Bio-functional Magnetic Nanoparticles: Novel High-Efficiency Targeting Agents for Localised Treatment of Metastatic Cancers

Lead Research Organisation: University College London
Department Name: Oncology

Abstract

One of the greatest healthcare challenges facing the world today is the treatment of metastatic cancer. Although we know a great deal about how to treat tumours once they grow more than a few millimetres in size, it is the unseen me-tastases that spread out from a primary site that more often than not are the cause of fatalities. We are forced to resort to systemic treatments, to chemotherapy and radiotherapy, which place the entire physiology under severe strain, af-fecting healthy cells almost as much as they do the cancer cells. There is a pressing need for viable alternatives, and clinicians and scientists have been pursuing such goals for decades. Although there have been successes, for the most part it has been impossible to deliver therapeutic agents to the sites of metastases in sufficiently high doses. Attention has turned to 'payload' methods, where the targeting biomolecule is used to carry a therapeutic agent to the cancer, and some external stimulus is applied to activate it. The best of these are based on the use of inorganic nanoparticles which, under stimulation, are designed to release heat. These hyperthermia approaches are ideally suited to cancers, which are highly susceptible to heat-induced cellular stress. Hyperthermia also has great potential as an adjuvant therapy, since just a degree or two of local heating can significantly increase the effectiveness of chemotherapy and radiotherapy, reducing their required doses and thereby reducing the harmful side-effects. Even so, to date there has been little real success in attempts to implement localised hyperthermia, despite promising bench results. The key failure lies in the required dose-response characteristics of the therapy, which exceed the capa-bilities of the best approaches attempted so far. One approach, volumetric induction heating of magnetic nanoparticles using megahertz applied fields, is intrinsically efficient. However, even here efforts are hampered by a reliance on 30-year-old induction heating electronics - more befitting an arc-welding workshop than a hospital clinic - so that only one clinical trial has yet been attempted. It is therefore no wonder that our announcement earlier this year of a new breakthrough invention - an induction heat-ing circuit we call the Magnetic Alternating Current Hyperthermia (MACH) system - was greeted with enormous media attention. The MACH system embodies three ground-breaking innovations which together enable, for the first time, construction of an extremely high performance, robust system that can feasibly be used in the clinic. Of particular note, it allows for a hand-held coil to be attached to the heater, and for miniaturisation or even catheterisation of the appli-cator. The prospects are suddenly wide open for real clinical application of hyperthermia to treat metastatic cancer, and for widespread exploitation of this UK-owned technology in an exceptionally large market. To translate this promise into achievement requires significant efforts, and most importantly, well-focused efforts. To this end we have consulted widely and brought together an excellent team of academics, clinicians and companies, from start-ups to conglomerates, to work together on an implementation plan. Key to this plan is to move as fast as possible to clinical outcomes, to engage quickly with patients, clinicians and health services to establish efficacy and credibility, and to build a platform for innovation for years to come. We have chosen to adopt a dual approach of (1) proving the clinical efficacy of the MACH system for localised hyperthermia on two especially well suited cancer exemplars - head and neck cancer and lung cancer; and (2) developing 'stealth' antibody-tagged magnetic nanoparticles suitable for intravenous injection, and able to evade the reticulo-endothelial system and accumulate at metastatic sites. These then are the goals of our Nanotechnology Grand Challenge.

Publications

10 25 50

publication icon
O'Brien, Paul; Green, Mark; Pattrick, Richard; Corr, Serena; Imai, Hiroaki; Haigh, Sarah; Young, Robert; Pradeep, T. (2012) Nanoscience: v. 1: Nanostructures Through Chemistry

publication icon
Ortega D (2012) Nanoscience

 
Description At the heart of this Grand Challenge there are two fundamental scientific concepts. Concept 1 is that 'stealth' particles comprising conjugates of cancer-seeking antibodies and magnetic nanoparticles can be developed that on injection into the bloodstream can evade the body's reticulo-endothelial system (RES) and lodge in significant concentrations at the sites of metastatic cancer. We have comprehensively proven this to be possible during the last three years, for two specific cases - 'Dartrix particles', which target via exceptionally high-affinity/specificity protein scaffolds called Darpins (designed ankyrin repeat proteins), and particle-loaded cancer-seeking mesenchymal stem cells (MSCs). In both cases we have used a commercially available particle (Ferucarbotran) that has excellent heating properties.

It should be noted that unlike the MSCs, the dextran-coated Dartrix particles do not naturally elude the RES, and in fact are usually taken up rapidly by the liver's Kuppfer cells. However, during our Stage 1 work we found that pre-treatment with dextran or dextran sulphate can substantially reduce the RES uptake in vivo. The use of dextran-70 (which was previously unknown and therefore is patentable IPR) is particularly attractive as it is a standard pharmaceutical plasma expander used in patients suffering from trauma, burns and hypotension.

Concept 2 is that localised hyperthermia is a viable therapeutic modality for treating cancer. This has also been comprehensively proven through our Stage 1 work, and the development of the MACH (magnetic alternating-current hyperthermia) system. As shown in Figure 3, local temperature rises as high as 10 °C are accessible, which is ample to elicit a therapeutic response: temperatures above 42 °C result in a pro-nounced increase in cell death rate, and even moderate hyperthermia (40-46 °C) results in cytotoxic protein destabilization, which can be used to good effect when synergistically combined with standard treatments such as radiotherapy, brachytherapy, and chemotherapy.

Two further underlying principles relate to the translational task of establishing a new medical technology and treatment pathway. Whereas radiotherapy is the currently established global technology for cancer therapy, magnetic hyperthermia is at the dawn of its applicability. It has the potential to transform the way cancer is treated in 5-10 years time, and in our follow-on work, steps will be taken to make this happen. It is essential to build trust and confidence amongst regulatory and clinical professionals and with patients.

Furthermore, it is essential that we offer something new and better: the targeted treatment of metastatic cancer. We therefore adopt Concept 3, which is that we should move as fast as possible to establish the efficacy of MACH hyperthermia in a human clinical trial - even if this is not a metastatic cancer model, and does not use stealth particles. In fact, we will use locally-administered antibody-targeted Ferucarbotran in a brain cancer clinical trial, followed soon thereafter by a prostate cancer trial using directly-injected Feru-carbotran. The reason to use Ferucarbotran is that it is the active ingredient of the FDA-approved MRI contrast agent, Resovist - and as such, there exists 20 years worth of recorded human-use data on which to base a safety risk assessment, and thereby secure ethics and regulatory approval for a trial. The downside is that Ferucarbotran particles are not stealth - indeed, they are designed for rapid take-up in the liver - hence the need for either local injection (with co-infused dextran-70 for RES interference), or cellular encapsulation in naturally homing MSCs.

Concept 4 is that the real goal remains the treatment of metastatic cancer. This is the true Grand Challenge. To get there we need to develop GMP-standard, FDA-approvable, targeted, stealth particles. As part of our Stage 1 work we synthesised three best-in-class MACH heating particles, including those from a world-first microwave-assisted Na2CO3-mediated production route. In our follow on work we are taking these through to GMP-standard production using the in-house UCL Oncology GMP Facility. A key part of our strategy is to develop and capture the IPR and the know-how needed to manufacture bespoke GMP magnetic nanoparticles - especially the standard operating procedures (SOPs) - so that in due course we might set up a commercial production venture to further promote the technology.
Exploitation Route Our findings are of general interest to the scientific community as they re;ate to the fundamental science of magnetic hyperthermia, as well as being of direct relevance to healthcare professionals, with respect to the potential to deliver therapeutic heat in a safe, effective and fundamentally new way.
Sectors Healthcare

 
Description The findings of our work here was the bedrock of a subsequent EU Framework 7 project, 'Dartrix', which is described below: DARTRIX, 'DARPinTargeted RX (therapy)' is a multidisciplinary collaborative project developing non-immunoglobulin protein scaffolds to create a new generation of targeted therapeutics. DARTRIX is pioneered for treatment of glioblastoma, a highly infiltrative and rapidly progressive tumour. DARTRIX comprises a novel experimental approach, integrating the disciplines of biology, physics and medicine, to investigate the treatment potential of localised hyperthermia with tumour-targeted biocompatible iron oxide particles. In current clinical practice, these particles are used as contrast agents for magnetic resonance imaging (MRI). However, iron oxide can be induced to generate heat when placed in an alternating field - a process called magnetic alternating current hyperthermia (MACH); the magnetic field is harmless but the heat released by the iron oxide transduction of the electromagnetic energy readily results in temperatures above 42°C. Ferucarbotran, an iron oxide particle that has been used clinically as an MRI contrast agent, is an excellent generator of heat in the MACH system has great potential to deliver hyperthermic therapy. However, Ferucarbotran is not tumour specific. Thus, the strategy of DARTRIX is to develop a means to localise Ferucarbotran in cancerous areas using tumour specific protein scaffolds made of Designed Ankyrin Repeat Proteins (DARPins). DARPins are small, human protein scaffolds that are readily generated to bind specific targets with exceptionally high-affinity. The DARTRIX project aims to exploit these properties to create a new safe and efficient medical device by coupling tumour-specific DARPins to Ferucarbotran to create a DARPin-Ferucarbotran complex or novel 'DARTRIX particle'. The work was also fundamental to an NIHR i4i grant, 'Magnetic Thermoablation in the Treatment of Early Prostate Cancer', described below: Men with prostate cancer that has not spread face a number of options. These lie between the extremes of care; active surveillance (monitoring the disease) and whole-gland surgery/radiotherapy. The difference between these ends of the spectrum in terms of reducing the chance of a man dying from his disease is small. The problem is that many men want to have treatment and those treatments carry side-effects. These occur because of damage to surrounding tissue and result in 1 man in 5 suffering incontinence of urine, 1 man in 2 with erectile dysfunction and 1 man in 10 with back-passage problems (bleeding, diarrhoea, discomfort). We have been working on reducing these treatment related harms for the last 5 years. We have used a number of minimally-invasive treatments which use heat, light or cold to destroy tissue. We have not found one yet that is the optimal treatment. In other words, one that can be done under local anaesthetic, repeated if necessary, can effectively destroy small prostate areas which are cancerous, limit damage to surrounding tissues and adaptable to future discoveries such as molecular targeting of cancer cells. We think magnetic thermoablation may be able to deliver on these attributes. This involves injection of iron particles which heat up when a magnetic field is applied. This means there is no radiation or surgery involved. If we can safely inject these iron particles close to the cancer cells the heating can be delivered very close to where we want it to be. Our group has done a lot of the preclinical work already to develop this type of treatment. We now need to take it to the next stage and develop a product that can be tested in larger trials and commercialised early so that patients in the NHS and beyond can benefit.
First Year Of Impact 2004
Sector Healthcare
Impact Types Societal

 
Description Cancer Research UK
Amount £213,800 (GBP)
Funding ID CRUK Research Fellowship-Tom Oxenham 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Company Name Resonant Circuits Limited 
Description Magnetic hyperthermia R&D 
Year Established 2009 
Impact Development of a magnetic hyperthermia device, MACH.
Website http://www.resonantcircuits.com