Investigation of a new strategy for the controlled-release of drugs from bioresorbable inorganic matrices

Project Information

CONTRELL

Grant agreement ID: 239206

Project closed

Start date 15 September 2009

End date 14 September 2012

Funded under

• Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)

Total cost € 45 000,00

EU contribution € 45 000,00

Coordinated by

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
France

Final Report Summary - CONTRELL (Investigation of a new strategy for the controlled-release of drugs from bioresorbable inorganic matrices)

Scientific and social context

With the ageing of the population and the prevalence of diseases like cancer, there is a real need to develop efficient drug therapies with fewer side effects. While many research teams have worked on the synthesis of new drugs, others have focused more specifically on their formulation, to favour an optimal delivery of these drugs in the body.

The main objective of the CONTRELL project was to determine new ways of formulating drugs containing boronic and phosphonic acid functions. Indeed, although an increasing number of drug molecules contain these two functions, such as bortezomib (boronic acid with anticancer properties) and zoledronate (bisphosphonate with antiosteoporotic properties), there is still much room to propose innovative and efficient formulations for them. Thus, our goal was to formulate them under the form of hybrid organic-inorganic materials, the organic component being the drug molecule itself, and the inorganic component a bioresorbable material. One of the specificities of the approach was to try to carefully tune the interaction between the drug molecule and the inorganic matrix, by varying the nature and strength of the bonds between the two, and thereby control the release of the drugs.

Overview of the main scientific results

In practice, we first tested the feasibility and efficiency of our approach using model boronic and phosphonic acids instead of real drugs. Most of the syntheses of hybrid materials were thus performed on commercial R-B(OH)2 and R-PO(OH)2 molecules, or their conjugate bases (boronates and phosphonates). Given that the local environment of these molecules or anions within the material was expected to have a strong influence on their kinetics of release, a particular effort was made throughout the project to characterise this environment in detail, using spectroscopic techniques like solid state nuclear magnetic resonance (NMR). Finally, the kinetics of release of the molecules in simulated body fluids were evaluated in vitro, and rationalised considering the structure of the materials.

Concerning boronic acid-based molecules, organic-inorganic hybrid materials were synthesised using either boronic acids or boronates. In the latter case, the interaction with an inorganic biomaterial was expected to occur either through coordination to metal cations such as those commonly found in biomaterials (Ca2+, Sr2+ or Mg2+), or simply through electrostatic interactions. Given that no research had been performed on the coordination chemistry of boronate anions, and that their spectroscopic characteristics in the solid state had not yet been established, a fundamental study of crystalline Ca and Sr boronate phases was first carried out, as this appeared as a necessary landmark prior to the development of complex formulations. Following this initial work, more sophisticated organic-inorganic materials were then synthesised, and in each case, the mode of interaction of the drug molecule with its carrier matrix was investigated by solid state NMR. In vitro kinetic studies were then performed, showing that depending on the inorganic matrix chosen, the kinetics of release of the model molecules can indeed be varied.

In the case of the phosphonic acid model molecules and phosphonates, one of the main aspects studied was their adsorption at the surface of calcite and apatite particles (both of which can be considered as biodegradable materials). The mode of interaction of these anions at the surface of the materials was identified using solid state NMR. The behaviour of the functionalised materials in simulated body fluids was then investigated, showing the fast exchange of surface phosphonates in physiological fluids.

As solid state NMR appeared to be one of the key techniques to use to characterise in detail the structure of these complex hybrid materials, much effort was made throughout this project to develop and apply different NMR techniques adapted to the structural analysis of biomaterials. In particular, NMR sequences suitable for the study of the local structure around Ca, Mg and Sr were looked into, these three elements being commonly found in inorganic and hybrid biomaterials.

Based on the results obtained on the model molecules, the work has been extended to the preparation of novel formulations for boronate based drugs, whose structure and properties have been evaluated in vitro.

Conclusions and outcomes

The work carried out throughout the CONTRELL project has led to significant outcomes, for both fundamental and applied research. The main highlights in our sense are the following:

1. First and foremost, the preparation of novel formulations of boronic acid drugs based on hybrid organic-inorganic materials. This is all the more important given the increasing number of boronic-acid based drugs developed.
2. The development of a new family of hybrid materials based on boronic acid / boronate building blocks. Given the wide range of applications of hybrid materials, it is expected that such materials will find developments well beyond the drug delivery applications explored here.
3. The development of solid state NMR characterisation techniques, adapted to the study of hybrid materials, and more specifically of the local environment of some of the metal cations present in such biomaterials, like calcium, magnesium and strontium, the latter actually being a very important element to consider for osteoporosis treatment.
4. The first extensive study of the coordination chemistry of boronate anions and of their spectroscopic characteristics in the solid state, which is important for the preparation of new molecular materials or coordination polymers.

Research on the work initiated during the CONTRELL is being continued at the Institut Charles Gerhardt in Montpellier, in collaboration with other laboratories in France and Europe. The results already obtained place the European Research Area (ERA) at the centre stage for the development of new exciting knowledge-based materials and drug formulations in the future.

Researchers to contact for further details about the project:

- Dr Danielle Laurencin ([e-mail] via e-mail)
- Dr Hubert Mutin ([e-mail] via e-mail)

Webpage:

http://www.cmos.icgm.fr/spip/IMG/pdf/CONTRELL_ERG.pdf

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