Rare-earth based materials: An effective toolbox for brain technology

Peer-Reviewed Publication

LIGHT PUBLISHING CENTER, CHANGCHUN INSTITUTE OF OPTICS, FINE MECHANICS AND PHYSICS, CAS

 

IMAGE: ILLUSTRATION OF FOUR APPLICATIONS OF RARE-EARTH BASED MATERIALS, INCLUDING BRAIN IMAGING, BRAIN DISEASES THERAPY, BRAIN DISEASE DIAGNOSIS AND MONITORING, AND BRAIN MODULATION THROUGH OPTOGENETICS. view more 

CREDIT: BY ZHENG WEI, YAWEI LIU, BO LI, JINGJING LI, SHUANG LU, XIWEN XING, KAI LIU, FAN WANG, AND HONGJIE ZHANG

Brain diseases, including tumors and neurodegenerative disorders, are among the most serious health problems. Non-invasively high-resolution imaging techniques are required to gain anatomical and functional information of the brain. In addition, efficient diagnosis technology is also needed to treat brain disease. Rare-earth based materials possess unique optical properties, superior magnetism, and high X-ray absorption abilities, enabling high-resolution imaging of the brain through magnetic resonance imaging, computed tomography imaging, and fluorescence imaging technologies. In addition, rare-earth based materials can be used for the detection, treatment, and regulation of brain diseases through fine modulation of their structures and functions. Importantly, rare-earth based materials coupled with biomolecules such as antibodies, peptides, and drugs are able to overcome the blood-brain barrier and can be used for targeted therapy.

In a new review published in Light Science & Applications, a team of scientists, led by Associate Professor Fan Wang from State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, China, and co-workers have summarized the recent research and development of rare-earth based materials for brain imaging, therapy, monitoring, and neuromodulation.

• brain imaging

1. Magnetic resonance imaging (MRI): MRI has emerged as a safe, painless, non-invasive, and powerful diagnostic tool, which is widely used in brain imaging. Rare-earth based composites with superior optical and magnetic properties attract great attention due to their unique 4f external electronic structure. In particular, Gd3+ ions can provide a high electron magnetic moment and effectively shorten the electron relaxation time owing to its seven unpaired 4f electrons (8S7/2) and symmetrical ground state. Gd-based complexes can significantly improve the imaging quality by increasing the imaging contrast between diseased tissue and normal tissue. This section summarizes the modification of traditional Gd-based small molecule contrast agents, for example, grafting them onto polymers to increase their relaxation rate and prolong their circulation time in vivo. In addition, surface modifications are also applied to improve their biocompatibility and enable them to pass through the blood-brain barrier (BBB).
2. Fluorescence imaging: Fluorescence imaging mainly focused on the visible region (400-700 nm) and NIR-I window (700-900 nm). However, photon scattering or photon absorption always occur when light enters tissue or bone, resulting in inevitable thermal damage, low signal-to-noise ratio and limited penetration depth. In addition, craniotomy, bone window opening and cranial grinding processes are usually required for traditional fluorescence imaging, further leading to damage to brain tissue and cerebral vessels. NIR-II fluorescence (1000-1700 nm) imaging technology is proved to have a higher spatial resolution, less thermal damage, deeper penetration depth and lower tissue auto-fluorescence. Rare earth-based materials have superior photostability, long fluorescence lifetimes, and narrow emission bandwidths. Particularly, their rich energy level transitions allow for the tunable NIR-II emission by changing the doped ion species. Thus, they are the ideal materials to realize NIR-II fluorescence imaging of the brain. Researchers have developed a series of Ce-doped Er-based rare earth nanoparticles with outstanding NIR-II emission at 1525 nm, which could support non-invasive cerebrovascular visualization. Besides, organic dyes and quantum dots (QDs) with large extinction coefficients are also employed as antennas to absorb and transfer energy effectively.
3. Multi-modal imaging: Due to the complex spatial structure and vascular information of the brain, single-mode imaging is difficult to meet the needs of multi-target detection and collaborative imaging. To address these shortcomings, multi-modal imaging was developed to provide more accurate imaging information of brain for further clinical applications. Ln3+ ions possess superior optical, magnetic properties, and high X-ray absorption coefficients, enabling simultaneous MRI, fluorescence imaging and CT imaging on a single material. The Multi-modal imaging realized real-time dynamic imaging and accurate diagnosis of brain tumor.

 

• brain diseases therapy

1. Radiotherapy: Gd-based therapeutic agents with a high X-ray attenuation coefficient are attractive agents for radiotherapy, which can increase the deposition of local radiation dose at the tumor site and significantly enhance the therapeutic effect.
2. Photodynamic therapy (PDT): PDT eliminates tumor cells by generating reactive oxygen species (ROS) through reacting photosensitizers with oxygen under the irradiation. However, most photosensitizer molecules are excited by the UV or visible light that hardly penetrates the deep tissues and brain skeleton. The rare earth-based nanoparticles (RENPs) could emit tunable luminescence to sensitize the photosensitizers under NIR excitation, which greatly improve the penetration depth of PDT.
3. Photothermal therapy (PTT): Photothermal therapy is another phototherapy that uses photothermal agents to convert light into heat energy to treat disease, which is also limited by the photothermal agents that need to be excited by UV or visible light. Rare earth-based upconversion nanoparticles (UCNPs) with anti-Stokes emissions under NIR light excitation can effectively activate the photothermal energy conversion of photothermal agents to  eliminate tumor cells.
4. Other therapies: Other new strategies have also been applied to synergistically treat brain disease with rare-earth based materials. For example, a NIR-light triggered nanophotosynthetic (NPT) biosystem consisting of core-shell Nd3+-doped UCNPs and photoautotroph cyanobacterium (S. elongatus) was developed to treat ischemic stroke.

 

• brain disease diagnosis and monitoring

RENPs are promising candidates for monitoring brain neuronal activity and diagnosing brain diseases due to their superior luminescent properties. UCNPs-mediated visualization of dynein-driven retrograde axonal transport provided insights into the mechanism of dynein movement, neurological disease pathology and the role of various neural circuits in the brain. Besides, by utilizing the Förster resonance energy transfer (FRET) strategy between hexanitrodiphenylamine (DPA) and UCNPs, NIR-excited optical voltage sensors were designed to real-time monitor the neuronal activity

 

• brain modulation through optogenetics

Optogenetics is an optical technique that exploits visible light to activate channel proteins expressed in specific cells for remote stimulation of specific neurons deep in the brain. However, the visible light is strongly scattered in the tissues and cannot penetrate deep into brain. In addition, optical fibers are always required and invaded into brain for the optogenetics. UCNP-mediated wireless optogenetics technology provides a minimally invasive technique that gets rid of the dependence on optical fibers, avoiding the damage to brain tissue caused by optical fibers. UCNP-mediated optogenetics realizes the activation / inhibition of neuronal cells, and further regulates the motor state and neural behavior of animals.

 

In the end, perspectives and potential challenges toward clinical application with rare-earth based materials are presented:

1. The development of highly robust synthetic methods and efficient structural modulation strategies is required to enhance the optical performance of RENPs.
2. The development of RENPs with excitation wavelengths located in the NIR-II region is required to achieve deeper tissue penetration depths and higher spatial resolution.
3. The development of longer wavelength fluorescent probes and imaging instruments is urgently required, which will promote the further expansion of multi-modal imaging technology based on the NIR-II region.
4. Other BBB-crossing methods including cell penetrating peptide/cells mediated brain delivery and receptor-mediated BBB opening need to be further explored
5. It is necessary to develop effective synthesis and assembly strategies to improve the stability, biocompatibility and in vivo clearance of rare-earth based materials.
6. Seeking new approaches to deliver UCNPs across BBB and anchor them onto specific neurons via exceptionally precise molecular recognition processes is urgently needed.

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JOURNAL

Light Science & Applications

DOI

10.1038/s41377-022-00864-y