New Imaging Methods for Functional Changes in Diagnostic Nanocomposite Particles

Background: Inorganic/Organic Nanocomposite Particles (I/O-NP) are being developed for use in diagnostic medicine. I/O-NP is a platform technology that is composed of functional polymeric organic nanoscale structures (50-200 nm) in which smaller metallic nanoparticles (2-20 nm) are encapsulated. I/O-NPs offer a new class of biologically responsive, functional materials through fine tuning nanostructure composition and architecture. The encapsulation of magnetic iron oxide nanoparticles within biologically responsive organic nanostructures are being developed; polymeric particles are designed to swell or contract in response to biological stimuli, causing reversible variation of interparticle proximity and rotation dynamics of the encapsulated iron oxide nanoparticles, which would elicit a responsive behaviour in their magnetic signal. Such stimuli could be achieved through tailored I/O-NP synthesis to incorporate disease specific targeting vectors or antibodies, allowing for disease pathogen and viral load quantification in response to pharmaceutical intervention. On an individual patient basis, such quantitative disease state monitoring would accelerate the transition from conventional medicine towards personalised, precision medicine. In the long-term, acquired data from larger patient cohort monitoring following response to drug dosage would be integrated into in-silico models to allow for greater predictive power for medical prescription, allowing for population driven predictive modelling towards optimising global drug regimen administration.

Problem: The detection of discrete, key functional changes in I/O-NP structure following biological stimulation. I/O-NPs offer novel functionality beyond traditional diagnostic imaging tracers. However, current standard detection methods are not capable of monitoring their key functional changes; imaging techniques such as MRI as well as laboratory techniques such as SQUID are not sensitive enough to detect such fine variation of magnetic signal.

Solution: To develop a prototype scanner, termed FS-MPI. The proposed novel device combines the principles of frequency dependent detection of magnetic susceptibility (FS) with the ultrasensitive detection mechanism of Magnetic Particle Imaging (MPI). MPI is a highly sensitive, emerging imaging technique able to detect nanomolar concentrations of Superparamagnetic Iron Oxide Nanoparticle (SPION) tracers. Magnetic tracers are imaged directly allowing for highly sensitive, quantitative detection with no background signal. Furthermore, MPI allows for both quantification and real-time functional imaging with more than a thousand-fold contrast-to-noise improvement on a per-mole basis over MRI, providing bright contrast. Through the combination of MPI with techniques established for characterising ferromagnetic and superparamagnetic thin film nanostructures (e.g. AC susceptibility; the background of the Solution Provider), a new FS-MPI imaging modality is proposed which offers the prospect of detecting such changes. MPI technologies are driven by tracer development and thus represents enormous potential for novelty and innovation through Advanced Materials Research if coupled with new imaging modalities for probing such functional tracers. Development of a prototype FS-MPI system designed to measure the functional behaviour of I/O-NP is highly ambitious, and the combination of novel I/O-NP material development and prototype imaging device for detection will create enormous potential for innovation for new diagnostic technologies, both in vivo and in vitro.

A series of amphiphilic pH responsive co-polymers will be synthesised via Atom Transfer Radical Polymerisation to generate linear and branched poly(ethylene glycol (PEG)-2-hydroxypropyl methacrylate (HPMA))-2-(Diisopropylamino) ethyl methacrylate (DPAEMA) A-B-C triblock and statistical co-polymers. pH responsive character will be manipulated through polymerisation ratios of HPMA and DPAEMA, and through architectural variation strategies. Oleic acid stabilised SPIONs will be developed following thermal decomposition (Nat.Mater.,2004,3,891). I/O-NPs are formed via nanoprecipitation, following established Problem Owner process (Nanoscale,2016,8,7224). Polymer characterisation will be via NMR and GPC. The degree of I/O-NP size variation and in response to pH change will be analysed by DLS. SPION characterisation will be via XRD and DLS, and SPION I/O-NP encapsulation characterised by TEM and TGA. Conventional MPI will be conducted using the Momentum Imager, unique to UoL.

Changes in I/O-NP size will be detected through variation in intraparticle SPION interaction strength and I/O-NP rotation/relaxation dynamics, through frequency dependent susceptometry (FS). FS will be combined with (1-D) MPI particle detection to provide spatially-resolved detection of I/O-NP distribution and configuration. MPI detection hardware already developed by the Solution Provider, including 1-D selection field gradients, will be adapted around a coupled pair of coilsets to provide FS. The system will provide a 10 ml sample space, with 4 T/m field gradient and >200 Oe drive field, capable of detecting non-linear MPI response in nm-diameter SPIONs. Signal processing electronics will be adapted to include FS detection between 10 and 100 kHz (encompassing Brownian and Néel relaxation). Under swelling, changes in particle size/distribution and interaction will directly be detected in FS changes via relaxation dynamics, demonstrating detection sensitivity required for functional I/O-NP use.