Inchan Youn

Heparin‐Coated Gold Nanoparticles for Liver‐Specific CT Imaging

Since computed tomography (CT) was developed and its resolution, sensitivity, and scan speed rapidly improved, the use of CT in the diagnosis of hepatic disease has been evaluated by various investigators. In particular, liver-specific X-ray CT imaging has attracted much attention in cancer diagnosis and cancer treatment because liver metastases are a common occurrence in the history of a patient affected by various cancers. The liver is the organ most frequently involved in metastases due to its high volume of blood flow, the suitable size of sinusoids for trapping metastatic cells, and rich environment for rapid growth. The sensitivity of liver imaging needs to be guaranteed in cancer detection because diagnosis of liver metastasis at an early stage mainly relies on imaging and all liver metastases begin with a microscopic-sized tumor. However, in CT imaging, the detection of liver lesions is impossible without the use of contrast-enhancing agents, although, even then, the problem of distinguishing between small vessels and small liver tumors is an issue. For this reason, the demand for a tissue-specific X-ray contrast agent has increased, although there are a few products available they have limitations for clinical application. Although low-molecular-weight iodinated contrast agents are generally used in CT imaging, they have serious limitations in clinical applications due to their low liver uptake, rapid renal excretion, and lack of membrane permeation; this leads to renal toxicity and high viscosity of the injectable formulation. To overcome the undesirable pharmacokinetics and limitations, low-molecular-weight iodinates have been chemically conjugated to high-molecular-weight polymers or encapsulated into liposomes and polymeric micelles. These macromolecular and nanosized contrast agents display enhanced blood-circulating characteristics in vivo as well as providing liver-specific CT images. However, they still show a lower imaging resolution with respect to differentiating liver tissues from other vessels, organs, and cancers because iodine-based contrast agents inherently possess a lower X-ray absorption coefficient. Another novel inorganic nanoparticle-based CT contrast agent has been proposed. Polymer-coated bismuth sulfide (Bi2S3) nanoparticles showed high X-ray absorption compared with iodinated imaging agents, but their size and shape were not easy to [a] I.-C. Sun, J. H. Na, Dr. S. Lee, Dr. I.-C. Youn, Dr. K. Choi, Dr. I. C. Kwon, Dr. K. Kim Biomedical Research Center Korea Institute of Science and Technology 39-1 Hawolgok-dong, Seongbuk-gu, Seoul, 136-791 (Korea) Fax: (+82)2-958-5909 E-mail : kim@kist.re.kr [b] D.-K. Eun, Dr. C.-H. Ahn Research Institute of Advanced Materials (RIAM) Department of Materials Science and Engineering Seoul National University San 56-1, Sillim, Gwanak, Seoul, 151-744 (Korea) Fax: (+82)2-883-8197 E-mail : chahn@snu.ac.kr [c] I.-J. Kim Department of Chemistry, College of Science, Korea University Anam-dong, Seongbuk-gu, Seoul 136-791 (Korea) [d] Dr. C.-Y. Ko, Dr. H.-S. Kim Department of Biomedical Engineering, Yonsei University Wonju, Ganwondo, 220-710 (Korea) [e] Dr. D. Lim Silver Technology Center, Korea Institute of Industrial Technology 35-5 Hongcheon, Ipjang, Cheonan, Chungnam (Korea) [f] Dr. P. B. Messersmith Biomedical Engineering, Northwestern University 2145 Sheridan Road, Evanstron, IL 60208 (USA) [g] Dr. T. G. Park Department of Biological Sciences Korea Advanced Institute of Science Technology Daejeon 305-701 (Korea) [h] Dr. S. Y. Kim Department of Otolaryngology-Head and Neck Surgery Asan Medical Center, College of Medicine, University of Ulsan Seoul 138-736 (South Korea) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.200902344.

Matrix Metalloproteinase Sensitive Gold Nanorod for Simultaneous Bioimaging and Photothermal Therapy of Cancer

Herein, we developed matrix metalloprotease (MMP) sensitive gold nanorods (MMP-AuNR) for cancer imaging and therapy. It was feasible to absorb NIR laser and convert into heat as well as visualize MMP activity. We showed the possibility of gold nanorods as a hyperthermal therapeutic agent and MMP sensitive imaging agent both in vitro and in vivo condition. The results suggested potential application of MMP-AuNR for simultaneous cancer diagnosis and therapy.

Dark quenched matrix metalloproteinase fluorogenic probe for imaging osteoarthritis development in vivo.

The early detection of osteoarthritis (OA) is currently a key challenge in the field of rheumatology. Biochemical studies of OA have indicated that matrix metalloproteinase-13 (MMP-13) plays a central role in cartilage degradation. In this study, we describe the potential use of a dark-quenched fluorogenic MMP-13 probe to image MMP-13 in both in vitro and rat models. The imaging technique involved using a MMP-13 peptide substrate, near-infrared (NIR) dye, and a NIR dark quencher. The results from this study demonstrate that the use of a dark-quenched fluorogenic probe allows for the visual detection of MMP-13 in vitro and in OA-induced rat models. In particular, by targeting this OA biomarker, the symptoms of the early and late stages of OA can be readily monitored, imaged, and analyzed in a rapid and efficient fashion. We anticipate that this simple and highly efficient fluorogenic probe will assist in the clinical management of patients with OA, not only for early diagnosis but also to assess individual patient responses to new drug treatments.

Early diagnosis of arthritis in mice with collagen-induced arthritis, using a fluorogenic matrix metalloproteinase 3–specific polymeric probe

OBJECTIVE Early treatment based on an early diagnosis of rheumatoid arthritis (RA) could halt progression of the disease, but early diagnosis is often difficult. Matrix metalloproteinase 3 (MMP-3) is thought to be particularly important in the pathogenesis of RA. The aim of this study was to investigate whether an MMP-3-specific polymeric probe could be used for early diagnosis and for visualizing the progression of arthritis, using a near-infrared fluorescence (NIRF) imaging system. METHODS The MMP-3-specific polymeric probe was developed by conjugating NIRF dye, MMP substrate peptide, and dark quencher to self-assembled chitosan nanoparticles. One hour after intravenous administration of the probe, fluorescent images of mice with collagen-induced arthritis at different stages of disease development were obtained. The correlation between the fluorescence recovered in in vivo imaging when using an MMP-3-specific polymeric probe and up-regulated MMP-3 activity in the joint tissues was evaluated by Western blotting and immunohistochemical staining. Histologic analysis and micro-computed tomography (micro-CT) were also used to assess arthritis progression. RESULTS A significantly higher NIRF signal was recovered from arthritic joints compared with normal joints at 14 days after the first immunization, before any erythema or swelling could be observed with the naked eye or any erosion was detected by histologic analysis or micro-CT. The results of immunohistochemical analysis and Western blotting confirmed that the fluorescence recovered in the in vivo imaging was related to up-regulated MMP-3 activity in the joint tissues. CONCLUSION An MMP-3-specific polymeric probe provided clear early diagnosis of arthritis and visualization of arthritis progression using an NIRF imaging system. This approach could be used for early diagnosis and for monitoring drug and surgical therapies in individual cases.

Cathepsin B-sensitive nanoprobe for in vivo tumor diagnosis

We developed a cathepsin B-sensitive nanoprobe (CB-NP) with a cathepsin B substrate peptide probe and tumor-targeting glycol chitosan nanoparticles. The CB-NP could accumulate in tumor tissues, enter into tumor cells, and generate fluorescent signals in cytosol in response to cathepsin B. The results of non-invasive fluorescence imaging in a tumor-bearing mouse model demonstrated the potential of CB-NP for tumor diagnosis in clinical fields.

Improvement of signal-to-interference ratio and signal-to-noise ratio in nerve cuff electrode systems

Cuff electrodes are effective for chronic electroneurogram (ENG) recording while minimizing nerve damage. However, the ENG signals are usually contaminated by electromyogram (EMG) activity from the surrounding muscles, stimulus artifacts produced by the electrical stimulation and noise generated in the first stage of the neural signal amplifier. This paper proposed a new cuff electrode to reduce the interference from EMG signals and stimulus artifacts. As a result, when an additional middle electrode was placed at the center of the cuff electrode, a significant improvement in the signal-to-interference ratio was achieved at 11% for the EMG signals and 12% for the stimulus artifacts when compared to a conventional tripolar cuff. Furthermore, a new low-noise amplifier was proposed to improve the signal-to-noise ratio. The circuit was designed based on a noise analysis to minimize the noise, and the results show that the total noise of the amplifier was below 1 μV for a cuff impedance of 1 kΩ and a frequency bandwidth of 300 to 5000 Hz.

An inside-out vein graft filled with platelet-rich plasma for repair of a short sciatic nerve defect in rats

Platelet-rich plasma containing various growth factors can promote nerve regeneration. An inside-out vein graft can substitute nerve autograft to repair short nerve defects. It is hypothesized that an inside-out vein graft filled with platelet-rich plasma shows better effects in the repair of short sciatic nerve defects. In this study, an inside-out vein autograft filled with platelet-rich plasma was used to bridge a 10 mm-long sciatic nerve defect in rats. The sciatic nerve function of rats with an inside-out vein autograft filled with platelet-rich plasma was better improved than that of rats with a simple inside-out vein autograft. At 6 and 8 weeks, the sciatic nerve function of rats with an inside-out vein autograft filled with platelet-rich plasma was better than that of rats undergoing nerve autografting. Compared with the sciatic nerve repaired with a simple inside-out vein autograft, the number of myelinated axons was higher, axon diameter and myelin sheath were greater in the sciatic nerve repaired with an inside-out vein autograft filled with platelet-rich plasma and they were similar to those in the sciatic nerve repaired with nerve autograft. These findings suggest that an inside-out vein graft filled with platelet-rich plasma can substitute nerve autograft to repair short sciatic nerve defects.

An Implantable Wireless Neural Interface System for Simultaneous Recording and Stimulation of Peripheral Nerve with a Single Cuff Electrode

Recently, implantable devices have become widely used in neural prostheses because they eliminate endemic drawbacks of conventional percutaneous neural interface systems. However, there are still several issues to be considered: low-efficiency wireless power transmission; wireless data communication over restricted operating distance with high power consumption; and limited functionality, working either as a neural signal recorder or as a stimulator. To overcome these issues, we suggest a novel implantable wireless neural interface system for simultaneous neural signal recording and stimulation using a single cuff electrode. By using widely available commercial off-the-shelf (COTS) components, an easily reconfigurable implantable wireless neural interface system was implemented into one compact module. The implantable device includes a wireless power consortium (WPC)-compliant power transmission circuit, a medical implant communication service (MICS)-band-based radio link and a cuff-electrode path controller for simultaneous neural signal recording and stimulation. During in vivo experiments with rabbit models, the implantable device successfully recorded and stimulated the tibial and peroneal nerves while communicating with the external device. The proposed system can be modified for various implantable medical devices, especially such as closed-loop control based implantable neural prostheses requiring neural signal recording and stimulation at the same time.

Measurement of MMP activity in synovial fluid in cases of osteoarthritis and acute inflammatory conditions of the knee joints using a fluorogenic peptide probe-immobilized diagnostic kit

Purpose: A fluorogenic peptide probe-immobilized diagnostic kit was used to analyze MMP activity in the synovial fluids (SFs) from patients with osteoarthritis (OA) and acute inflammatory conditions of the knee joint. Methods: The MMP diagnostic kit containing a polymer-conjugated MMP probe immobilized on a 96-well plate was utilized for high-throughput screening of MMP activity in SFs from OA patients (n = 33) and patients with acute inflammatory conditions of the knee joint (n = 5). Results: Compared to SF from OA patients, SF from patients with acute inflammatory conditions of the knee joint presented stronger NIR fluorescent signals. In gelatin zymography, most samples from patients with acute inflammatory conditions of the knee joint also displayed 92 kDa (pro-form) MMP-9 and faint 84 kDa (active form) MMP-9, while SF from OA patients did not display detectable MMP-9 activity . Conclusion: The presence of a strong fluorescence signal from the MMP diagnostic kit corresponded well with patients with acute inflammatory conditions of the knee joint. The results suggest that our MMP diagnostic kit can be useful in differentiation between early stages of OA and acute inflammatory conditions of the knee joint.

Optimization of matrix metalloproteinase fluorogenic probes for osteoarthritis imaging.

Among the classical collagenases, matrix metalloproteinase-13 (called MMP-13, collagenase-3) is one of the most important components for cartilage destruction of osteoarthritis (OA) developments. Despite many efforts, the detection methods of MMP-13 activity have been met with limited success in vivo, in part, due to the low sensitivity and low selectivity by homology of MMP family. Previously, we demonstrated the use of strongly dark-quenched fluorogenic probe allowed for the visual detection of MMP-13 in vitro and in OA-induced rat models. In this study, we described the optimization of MMP-13 fluorogenic probe for OA detection in vivo. Three candidate probes demonstrated recovered fluorescent intensity proportional with MMP-13 concentrations, respectively; however, Probe 2 exhibited both high signal amplification and selective recognition for MMP-13, not MMP-2 and MMP-9 in vitro. When Probe 2 was applied to OA-induced rat models, clear visualization of MMP-13 activity in OA-induced cartilage was obtained. Optimized MMP-13 fluorogenic probe can be applied to detect and image OA and have potential for evaluating the in vivo efficacy of MMP-13 inhibitors which are being tested for therapeutic treatment of OA.