Production and evaluation of microparticulate drug delivery systems to enhance arterial chemoembolization

Embolization procedures are those that cut off the blood supply to an unwanted tumour using polymer microparticles or foams. The disruption of blood flow to these tumours prevents them from receiving adequate oxygen and nutrients, causing them to shrink or die. When a drug is also administered at the site of embolization to enhance treatment, the procedure is known as chemoembolization. Currently, chemoembolization is a widely used method for the treatment of a cancer known as hepatocellular carcinoma (HCC) which affects more that 1 million people, worldwide, each year. Chemoembolization for this condition usually involves the administration of a drug-containing emulsion into the hepatic artery, followed by the placement of an embolizing foam into the same blood vessel. Although relatively effective, there are two key drawbacks to this approach: 1) it involves two stages, adding complexity to the procedure and 2) drug release from the emulsion is not well controlled, which limits the exposure time of the tumour to the drug and may increase the drug-related side-effects that the patient experiences.The overall objective of this research is therefore to develop embolization particles that can also act as drug delivery systems. These would be able to block tumour blood vessels and deliver the required drugs in the most appropriate fashion. Emphasis will be placed on creating formulations that can be used to deliver a whole spectrum of different therapeutic agents, potentially extending the range of treatment options that clinicians have at their disposal. These particles could also be useful for treating other conditions such as uterine fibroids, which is a problem that troubles up to 25% of women at some point in their lives. Embolization is already used for the treatment of fibroids, but the co-administration of drugs at the target site could be beneficial e.g. to treat pain.A key part of the research will focus on developing the processes that can be used to produce these particles. A combination of conventional particle engineering strategies and those that use supercritical fluids will be explored. A supercritical fluid (SCF) is a fluid above its critical temperature and pressure. SCFs possess low viscosity and high diffusivity, and their density and solvent power are readily tunable by changing the temperature or pressure. Their interesting properties make them particularly useful in particle engineering and several techniques have been developed in which nano- and microparticles can be produced using SCFs. These methods can be more attractive than many conventional particle production techniques because:1. Micro and nano particles with a narrow size distribution can be produced in one step,2. The use of organic solvents can be eliminated or greatly reduced,3. The processes can be less damaging to labile substances, 4. The porosity of the resultant particles can be controlled by selecting appropriate operating conditions and materials. In this project, all of the above advantages are important, as it will be necessary to produce particles with defined size and microstructure and incorporate delicate drug molecules.Another important aspect of the work will be to test the products and ensure that they are of potential clinical use. In vitro studies to assess the drug loading capacity, drug release profiles, embolizing ability and physical properties of the particles will therefore be carried out.