Student: Patrick Bergstrom Mann
The use of quantum dots (QDs) in imaging is now widespread, but the preparation of water-soluble and non-toxic luminescent materials is non-trivial and still the topic of much investigation; the correct emitting core, shell species and surface ligands are essential if one is to reproducibly prepare nanoparticles with stable optical properties and biocompatibility.
Organometallic synthesis is the usual route to prepare quantum dots used for cell labelling and is now relatively routine however, the majority of materials are initially insoluble in water and require phase transfer using a specific surface ligand, into which can be engineered further functionalities for conjugation. This ligand system is the key factor for the successful preparation of such materials. Numerous simple ligands have been used with varying degrees of success, and a successful ligand system can be broken down into three major components; 1) the surface coordinating group; 2) the ligand backbone; 3) the optional functional group for further conjugation.
The surface coordinating group is required to strongly bind to the nanoparticle surface. QDs stabilised with bidentate species have been shown to maintain stability in solution for months, whereas monodentate passivated species are often only stable for a matter of hours. The ligand backbone is often used to impart water solubility, by using a polyethylene glycol (PEG) species. PEGylated ligands are known to reduce the toxicity of the nanoparticles and improve their systemic circulation, improving their efficiency. The final element of a capping agent is the linking functional group. This unit is often used in induce water solubility, although this is problematic as once the functional group is linked to a biological material such as an antibody, the water solubility of the particle may be lost. For a system to be ideal, all three elements need to be available and controlled, allowing efficient, strong and irreversible coordination to a nanoparticle surface, a controllable ligand back bone and functional group. Bisphosphonate ligands are ideal as they allow all these elements to be controllable. Bisphosphonates are available as therapeutic agents (osteoporosis) and have been clinically used for more than 20 years. Their mechanism of action is that they “stick” onto the calcium and in this way protect the bone from enzymes. In our project, we aim to mimic this effect and use this ability of bisphosphonates to coordinate metals to passivate QDs.
During the last three years, the research groups of Prof Long, Dr Green and Dr Thanou have carried out preliminary experiments on the potential of bisphosphonates (synthesised and commercially available) to be used as capping ligands for cadmium-based QDs. Their results have confirmed the potential of bisphosphonates to be used as ligands for QDs. The resulting bisphosphonate QDs showed dramatically enhanced water solubility without the loss of fluorescence intensity. Cytotoxicity experiments showed that these QDs did not affect cell viability nor increase the reactive oxygen species. In preliminary experiments, these dots were able to clearly label cell compartments, as well as labelling different organs when injected in vivo into mice.