Developing functionalised artificial magnetosomes as theranostic agents for cancer nanomedicine

Nanomedicine is a rapidly developing field which utilises the unique properties of nanomaterials for the treatment and diagnosis of disease. Current nanomedicines are predominantly used for the delivery of drugs and other treatments, and the majority of these are liposome based. Although they have been shown to be able to deliver treatments directly to the cell there are disadvantages such as the high cost of synthesis and difficulty in storage. The development of newer nanomaterials, including polymersomes, allow for the formation of nanomedicines that are biologically safe and have the ability to be functionalised. Magnetic nanoparticles (MNPs) offer unique properties for nanomedicine. Their magnetism allows them to not only be magnetically targeted to the site of interest but also the ability to generate heat when exposed to alternating magnetic fields, allowing for a targeted method of hyperthermia treatment. Here I show that MNPs can be synthesised with sufficient magnetic properties to generate heat at therapeutically relevant temperatures of over 45 °C with a specific absorbance ratio of 49.82 ± 3.412 W/g. These particles are coated with a biocompatible coating that enables the functionalisation of the MNPs. These particles were synthesised at two clinically relevant sizes to compare their suitability for use. These were 21.9 ± 3.2 nm and 42.12 ± 12.66 nm and produced using a coprecipitation reaction with a forward and reverse addition of iron salt solution. The synthesised particles were well tolerated by two breast cancer cells lines at concentrations up to 200 µg/ml and internalised at concentrations from 5 – 200 µg/ml, this internalisation was observed to be a concentration dependant effect with higher concentrations showing a greater amount of internalisation. Internalisation was measured over a 24-hour period and there was seen to be no time dependent factor in the internalisation of these particles. The use of hyperthermia in the treatment of cancer has been well established.1 Here I show that hyperthermia is not only capable of inducing thermoablation and coagulative necrosis of cancers of tumours, but that mild hyperthermia can sensitise cells to poly ADP ribose (PARP) inhibitors through the degradation of Breast Cancer Gene 2 (BRCA2) protein. Although a single treatment was sufficient for BRCA2 degradation it was seen that multiple treatments were required for effective treatment with hyperthermia and combined PARP inhibition. Although the synthesised MNPs showed great promise in hyperthermia treatment, they are not true bio-mimics of magnetosomes, I have developed a method of synthesis of iron oxide within a pre-formed polymersome. The advantage of this method is that it allows the predetermination of the vesicle size and the composition by altering the ratio of polymer chains and the functional groups. The presence of acidic residues on the inner membrane was seen to dramatically affect the formation of iron oxides within the inner lumen of the polymersomes. By altering the concentration of the iron salt solution as well as the size of the lumen core, the size of the formed iron oxide nano particle was altered.