Nohyun Lee

Multifunctional Uniform Nanoparticles Composed of a Magnetite Nanocrystal Core and a Mesoporous Silica Shell for Magnetic Resonance and Fluorescence Imaging and for Drug Delivery

During the past two decades, extensive research has been carried out on the biomedical applications of nanostructured materials. Among these various nanomaterials, mesoporous silica materials have been intensively investigated for their potential application as delivery vehicles for small-molecule drugs, DNA, and proteins, owing to their uniform pore size, large surface area, and high accessible pore volume. However, to date, there are only a few reports on the in vivo application of mesoporous silica materials administrated by intravenous injection, because it is difficult to synthesize discrete and monodisperse mesoporous silica particles smaller than around 100 nm that possess high colloidal stability in a physiological environment and small enough size to allow a long blood circulation. In general, bigger nanoparticles (NPs) result in more rapid uptake by the reticuloendothelial system (RES), such as liver and spleen, but smaller NPs can escape from phagocytes in RES and circulate through blood vessels with a long blood half-life. Although there have been several reports on the synthesis of uniform mesoporous silica particles smaller than 200 nm observed in TEM, the particles are not discrete but aggregated. Consequently, it is still a challenge to synthesize discrete, monodisperse, and size-controllable mesoporous silica NPs for in vivo applications. Recently, multifunctional nanostructured materials have been applied to multimodal imaging and simultaneous diagnosis and therapy. In this context, the integration of mesoporous silica with superparamagnetic monodisperse nanocrystals to form uniform core–shell composite particles has great potential for simultaneous bioimaging and drug delivery. Although there have been several reports on composite materials of magnetic nanocrystals and mesoporous silica materials, these materials have not been used for in vivo applications because of their size and aggregation. Herein, we present discrete, monodisperse, and precisely sizecontrollable core–shell mesoporous silica NPs smaller than 100 nm by using single Fe3O4 nanocrystals as cores (designated as Fe3O4@mSiO2). We also demonstrate the multifunctional bioapplications of the core–shell NPs for simultaneous magnetic resonance (MR) and fluorescence imaging, and for drug delivery. The synthetic protocol is represented in Scheme 1. Cetyltrimethylammonium bromide (CTAB) serves not only as the stabilizing surfactant for the transfer of hydrophobic Fe3O4 nanocrystals [10] to the aqueous phase but also as the organic template for the formation of mesopores in the sol– gel reaction. After removing the CTAB templates from the as-synthesized materials by heating them at reflux in acidic ethanol solution (pH 1.4), we collected the Fe3O4@mSiO2 particles. When we decreased the pH value of the extraction solution below 1.0, Fe3O4 nanocrystals as well as CTAB were fully removed from the as-synthesized Fe3O4@mSiO2, resulting in hollow mesoporous silica NPs (designated as H-mSiO2). Finally, for biomedical applications, the surface of the NPs was modified with PEG to render them biocompatible by

Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery.

Highly versatile nanocomposite nanoparticles were synthesized by decorating the surface of mesoporous dye-doped silica nanoparticles with multiple magnetite nanocrystals. The superparamagnetic property of the magnetite nanocrystals enabled the nanoparticles to be used as a contrast agent in magnetic resonance (MR) imaging, and the dye molecule in the silica framework imparted optical imaging modality. Integrating a multitude of magnetite nanocrystals on the silica surface resulted in remarkable enhancement of MR signal due to the synergistic magnetism. An anticancer drug, doxorubicin (DOX), could be loaded in the pores and induced efficient cell death. In vivo passive targeting and accumulation of the nanoparticles at the tumor sites was confirmed by both T2 MR and fluorescence imaging. Furthermore, apoptotic morphology was clearly detected in tumor tissues of mice treated with DOX loaded nanocomposite nanoparticles, demonstrating that DOX was successfully delivered to the tumor sites and its anticancer activity was retained.

Multifunctional Mesoporous Silica Nanocomposite Nanoparticles for Theranostic Applications

Clever combinations of different types of functional nanostructured materials will enable the development of multifunctional nanomedical platforms for multimodal imaging or simultaneous diagnosis and therapy. Mesoporous silica nanoparticles (MSNs) possess unique structural features such as their large surface areas, tunable nanometer-scale pore sizes, and well-defined surface properties. Therefore, they are ideal platforms for constructing multifunctional materials that incorporate a variety of functional nanostructured materials. In this Account, we discuss recent progress by our group and other researchers in the design and fabrication of multifunctional nanocomposite nanoparticles based on mesoporous silica nanostructures for applications to simultaneous diagnosis and therapy. Versatile mesoporous silica-based nanocomposite nanoparticles were fabricated using various methods. Here, we highlight two synthetic approaches: the encapsulation of functional nanoparticles within a mesoporous silica shell and the assembly of nanoparticles on the surface of silica nanostructures. Various nanoparticles were encapsulated in MSNs using surfactants as both phase transfer agents and pore-generating templates. Using MSNs as a scaffold, functional components such as magnetic nanoparticles and fluorescent dyes have been integrated within these systems to generate multifunctional nanocomposite systems that maintain their individual functional characteristics. For example, uniform mesoporous dye-doped silica nanoparticles immobilized with multiple magnetite nanocrystals on their surfaces have been fabricated for their use as a vehicle capable of simultaneous magnetic resonance (MR) and fluorescence imaging and drug delivery. The resulting nanoparticle-incorporated MSNs were then tested in mice with tumors. These in vivo experiments revealed that these multifunctional nanocomposite nanoparticles were delivered to the tumor sites via passive targeting. These nanocomposite nanoparticles served as successful multimodal imaging probes and also delivered anticancer drugs to the tumor site. With innumerable combinations of imaging modalities and drug delivery available within these vehicles, multifunctional nanocomposite nanoparticles provide new opportunities for clinical diagnostics and therapeutics.

Large-Scale Synthesis of Uniform and Extremely Small-Sized Iron Oxide Nanoparticles for High-Resolution T1 Magnetic Resonance Imaging Contrast Agents

Uniform and extremely small-sized iron oxide nanoparticles (ESIONs) of < 4 nm were synthesized via the thermal decomposition of iron-oleate complex in the presence of oleyl alcohol. Oleyl alcohol lowered the reaction temperature by reducing iron-oleate complex, resulting in the production of small-sized nanoparticles. XRD pattern of 3 nm-sized nanoparticles revealed maghemite crystal structure. These nanoparticles exhibited very low magnetization derived from the spin-canting effect. The hydrophobic nanoparticles can be easily transformed to water-dispersible and biocompatible nanoparticles by capping with the poly(ethylene glycol)-derivatized phosphine oxide (PO-PEG) ligands. Toxic response was not observed with Fe concentration up to 100 μg/mL in MTT cell proliferation assay of POPEG-capped 3 nm-sized iron oxide nanoparticles. The 3 nm-sized nanoparticles exhibited a high r(1) relaxivity of 4.78 mM(-1) s(-1) and low r(2)/r(1) ratio of 6.12, demonstrating that ESIONs can be efficient T(1) contrast agents. The high r(1) relaxivities of ESIONs can be attributed to the large number of surface Fe(3+) ions with 5 unpaired valence electrons. In the in vivo T(1)-weighted magnetic resonance imaging (MRI), ESIONs showed longer circulation time than the clinically used gadolinium complex-based contrast agent, enabling high-resolution imaging. High-resolution blood pool MR imaging using ESIONs enabled clear observation of various blood vessels with sizes down to 0.2 mm. These results demonstrate the potential of ESIONs as T(1) MRI contrast agents in clinical settings.

Mesoporous Silica-Coated Hollow Manganese Oxide Nanoparticles as Positive T1 Contrast Agents for Labeling and MRI Tracking of Adipose-Derived Mesenchymal Stem Cells

Mesoporous silica-coated hollow manganese oxide (HMnO@mSiO2) nanoparticles were developed as a novel T1 magnetic resonance imaging (MRI) contrast agent. We hypothesized that the mesoporous structure of the nanoparticle shell enables optimal access of water molecules to the magnetic core, and consequently, an effective longitudinal (R1) relaxation enhancement of water protons, which value was measured to be 0.99 (mM−1s−1) at 11.7 T. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, with much shorter T1 values as compared to direct incubation without electroporation, which was also evidenced by signal enhancement on T1-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO2-labeled MSCs enabled serial MR monitoring of cell transplants over 14 days. These novel nanoparticles may extend the arsenal of currently available nanoparticle MR contrast agents by providing positive contrast on T1-weighted images at high magnetic field strengths.

Synthesis of Uniform Ferrimagnetic Magnetite Nanocubes

We synthesized uniform ferrimagnetic magnetite nanocubes in the size range from 20 to 160 nm. The magnetic property of the nanocubes was characterized, and magnetic separation of the histidine-tagged protein was demonstrated.

Iron Oxide Based Nanoparticles for Multimodal Imaging and Magnetoresponsive Therapy

Magnetoresponsive Therapy Nohyun Lee, Dongwon Yoo, Daishun Ling,†,‡,⊥ Mi Hyeon Cho, Taeghwan Hyeon,*,†,‡ and Jinwoo Cheon* †Center for Nanoparticle Research, Institute for Basic Science (IBS), Seoul 151-742, Korea ‡School of Chemical and Biological Engineering, Seoul National University, Seoul 151-742, Korea Department of Chemistry, Yonsei University, Seoul 120-749, Korea School of Advanced Materials Engineering, Kookmin University, Seoul 136-702, Korea Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China

Theranostic Probe Based on Lanthanide-Doped Nanoparticles for Simultaneous In Vivo Dual-Modal Imaging and Photodynamic Therapy

Dual-modal in vivo tumor imaging and photodynamic therapy using hexagonal NaYF(4):Yb,Er/NaGdF(4) core-shell upconverting nanoparticles combined with a photosensitizer, chlorin e6, is reported. Tumors can be clearly observed not only in the upconversion luminescence image but also in the magnetic resonance image. In vivo photodynamic therapy by systemic administration is demonstrated under 980 nm irradiation.

Nano‐Sized CT Contrast Agents

Computed tomography (CT) is one of the most widely used clinical imaging modalities. In order to increase the sensitivity of CT, small iodinated compounds are used as injectable contrast agents. However, the iodinated contrast agents are excreted through the kidney and have short circulation times. This rapid renal clearance not only restricts in vivo applications that require long circulation times but also sometimes induces serious adverse effects related to the excretion pathway. In addition, the X-ray attenuation of iodine is not efficient for clinical CT that uses high-energy X-ray. Due to these limitations, nano-sized iodinated CT contrast agents have been developed that can increase the circulation time and decrease the adverse effects. In addition to iodine, nanoparticles based on heavy atoms such as gold, lanthanides, and tantalum are used as more efficient CT contrast agents. In this review, we summarize the recent progresses made in nano-sized CT contrast agents.

Self-assembled Fe3O4 nanoparticle clusters as high-performance anodes for lithium ion batteries via geometric confinement.

Although different kinds of metal oxide nanoparticles continue to be proposed as anode materials for lithium ion batteries (LIBs), their cycle life and power density are still not suitable for commercial applications. Metal oxide nanoparticles have a large storage capacity, but they suffer from the excessive generation of solid-electrolyte interphase (SEI) on the surface, low electrical conductivity, and mechanical degradation and pulverization resulted from severe volume expansion during cycling. Herein we present the preparation of mesoporous iron oxide nanoparticle clusters (MIONCs) by a bottom-up self-assembly approach and demonstrate that they exhibit excellent cyclic stability and rate capability derived from their three-dimensional mesoporous nanostructure. By controlling the geometric configuration, we can achieve stable interfaces between the electrolyte and active materials, resulting in SEI formation confined on the outer surface of the MIONCs.