Development of a Personalised Device for Systemic Magnetic Drug Targeting to Brain Tumours.

Delivering therapies to deeply seated brain tumours (BT) is a major clinical challenge. Magnetic drug targeting (MDT) could overcome this by rapidly transporting magnetised drugs directly into BT. We have developed a magnetic device for application in murine BT models using an array of neodymium magnets with a combined strength of 0.7T. In a closed fluidic system, the magnetic device trapped magnetic nanoparticles (MNP) up to distances of 0.8cm. In mice, the magnetic device guided intravenously administered MNP (<50nm) from the circulation into the brain where they localised within mouse BT. Furthermore, MDT of magnetised Temozolomide (TMZmag+) significantly reduced tumour growth and extended mouse survival to 48 days compared to the other treatment groups. Using the same principles, we built a proof of principle scalable magnetic device for human use with a strength of 1.1T. This magnetic device demonstrated trapping of MNP undergoing flow at distances up to 5cm. MDT using our magnetic device provides an opportunity for targeted delivery of magnetised drugs to human BT.

Magnetosomes and Magnetosome Mimics: Preparation, Cancer Cell Uptake and Functionalization for Future Cancer Therapies.

Magnetic magnetite nanoparticles (MNP) are heralded as model vehicles for nanomedicine, particularly cancer therapeutics. However, there are many methods of synthesizing different sized and coated MNP, which may affect their performance as nanomedicines. Magnetosomes are naturally occurring, lipid-coated MNP that exhibit exceptional hyperthermic heating, but their properties, cancer cell uptake and toxicity have yet to be compared to other MNP. Magnetosomes can be mimicked by coating MNP in either amphiphilic oleic acid or silica. In this study, magnetosomes are directly compared to control MNP, biomimetic oleic acid and silica coated MNP of varying sizes. MNP are characterized and compared with respect to size, magnetism, and surface properties. Small (8 ± 1.6 nm) and larger (32 ± 9.9 nm) MNP are produced by two different methods and coated with either silica or oleic acid, increasing the size and the size dispersity of the MNP. The coated larger MNP are comparable in size (49 ± 12.5 nm and 61 ± 18.2 nm) to magnetosomes (46 ± 11.8 nm) making good magnetosome mimics. All MNP are assessed and compared for cancer cell uptake in MDA-MB-231 cells and importantly, all are readily taken up with minimal toxic effect. Silica coated MNP show the most uptake with greater than 60% cell uptake at the highest concentration, and magnetosomes showing the least with less than 40% at the highest concentration, while size does not have a significant effect on uptake. Finally, surface functionalization is demonstrated for magnetosomes and silica coated MNP using biotinylation and EDC-NHS, respectively, to conjugate fluorescent probes. The modified particles are visualized in MDA-MB-231 cells and demonstrate how both naturally biosynthesized magnetosomes and biomimetic silica coated MNP can be functionalized and readily up taken by cancer cells for realization as nanomedical vehicles.

Targeted magnetic nanoparticle hyperthermia for the treatment of oral cancer.

INTRODUCTION: Patients with oral squamous cell carcinoma currently experience a five-year survival rate of approximately 60% with conventional surgical, chemotherapy and radiotherapy treatments. Magnetic hyperthermia offers an alternative treatment method by utilising the heating properties of magnetic nanoparticles to produce thermal ablation of the tumour site when exposed to an alternating magnetic field. In this study, we investigate in vitro if targeted magnetic hyperthermia offers a potential treatment for oral squamous cell carcinoma. MATERIALS AND METHODS: Magnetic iron oxide nanoparticles, with a biocompatible silica coating, were produced and conjugated with antibodies to target integrin αvß6, a well-characterised oral squamous cell carcinoma biomarker. Utilising the heating properties of the magnetic nanoparticles, we exposed them to an alternating magnetic field to produce thermo ablation of tumour cells either negative for or overexpressing integrin αvß6. RESULTS: The cell surface biomarker, αvß6 integrin, was upregulated in tissue biopsies from oral squamous cell carcinoma patients compared to normal tissue. Functionalisation of the silica coating with anti-αvß6 antibodies enabled direct targeting of the nanoparticles to αvß6 overexpressing cells and applying thermal therapy significantly increased killing of the targeted tumour cells compared to control cells. CONCLUSION: Combining antibody-targeting magnetic nanoparticles with thermal ablation offers a promising therapy for the targeted treatment of oral squamous cell carcinoma.

A biomimetic magnetosome: formation of iron oxide within carboxylic acid terminated polymersomes.

Bioinspired macromolecules can aid nucleation and crystallisation of minerals by mirroring processes observed in nature. Specifically, the iron oxide magnetite (Fe3O4) is produced in a dedicated liposome (called a magnetosome) within magnetic bacteria. This process is controlled by a suite of proteins embedded within the liposome membrane. In this study we look to synthetically mimic both the liposome and nucleation proteins embedded within it using preferential orientation polymer design. Amphiphilic block co-polymers self-assemble into vesicles (polymersomes) and have been used to successfully mimic liposomes. Carboxylic acid residue-rich motifs are common place in biomineralisation nucleating proteins and several magnetosome membrane specific (Mms) proteins (namely Mms6) have a specific carboxylic acid motifs that are found to bind both ferrous and ferric iron ions and nucleate the formation of magnetite. Here we use a combination of 2 diblock co-polymers: Both have the hydrophobic 2-hydroxypropyl methacrylate (PHPMA) block with either a poly(ethylene glycol) (PEG) block or a carboxylic acid terminated poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) block. These copolymers ((PEG113-PHPMA400) and (PMPC28-PHPMA400) respectively) self-assemble in situ to form polymersomes, with PEG113-PHPMA400 displaying favourably on the outer surface and PMPC28-PHPMA400 on the inner lumen, exposing numerous acidic iron binding carboxylates on the inner membrane. This is a polymersome mimic of a magnetosome (PMM28) containing interior nucleation sites. The resulting PMM28 were found to be 246 ± 137 nm in size. When the PMM28 were subjected to electroporation (5 pulses at 750 V) in an iron solution, iron ions were transported into the PMM28 polymersome core where magnetic iron-oxide was crystallised to fill the core; mimicking a magnetosome. Furthermore it has been shown that PMM28 magnetopolymersomes (PMM28Fe) exhibit a 6 °C temperature increase during in vitro magnetic hyperthermia yielding an intrinsic loss power (ILP) of 3.7 nHm2 kg-1. Such values are comparable to commercially available nanoparticles, but, offer the added potential for further tuning and functionalisation with respect to drug delivery.