Rare-Earth-Based Materials: An Effective Tool

Brain diseases, including tumors and neurodegenerative diseases, are among the most serious health problems. Non-invasive high-resolution imaging methods are required to obtain anatomical and functional information of the brain. In addition, efficient diagnostic technology is also required for the treatment of brain diseases. Rare-earth-based materials possess unique optical properties, superior magnetism, and high x-ray absorbance capabilities that enable high-resolution imaging of the brain by magnetic resonance imaging, computed tomography, and fluorescence imaging. In addition, rare earth-based materials can be used to detect, treat, and regulate brain diseases by finely modulating their structures and functions. Importantly, rare-earth-based materials combined with biomolecules such as antibodies, peptides, and drugs can cross the blood-brain barrier and be used for targeted therapy.

In a new review published in Light Science & ApplicationsA 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 collaborators has summarized the recent research and development of rare earth based materials for Imaging, therapy, monitoring and neuromodulation of the brain.

1. Magnetic resonance imaging (MRI): MRI has emerged as a safe, painless, non-invasive and powerful diagnostic tool widely used in brain imaging. Rare-earth-based composites with superior optical and magnetic properties are attracting great attention due to their unique 4f external electronic structure. In particular Gd³⁺ -ions can, because of their seven unpaired 4f electrons (^8thS_7/2) and symmetric ground state. Gd-based complexes can significantly improve image quality by increasing image contrast between diseased tissue and normal tissue. This section summarizes the modification of traditional Gd-based small molecule contrast agents, e.g. B. grafting onto polymers to increase their relaxation rate and increase their circulation time in vivo. In addition, surface modifications are applied to improve their biocompatibility and allow them to cross the blood-brain barrier (BBB).
2. Fluorescence imaging: Fluorescence imaging mainly focused on the visible range (400–700 nm) and the NIR-I window (700–900 nm). However, photon scattering or photon absorption occurs whenever light enters tissue or bone, resulting in inevitable thermal damage, low signal-to-noise ratio, and limited depth of penetration. In addition, craniotomy, bone window opening, and cranial grinding processes are usually required for conventional fluorescence imaging, further causing damage to brain tissue and cerebral vessels. NIR-II fluorescence imaging technology (1000-1700 nm) has been shown to have higher spatial resolution, less thermal damage, greater depth of penetration and less intrinsic tissue fluorescence. Rare earth-based materials have superior photostability, long fluorescence lifetimes, and narrow emission bandwidths. In particular, their rich energy level transitions enable tunable NIR-II emission by changing the doped ion species. Therefore, 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 excellent NIR-II emission at 1525 nm that could support non-invasive cerebrovascular visualization. In addition, organic dyes and quantum dots (QDs) with large extinction coefficients are also used as antennas to effectively absorb and transmit energy.
3. Multimodal 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, multimodal imaging has been developed to provide more accurate brain imaging information 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. Multimodal imaging realized real-time dynamic imaging and accurate diagnosis of brain tumors.

1. Radiotherapy: Gd-based therapeutics with a high X-ray attenuation coefficient are attractive agents for radiotherapy, which can increase the local radiation dose deposition 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 the reaction of photosensitizers with oxygen under irradiation. However, most of the photosensitizer molecules are excited by the UV or visible light, which hardly penetrates into the deep tissues and brain skeleton. The rare earth-based nanoparticles (RENPs) could emit tunable luminescence to sensitize the photosensitizers under NIR excitation, which significantly improves the PDT penetration depth.
3. Photothermal Therapy (PTT): Photothermal therapy is another phototherapy that uses photothermal agents to convert light into heat energy to treat diseases that are also limited by the photothermal agents that need to be stimulated 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 treat brain diseases synergistically with rare-earth-based materials. For example, a NIR light-triggered nanophotosynthetic (NPT) biosystem composed of core-shell Nd³⁺-doped UCNPs and photoautotrophic cyanobacterium (S. extended) was developed to treat ischemic stroke.

• Diagnosis and monitoring of brain diseases

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

• Brain modulation by optogenetics

Optogenetics is an optical technique that uses visible light to activate channel proteins expressed in specific cells to remotely stimulate specific neurons deep in the brain. However, the visible light is strongly scattered in the tissue and cannot penetrate deep into the brain. In addition, optical fibers are always required for optogenetics and penetrate the brain. UCNP-mediated wireless optogenetics technology provides a minimally invasive technique that eliminates fiber optic dependency and avoids fiber optic-induced brain tissue damage. UCNP-mediated optogenetics realize activation/inhibition of neuronal cells and further regulate animal motor state and neural behavior.

Finally, perspectives and potential challenges for clinical application with rare earth based materials are presented:

1. To improve the optical performance of RENPs, the development of extremely robust synthetic methods and efficient structure modulation strategies is required.
2. The development of RENPs with excitation wavelengths in the NIR-II range 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 needed, which will drive the further expansion of multimodal imaging technology based on the NIR-II region.
4. Other BBB crossing methods, including cell-penetrating peptides/cell-mediated delivery to the brain and receptor-mediated BBB opening, need to be further explored
5. It is necessary to develop effective synthetic and assembly strategies to ensure stability, biocompatibility, etc in vivo Release of rare earth based materials.
6. The search for new approaches to transport UCNPs across BBB and anchor them to specific neurons via exceptionally precise molecular recognition processes is urgently needed.

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