Ph.D. University of Bordeaux 1 (France) 2003; Post-Doctoral Tokyo University (Japan) 2004; Post-Doctoral Indiana University (IN) 2004
Preparation of nanovectors
Need of better delivery systems
Several challenges need to be overcome in chemotherapy to markedly increase its efficacy and potency. Chief among them, multiple side effects and the occurrence of drug resistance severely compromise the efficacy of chemotherapy. Whereas several drug delivery systems exist and intense research is done on combined therapy and on tumor targeting, the simultaneous targeting of different therapeutic entities to the cancer cells is still an area of research to be developed.
Nanovectors: new types of drug delivery systems
Nanovectors represent a valid approach to fulfil this need due to their inherent high multivalency and versatility. Indeed, nanovectors are in general composed of at least three main parts: - a nanometer sized core (hollow or solid) - a therapeutic and/or imaging load and some tumor cell recognition component.
The nanoscale of the nanovectors endows them with unique properties. Among them, their potential for a large cargo of similar and/or different functions and their reduced clearance time confer on them superiority over traditional drug carriers. Indeed, their dimensions make them big enough to avoid elimination by renal filtration while enabling them to bear multiple functionalities. Also, they can integrate means to bypass biological barriers. For instance, it is now well established that the use of PEG is a very good option to avoid recognition by the immune system. Nanovectors are still small enough (< 100 nm) such that the uptake by macrophages of the RES, leading to body clearance, remains minimal.
Advantages of gold nanoaprticles and dendrimers
Gold nanoparticles (GNPs) and dendrimers have already shown great potential for therapeutic use. GNPs are biocompatible and inert. Their synthesis is easy and cheap. Their size and coating can be modulated as desired (2 to 100 nm in size). Dendrimers are synthetic polymeric molecules composed of multiple perfectly branched monomers that emanate radially from a central core, leading to a spherical shape. Due to their size (nanometer scale), their low polydispersity and their multifunctionality, dendrimers have found use as drug carriers conferring low cytotoxicity, membrane permeability and targeting capabilities.
Dendrons can be described as fragments of dendrimers, being hyper-branched organic molecules with a terminal focal point allowing for attachment to a central core. In this project, the focal point is used as the site of binding to the surface of the GNPs.
The strategy here is as follows. By using a central anchoring GNP, and attaching dendron units with distinct functionalities, it will be possible to generate a potent drug delivery vehicle for different tumor therapies. These functionalities are chemotherapeutic drugs, targeting ligands and imaging enhancers. This strategy will be applied to three types of cancer: pancreatic, breast and prostate cancers.