Non-invasively imaging small numbers of molecular probes, to help image particular targets or pathways in vivo, is currently undergoing a technological revolution. Recent breakthroughs in molecular hyperpolarization proved the potential for > 10,000-fold increase in sensitivity on conventional magnetic resonance imaging (MRI) systems, thus providing insight into previously unseen metabolic processes with enormous potential for socioeconomic relevant diseases. For example, pyruvate-based hyperpolarized imaging was clinically demonstrated to be effective for prostate cancer diagnostics in human patients. However, the current state-of-the-art hyperpolarization methods are expensive and cumbersome, preventing the widespread access to hyperpolarization technology, and require long hyperpolarization times of 60-90 minutes per dosage and use hyperpolarization probes that exhibit short hyperpolarization duration (1-5 minutes), limiting the usage of hyperpolarization to metabolic imaging. A quantum technological breakthrough, Nitrogen-Vacancy defects (NV centres) in diamonds, is set to revolutionize the field of hyperpolarization for both hyperpolarizer and probes.
The primary objective of HYPERDIAMOND is the development and commercialization of two new molecular imaging technologies for sensitive diagnosis and treatment monitoring, based on NV centres:
HYPERDIAMOND will bridge the gap between novel quantum and nanotechnology and their applications in hyperpolarized imaging, producing innovation not feasible with current technology.
In order to achieve the project goals, the HYPERDIAMOND consortium has structured the work to be undertaken in three scientific-technical work packages for establishing the enabling technologies, two innovation focused work packages, a preclinical imaging work package, a benchmarking work package for final assessment of the produced results, and two work packages for project management and the dissemination and exploitation of the project results.
WP1 Hyperpolarization techniques - Significant advances were achieved beyond the state of the art, including experimental proof of concept of efficient polarization transfer from NV centres to molecules, including pyruvate [Fernandez-Acebal et al. E-print arXiv:1708.02427], best-in-class MW scheme for the NV-based hyperpolarization of NDs and molecules [Schwartz et al. submitted to PRX], and novel experimental methods for quantifying hyperpolarization [Scheuer et al. E-print arXiv:1706.01315, Schwartz et al. E-print arXiv:1706.07134 (2017)].
WP2 Diamond material science - We have established methods for the efficient synthesis of 13C doped nanodiamonds (ND), resulting in an average yield about 90% when starting with commercial NDs and 20% 13C concentration. With these procedure ND-13C size ranging between 5 and 500 nm could be obtained, and in grams’ quantity. Project partner KIT has carried out NMR measurements of over 20 different powder and ND solution samples, for optimizing the ND parameters for MRI.
WP3 Diamond Functionalization - We have developed the surface chemistry for NDs that will enable their use as targeted hyperpolarised MRI probes. As a result, bioactive surface coatings are now available and can be customized for the needs of teh medical partners. Peptides, proteins and oligonucleotides can be attached and the fate of coated NDs has been assessed thoroughly in vitro. Furthermore, functionalized NDs that can penetrate the blood brain barrier have been achieved and NDs have been found in brain slices.
WP4 Polarizer development - The hyperpolarization system is installed and working. It is the first functional system developed which enables achieving over 1% polarization in a diamond via optical polarization using pulsed microwave protocols, and has shown to be compatible with the novel sequences developed in WP1.
WP5 Magnetic Resonance Spectroscopy and Imaging - We have commenced synthesis, formulation and characterisation of molecular imaging probes. Pyruvic acid was selected for further studies due to longest T1 at 5.9T (T1 > 51 s in biological media at 37 °C). Additionally, we started studies in xenograft tumours and optimised the 13C coil, taking the first MR spectra and ZTE images from 20% enriched NDs.
WP6 Production of fluorescent NDs - A fluorescence/NV concentration roughly eight times higher than commercial ND has been achieved.
WP7 Preclinical assessment of developed technologies - PET studies were started ahead of time (planned start date of M19) by initiating the biological and in vivo evaluation of radiotracers in animal models. Tumour uptake reached the maximum level already 2 min after injection.
WP8 Dissemination and Exploitation of Results - In period 1, the project successfully released its Dissemination Plan and started promoting the project progress in conferences worldwide. An Advisory Board of leading scientists and clinicians was put in place. In parallel we have established a roadmap for the regulatory process of the Diamond Hyperpolarizer, and performed a market analysis, including market size estimation, customer segmentation, main potential clinical applications and advantages over incumbent technologies.
HYPERDIAMOND has developed a set of highly performing polarisation protocols and the first functional NV-based hyperpolarisation system with robust pulse sequences. Building on this, it will develop a fully functional prototype of a novel polarizer for in vivo hyperpolarized MR imaging. Significant progress has been made in the functionalization of nanodiamonds with biomolecules, with the process now streamlined, the novel production of high NV and 13C concentration in nanodiamonds, as well as the characterization and understanding of the ND MRI properties, and demonstration of no acute toxicity and in vivo biocompatibility, paving the way for ideal NDs as MRI probes.
The Diamond Hyperpolarizer and ND Probe will serve for both research and clinical usage that will radically improve the established pyruvate-based metabolic MRI. The fully functional prototype will be the basis of future commercialization of the technology for introducing low-cost, widely accessible metabolic imaging capabilities worldwide.
A key outcome of the HYPERDIAMOND project is the impact on future scientific and innovation capacity with the novel hyperpolarization platforms. By the end of the project both the Diamond Hyperpolarizer and the ND-probes will reach the preclinical imaging market. In addition to being an attractive market for growth for the SME partners in HYPERDIAMOND, preclinical imaging is a main source of innovation for future technologies. Just as with dissolution-DNP polarizers and superparamagnetic iron-oxide nanoparticles (SPIOs), the HYPERDIAMOND technological platforms could lead to an explosion of new research and innovation ideas by medical and biological research institutes, as well as bio-chemistry SMEs and pharmaceutical companies.