Multi-scale approach to designing novel colloidal drug delivery vehicles

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A large number of the small molecules currently under development as drug candidates are hydrophobic, and as a result many of these drugs may not make it to market because of problems encountered due to poor water solubility. Therefore, in order to fully exploit their therapeutic potential, it is essential to incorporate such drugs in nontoxic, biocompatible and/or biodegradable formulations that both protect the drug during transportation in the body and release it at the target tissue. In the past few decades, there have been an increasingly large number of nanoparticle formulations created, many of which have been investigated for their biomedical applications. Among these applications, drug delivery has been one of the more prevalent for nanoparticles composed of organic molecules, as such particles can be used to enhance the apparent aqueous solubility of the encapsulated molecules as well as specifically direct the molecules to the site of the diseased tissue. One class of lipid of particular interest in drug delivery is phosphatidylcholines. Phosphatidylcholines are predominantly known as the majority components of cell membranes but they are also amphiphilic lipids that can self-assemble to form micelles. These lipids have low CMCs and small alterations in their hydrophobic tail length can cause dramatic changes to their micelle properties. This, along with their biocompatibility, makes them attractive compounds to investigate with regards to their use in the delivery of poorly soluble drugs as solubility can be increased by encapsulating them within the hydrophobic core of the micelle. The resulting micelles are then degraded in the body to release the drug load and functionalisation of these molecules can allow targeting of specific tissues. This project combines the relative strengths of atomistic and coarse-grain molecular dynamics (MD) simulations with a range of advanced biophysical tools, such as small-angle neutron and light scattering and NMR, to generate a very detailed picture of how the underlying chemical properties of lipidic molecules used to prepare self-assembling nanoparticles (SANs) affect the architecture of the resulting drug delivery vehicle. This project will initially involve investigating a series of zwitterionic lipids, including phosphoatidylcholine lipids of different lengths, to evaluate the internal and interfacial structure of the SANs that they form. Additionally, we will characterise the location and amount of small hydrophobic drug molecules (including testerosterone enanthate and proprionate) loaded within the SANs. After understanding how the basic chemical properties of these initial molecules influence the architecture and ability of the resulting SANs to act as drug delivery vehicles the project will then go on to investigate the formation of novel SANs through selection of lipids and monomers based on their respective strengths in order to achieve the optimum combination of properties that the SANs require, this includes the possibility of functionalizing these SANs for targeted drug delivery and looking at the impact this may have on the nanoparticle.We will be able to discern the self-assembly and drug encapsulation mechanisms of these SANs, and determine the interactions which are key in both processes. Both MD simulations and experimental techniques will additionally be used to understand and model the degradation of these drug delivery vehicles and to investigating the fate of the degradation products.