Recent progress in liquid embolic agents.

Vascular embolization is a non-surgical procedure used to treat diseases or morbid conditions related to blood vessels, such as bleeding, arteriovenous malformation, aneurysm, and hypervascular tumors, through the intentional occlusion of blood vessels. Among various types of embolic agents that have been applied, liquid embolic agents are gaining an increasing amount of attention owing to their advantages in distal infiltration into regions where solid embolic agents cannot reach, enabling more extensive embolization. Meanwhile, recent advances in biomaterials and technologies have also contributed to the development of novel liquid embolic agents that can resolve the challenges faced while using the existing embolic materials. In this review, we briefly summarize the clinically used embolic agents and their applications, and then present selected research results that overcome the limitations of the embolic agents in use. Through this review, we suggest the required properties of liquid embolic agents that ensure efficacy, which can replace the existing agents, providing directions for the future development in this field.

In Vivo Sol-Gel Reaction of Tantalum Alkoxide for Endovascular Embolization.

Liquid embolic agents are considered the most promising for various embolization procedures because they enable deep penetration. For realizing effective procedures, the delivery of liquid embolic agents should be guided under X-ray imaging systems and the solidification time should be optimized for the specific indication. The biocompatibility of embolic agents is also crucial because they remain in the vessel after embolization. In this study, new biocompatible embolic agents based on tantalum ethoxide is synthesized. Tantalum alkoxide liquid embolics (TALE) possess the radiopacity for fluoroscopy and can control the penetration depth by modifying the sol-gel kinetics. Furthermore, TALE can serve as drug carriers for synergistic treatment. Using these excellent characteristics, it is demonstrated that TALE agents can be used in various situations including the transarterial chemoembolization of hepatocellular carcinoma and embolotherapy of massive bleeding from the femoral artery.

Highly Fluorescent Gold Cluster Assembly.

The photoluminescence (PL) of metal nanoclusters (NCs), originating from their molecule-like electronic structure, is one of the most intriguing properties of NCs. Although various strategies such as tailoring the size, structure, and chemical environment of NCs have shown to improve the PL, their quantum yields (QYs) are still lagging far behind those of conventional luminescent materials, including quantum dots and organic fluorophores. Herein, we report the synthesis of highly luminescent gold cluster assembly (GCA) from Zn2+-ion-mediated assembly of Au4(SRCOO-)4 clusters using mercaptocarboxylic acid as a protective ligand and reductant as well as a growth suppressor. The synergetic combination of unique aurophilic interactions among Au4 clusters and the rigidified chemical environment induced by metal ion chelation through carboxylate groups is responsible for the ultrabright greenish-blue fluorescence with a QY up to 90%. Furthermore, the unique flexibility of dis/reassembly and the aggregation-dependent strong fluorescence of GCA offer a great potential for applications in biodegradable and trackable drug delivery systems.

A sensitive and specific nanosensor for monitoring extracellular potassium levels in the brain.

Extracellular potassium concentration affects the membrane potential of neurons, and, thus, neuronal activity. Indeed, alterations of potassium levels can be related to neurological disorders, such as epilepsy and Alzheimer's disease, and, therefore, selectively detecting extracellular potassium would allow the monitoring of disease. However, currently available optical reporters are not capable of detecting small changes in potassium, in particular, in freely moving animals. Furthermore, they are susceptible to interference from sodium ions. Here, we report a highly sensitive and specific potassium nanosensor that can monitor potassium changes in the brain of freely moving mice undergoing epileptic seizures. An optical potassium indicator is embedded in mesoporous silica nanoparticles, which are shielded by an ultrathin layer of a potassium-permeable membrane, which prevents diffusion of other cations and allows the specific capturing of potassium ions. The shielded nanosensor enables the spatial mapping of potassium ion release in the hippocampus of freely moving mice.

Highly selective microglial uptake of ceria-zirconia nanoparticles for enhanced analgesic treatment of neuropathic pain.

Neuropathic pain is a chronic and pathological pain caused by injury or dysfunction in the nervous system. Pro-inflammatory microglial activation with aberrant reactive oxygen species (ROS) generation in the spinal cord plays a critical role in the development of neuropathic pain. However, the efficacy of current therapeutic methods for neuropathic pain is limited because only neurons or neural circuits involved in pain transmission are targeted. Here, an effective strategy to treat pain hypersensitivity using microglia-targeting ceria-zirconia nanoparticles (CZ NPs) is reported. The CZ NPs are coated with microglia-specific antibodies to promote their delivery to microglia, and thus to improve their therapeutic efficacy. The targeted delivery facilitates the elimination of both pro-inflammatory cytokines and ROS in microglia, enabling the rapid and effective inhibition of microglial activation. As a result, greatly ameliorated mechanical allodynia is achieved in a spinal nerve transection (SNT)-induced neuropathic pain mouse model, proving the potent analgesic effect of the microglia-targeting CZ NPs. Given the generality of the approach used in this study, the microglia-targeting CZ NPs are expected to be useful for the treatment of not only neuropathic pain but also other neurological diseases associated with the vicious activation of microglia.

Deep Tumor Penetration of Drug-Loaded Nanoparticles by Click Reaction-Assisted Immune Cell Targeting Strategy.

Nanoparticles have been extensively used to deliver therapeutic drugs to tumor tissues through the extravasation of a leaky vessel via enhanced permeation and retention effect (EPR, passive targeting) or targeted interaction of tumor-specific ligands (active targeting). However, the therapeutic efficacy of drug-loaded nanoparticles is hampered by its heterogeneous distribution owing to limited penetration in tumor tissue. Inspired by the fact that cancer cells can recruit inflammatory immune cells to support their survival, we developed a click reaction-assisted immune cell targeting (CRAIT) strategy to deliver drug-loaded nanoparticles deep into the avascular regions of the tumor. Immune cell-targeting CD11b antibodies are modified with trans-cyclooctene to enable bioorthogonal click chemistry with mesoporous silica nanoparticles functionalized with tetrazines (MSNs-Tz). Sequential injection of modified antibodies and MSNs-Tz at intervals of 24 h results in targeted conjugation of the nanoparticles onto CD11b+ myeloid cells, which serve as active vectors into tumor interiors. We show that the CRAIT strategy allows the deep tumor penetration of drug-loaded nanoparticles, resulting in enhanced therapeutic efficacy in an orthotopic 4T1 breast tumor model. The CRAIT strategy does not require ex vivo manipulation of cells and can be applied to various types of cells and nanovehicles.

Large-Scale Synthesis and Medical Applications of Uniform-Sized Metal Oxide Nanoparticles.

Thanks to recent advances in the synthesis of high-quality inorganic nanoparticles, more and more types of nanoparticles are becoming available for medical applications. Especially, metal oxide nanoparticles have drawn much attention due to their unique physicochemical properties and relatively inexpensive production costs. To further promote the development and clinical translation of these nanoparticle-based agents, however, it is highly desirable to reduce unwanted interbatch variations of the nanoparticles because characterizing and refining each batch are costly, take a lot of effort, and, thus, are not productive. Large-scale synthesis is a straightforward and economic pathway to minimize this issue. Here, the recent achievements in the large-scale synthesis of uniform-sized metal oxide nanoparticles and their biomedical applications are summarized, with a focus on nanoparticles of transition metal oxides and lanthanide oxides, and clarifying the underlying mechanism for the synthesis of uniform-sized nanoparticles. Surface modification steps to endow hydrophobic nanoparticles with water dispersibility and biocompatibility are also briefly described. Finally, various medical applications of metal oxide nanoparticles, such as bioimaging, drug delivery, and therapy, are presented.

Multifunctional nanoparticles as a tissue adhesive and an injectable marker for image-guided procedures.

Tissue adhesives have emerged as an alternative to sutures and staples for wound closure and reconnection of injured tissues after surgery or trauma. Owing to their convenience and effectiveness, these adhesives have received growing attention particularly in minimally invasive procedures. For safe and accurate applications, tissue adhesives should be detectable via clinical imaging modalities and be highly biocompatible for intracorporeal procedures. However, few adhesives meet all these requirements. Herein, we show that biocompatible tantalum oxide/silica core/shell nanoparticles (TSNs) exhibit not only high contrast effects for real-time imaging but also strong adhesive properties. Furthermore, the biocompatible TSNs cause much less cellular toxicity and less inflammation than a clinically used, imageable tissue adhesive (that is, a mixture of cyanoacrylate and Lipiodol). Because of their multifunctional imaging and adhesive property, the TSNs are successfully applied as a hemostatic adhesive for minimally invasive procedures and as an immobilized marker for image-guided procedures.