs, e.g. proteins risk loosing their pharmacodynamic activity when exposed to liquid-liquid interfaces. Adequate precautions will be taken and the biological activity will be monitored with cell culture tests.

For the evaluation of the in vivo performance of the newly developed devices, WP4 encompasses animal studies for both types of diseases (brain tumour and neurodegenerative disorders). The results obtained will be essential to provide immediate feedback to the other WPs. The in vivo data will be used to optimise the design of the new systems and evaluate the theories concerning the drug transport mechanisms. Particular attention will be paid to the establishment of possible in vitro/in vivo correlations, allowing the minimisation of the required number of animal studies to test and optimise the new pharmaceutical dosage forms.

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DELIVERABLES
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  • Determination of the mechanisms involved in target-specific drug delivery to CNS cells.
  • Development of new biodegradable microparticles and intracranial implants being able to release highly potent drugs at optimal, pre-determined rates into the brain tissue.
  • In vivo evaluation of promising candidates in animal models for brain tumor and neurodegenerative disorders.
  • Transfer of the obtained new scientific knowledge to industrial applications, e.g., scale-up of manufacturing procedures.

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CONSORTIUM
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COORDINATOR
  Jean-Pierre Benoit
UFR de Pharmacie
University of Angers
49045 Angers, France
Tel: +33 241735858
Fax: +33 241735853
jean-pierre.benoit@univ-angers.fr

PARTNERS
  Achim Goepferich
College of Pharmacy
Universitaet Regensburg
93040 Regensburg, Germany
Tel: +49 9419434842
Fax: +49 9419434807
achim.goepferich@chemie.uni-regensburg.de

Alexander T Florence
School of Pharmacy
University of London
WC1N 1AX London, United Kingdom
Tel: +44 2077535819
Fax: +44 2078375092
a.t.florence@ulsop.ac.uk

Philippe Menei
School of Medicine
University of Angers
49045 Angers, France
Tel: +33 241354822
Fax: +33 241354508
Phmenei@chu-angers.fr
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