Mi Kyung Yu

Korea Advanced Institute of Science and Technology, Sŏul, Seoul, South Korea

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Publications (23)137.83 Total impact

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    ABSTRACT: Fibronectin extra domain B (EDB) is specifically expressed in cancer-associated blood vessels and extracellular matrix, and thus is a promising cancer biomarker. Very recently, we developed a novel class of high-affinity (<100nM) peptides, termed 'aptides', that specifically bind a variety of protein targets. Here, we describe superparamagnetic iron oxide nanoparticles (SPIONs) conjugated with EDB-specific aptides for use in targeted magnetic resonance imaging (MRI) of cancer. An anti-EDB aptide (APT(EDB)) containing an additional cysteine residue reacted with maleimide-terminated, PEGylated phospholipid (Mal-PEG(2000)-DSPE) to give an aptide-conjugated PEGylated phospholipid (APT(EDB)-PEG(2000)-DSPE). A nanoemulsion method was then used to coat oleic acid-stabilized SPIONs with amphiphilic phospholipids, including APT(EDB)-PEG(2000)-DSPE, methoxy-PEG(2000)-DSPE, and rhodamine-DMPE. The resulting nanoparticles (APT(EDB)-SPIONs) had a hydrodynamic size of less than 50nm and remained stable in an aqueous solution for at least 1week. In in vitro studies, APT(EDB)-SPIONs showed specific uptake by EDB-overexpressing cell lines. In an in vivo Lewis lung carcinoma model that expresses a high level of the target EDB protein, MRI clearly revealed that APT(EDB)-SPIONs injected via the tail vein specifically accumulated at the tumor site. Non-targeting SPIONs lacking the anti-EDB aptide showed much lower uptake in tumor tissues than did aptide-conjugated nanoparticles. Further, we confirmed that the distribution of nanoparticles within the tumor tissue was well correlated with the areas where EDB was expressed. Our APT(EDB)-SPIONs hold high potential as a specific imaging modality for the detection of EDB-overexpressing tumors.
    Journal of Controlled Release 09/2012; 163(2):111-8. DOI:10.1016/j.jconrel.2012.08.029 · 7.26 Impact Factor
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    ABSTRACT: Delivery tracking: Goldnanoparticles (AuNPs) were functionalized with a red fluorescent protein (RFP, pink shapes in picture) as model antigen and an oligonucleotide (CpG) that stimulates the immune response. These functionalized AuNPs were used as cancer vaccines in a tumor model, where they enabled efficient delivery of an antigen to target sites, tracking of the vaccines using noninvasive clinical imaging, and cancer prevention and therapy.
    Angewandte Chemie International Edition 08/2012; 51(35):8800-5. DOI:10.1002/anie.201203193 · 11.34 Impact Factor
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    ABSTRACT: Purpose: This study was performed to compare the cytotoxicity and magnetic resonance (MR) contrast in diverse cultured cells and xenograft tumors models of two ultra-small superparamagnetic iron oxides (USPIOs), thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) and monocrystalline iron oxide nanoparticles (MION-47).Materials and methods: Transmission electron microscopy (TEM) images and R(2) relaxivity values of the TCL-SPION and MION-47 were obtained and the cell viability and cell growth velocity of treated and untreated human fibroblasts and human umbilical vein endothelial cells (HUVEC) were evaluated. The effect of TCL-SPION and MION-47 on the secretion of interlukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), the production of nitric oxides and the mitochondrial membrane potentials in murine macrophage cells (RAW264.7) was compared. Human hepatocellular carcinoma cells (HepG2, 5x10(5)) were subcutaneously injected into nude mice (BALB/c) and in vivo MR imaging of tumors before and after injection with TCL-SPION or MION-47 (12.5 mg Fe/kg) was performed on a 1.5 Tesla MRI scanner.Results: On TEM images, the average core diameter of TCL-SPION was 9 nm whereas that of MION-47 was 5 nm. TCL- SPION (345.0 ± 6.2 mM(-1)sec(-1)) had higher relaxivity (R(2)) than MION-47 (130.7 ± 1.1 mM(-1)sec(-1)). Significant changes in cell viability and growth were not found in human fibroblasts and HUVEC exposed to TCL-SPION and MION-47. However, IL-6 and TNF-α secretions increased dose-dependently and significantly in the macrophages treated with MION-47 or TCL-SPION. TCL-SPION had a lower stimulatory effect on IL-6 secretions than did MION-47 (P <0.05) and nitric oxides were produced in the macrophages by MION-47 but not TCL-SPION. A change in the mitochondrial membrane potential of the macrophages was observed 24 hours after the exposure, and MION-47 induced more collapses of the mitochondrial membrane potential than did TCL-SPION. In the in vivo MR imaging, 33.0 ± 1.3% and 7.5 ± 0.4% signal intensity decrease on T(2)*-weighted images was observed in the tumors injected with TCL-SPION and MION-47, respectively.Conclusion: Due to the modified surface properties and larger core size of its iron oxide nanoparticles, TCL-SPION achieves lower cytotoxicity and better tumor MR contrast than MION-47. Our study suggests that TCL-SPION may be used as a new platform for tumor imaging and therapy monitoring.
    Theranostics 01/2012; 2(1):76-85. DOI:10.7150/thno.3462 · 7.83 Impact Factor
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    Mi Kyung Yu, Jinho Park, Sangyong Jon
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    ABSTRACT: Nanomaterials offer new opportunities for cancer diagnosis and treatment. Multifunctional nanoparticles harboring various functions including targeting, imaging, therapy, and etc have been intensively studied aiming to overcome limitations associated with conventional cancer diagnosis and therapy. Of various nanoparticles, magnetic iron oxide nanoparticles with superparamagnetic property have shown potential as multifunctional nanoparticles for clinical translation because they have been used asmagnetic resonance imaging (MRI) constrast agents in clinic and their features could be easily tailored by including targeting moieties, fluorescence dyes, or therapeutic agents. This review summarizes targeting strategies for construction of multifunctional nanoparticles including magnetic nanoparticles-based theranostic systems, and the various surface engineering strategies of nanoparticles for in vivo applications.
    Theranostics 01/2012; 2(1):3-44. DOI:10.7150/thno.3463 · 7.83 Impact Factor
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    ABSTRACT: We designed a bioconjugate between duplex oligodeoxynucleotides (dODNs) and a dendrimer (DEN) and demonstrate its feasibility as a novel delivery system for doxorubicin (Dox) in animal tumor models and against cancer cells in vitro. The dODNs-DEN conjugates formed stable complexes with Dox (~184 Dox molecules per conjugate) and the resulting Dox-loaded conjugate exhibited a sustained drug release pattern both in vitro and in vivo. Pharmacokinetic studies showed that Dox-loaded dODNs-DEN conjugates were cleared from plasma much more slowly (up to 5.3h) than was free Dox (0.65h). Furthermore, tumors retained a higher amount of Dox in mice treated with the conjugate group compared to that of free Dox-treated group at the same dosage. In mice bearing 4T1 murine breast tumor allografts, the dendrimer conjugate, at a Dox concentration of 1mg/kg, was more effective than the equivalent concentration of free Dox and tumor size reduction was equivalent to that seen using 4mg/kg free Dox. We observed no severe systemic toxicity or cardiotoxicity in mice treated with the conjugate, as indicated by body weight change and heart tissue histology. These findings indicate that dODNs-DEN conjugates can be used to administer Dox with improved pharmacokinetics, lower toxicity, and an increased ability to concentrate drugs in tumors, compared with free drug, and that such conjugates are effective against tumors in vivo.
    Journal of Controlled Release 10/2011; 155(1):88-95. DOI:10.1016/j.jconrel.2010.09.008 · 7.26 Impact Factor
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    ABSTRACT: CG-rich duplex containing prostate-specific membrane antigen (PSMA) aptamer-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPIONs) is reported as prostate cancer-specific nanotheranostic agents. These agents are capable of prostate tumor detection in vivo by magnetic resonance imaging (MRI) and selective delivery of drugs to the tumor tissue, simultaneously. The prepared PSMA-functionalized TCL-SPION via a hybridization method (Apt-hybr-TCL-SPION) exhibited preferential binding towards target prostate-cancer cells (LNCaP, PSMA+) in both in vitro and in vivo when analyzed by T(2) -weighted MRI. After Dox molecules were loaded onto the Apt-hybr-TCL-SPION through the intercalation of Dox to the CG-rich duplex containing PSMA aptamer as well as electrostatic interaction between the Dox-and-polymer coating layer of the nanoparticles, the resulting Dox@Apt-hybr-TCL-SPION showed selective drug-delivery efficacy in the LNCaP xenograft mouse model. These results suggest that Dox@Apt-hybr-TCL-SPION has potential for use as novel prostate cancer-specific nanotheranostics.
    Small 08/2011; 7(15):2241-9. DOI:10.1002/smll.201100472 · 7.51 Impact Factor
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    ABSTRACT: We reported an innovative, targeted chemoimmuno drug-delivery system. Although chemoimmunotherapy, as an alternative to or in combination with conventional therapeutic systems, has been in the forefront of recent oncological research, as presently configured, such systems face several major obstacles for efficient clinical application. Here, we establish a novel nano-platform for effective chemoimmunotherapy designed to overcome the drawbacks of conventional cancer therapies, describing a delivery system based on a dendrimer and a single-strand DNA-A9 PSMA (prostate-specific membrane antigen) RNA aptamer hybrid. Employing these vehicles, we demonstrate the promising possibility of this chemoimmuno therapeutic system against prostate cancer in in vivo and in vitro models.
    Journal of Controlled Release 05/2011; 155(3):435-41. DOI:10.1016/j.jconrel.2011.05.025 · 7.26 Impact Factor
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    ABSTRACT: The aim of this study was to assess the feasibility of thermally cross-linked superparamagnetic iron oxide nanoparticle contrast (TCL-SPION) in magnetic resonance (MR) imaging (MRI) for the detection of lymph node metastasis in experimental model. B16F1 human melanoma cells were subcutaneously injected into the thighs of C57BL/6 mice (n = 10). MRI was performed 21 days after tumor injection using a 4.7-T MR scanner. In vivo MRI was performed before and after the intravenous administration of TCL-SPION using T2 fast spin-echo and T2 gradient-echo pulse sequences. Then, ex vivo MR images were obtained for resected inguinal lymph nodes (n = 18) using the same pulse sequences as for in vivo imaging. On the basis of hematoxylin and eosin staining results, the lymph nodes were classified into three groups: group 1, nonmetastatic; group 2, tumor volume <50% of the resected sample; and group 3, tumor volume >50% of the resected sample. Size, signal-to-background ratio, and enhancement pattern were evaluated in each of the three groups on ex vivo images. The findings observed on ex vivo MR images of 18 inguinal lymph nodes were compared with histopathologic findings. All nodes were classified into three groups: group 1, n = 6; group 2, n = 5; and group 3, n = 7. The sizes of the lymph nodes in group 1 were significantly different from the sizes of those in group 3 (P = .014), but there was no significant difference in lymph node sizes between groups 1 and 2 (P = .792). Signal-to-background ratios of samples in groups 2 and 3 were significantly higher than those of samples in group 1 (P = .045 and P = .007, respectively). Each group of lymph nodes showed characteristic enhancement patterns that were well correlated between the images and pathology, except for one node. The features and extent of metastasis in the lymph nodes corresponded to those observed on TCL-SPION-enhanced MR images. TCL-SPION-enhanced MRI is useful for the detection and estimation of lymph node metastasis.
    Academic radiology 04/2011; 18(4):504-11. DOI:10.1016/j.acra.2010.10.017 · 2.08 Impact Factor
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    ABSTRACT: We describe hybrid nanoparticles, composed of iron oxide and gold nanoparticles, as potential dual contrast agents for both computed tomography (CT) and magnetic resonance imaging (MRI). The hybrid nanoparticles are synthesized by thermal decomposition of mixtures of Fe-oleate and Au-oleylamine complexes. Using a nano-emulsion method, the nanoparticles are coated with amphiphilic poly(DMA-r-mPEGMA-r-MA) to impart water-dispersity and antibiofouling properties. An in vitro phantom study shows that the hybrid nanoparticles have high CT attenuation, because of the constituent gold nanoparticles, and afford a good MR signal, attributable to the contained iron oxide nanoparticles. Intravenous injection of the hybrid nanoparticles into hepatoma-bearing mice results in high contrast between the hepatoma and normal hepatic parenchyma in both CT and MRI. These results suggest that the hybrid nanoparticles may be useful as CT/MRI dual contrast agents for in vivo hepatoma imaging.
    Nanotechnology 04/2011; 22(15):155101. DOI:10.1088/0957-4484/22/15/155101 · 3.67 Impact Factor
  • Mi Kyung Yu, Jinho Park, Sangyong Jon
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    ABSTRACT: Magnetic iron oxide nanoparticles have been shown to be suitable for use as theranostic agents owing to their intrinsic diagnostic capabilities in magnetic resonance imaging (MRI) applications, hyperthermia properties, and ability to deliver drugs via magnetic attraction and/or systemic delivery. In addition, surface modifications are easily introduced through conjugation with targeting moieties (e.g., antibodies, peptides, or aptamers), genes, or therapeutic drugs to provide multimodal functionalities. Such valuable characteristics apply to image-guided drug delivery, especially MRI-guided drug delivery—a form of individualized therapy in which imaging methods are used to guide and monitor delivery of therapeutic agents to target tissues. This review summarizes the intrinsic physicochemical properties and pharmacokinetics of magnetic nanoparticles and highlights recent reports describing theranostic systems, including magnetic nanoparticle-based nanoplatforms, and their applications in MRI-guided drug delivery.
    02/2011; 2(1). DOI:10.1007/s13346-011-0049-8
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    ABSTRACT: Superparamagnetic iron oxide nanoparticles (SPION) were used to transfer gene into umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) in this study. This novel transfection method using SPION is safe and effective to UCB-MSCs, and would be a tool for genetic optimization with a significant potential for cell tracing.
    Journal of Nanoscience and Nanotechnology 02/2011; 11(2):1507-10. DOI:10.1166/jnn.2011.3402 · 1.34 Impact Factor
  • Small 12/2010; 6(24):2863-8. DOI:10.1002/smll.201001418 · 7.51 Impact Factor
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    ABSTRACT: We report multifunctional nanoparticles that are capable of cancer targeting and simultaneous cancer imaging and therapy. The nanoparticles are composed of cyclic arginine-glycine-aspartic acid (cRGD) peptide ligand bioconjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) that enable loading of the anticancer drug doxorubicin (Dox). The cyclic RGD-conjugated TCL-SPION (cRGD_TCL-SPION) had a mean hydrodynamic size of 34 ± 8 nm with approximately 0.39 wt% of cyclic RGD attached to the surface of the nanoparticles. The cRGD_TCL-SPION exhibited preferential binding towards target cancer cells (U87MG, integrin α(v)β(3)+) when analyzed by T(2)-weighted magnetic resonance (MR) imaging. When Dox was loaded onto the polymeric coating layers of cRGD_TCL-SPION via ionic interaction, the resulting Dox-loaded cRGD_TCL-SPION (Dox@cRGD_TCL-SPION) showed much higher cytotoxicity in U87MG cells than Dox@TCL-SPION lacking cRGD (IC(50) value of 0.02 µM versus 0.12 µM). These results suggest that Dox@cRGD_TCL-SPION has potential for use as an integrin-targeted, combined imaging and therapeutic agent.
    Nanotechnology 10/2010; 21(41):415102. DOI:10.1088/0957-4484/21/41/415102 · 3.67 Impact Factor
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    ABSTRACT: This paper reports a novel means of preparing HAp crystals. X-ray diffraction showed that the lactic acid route leads to good crystallinity and pure HAp phases compared to other routes. Impurity phases disappeared with a decrease in the number of carboxyl groups. FTIR indicated the presence of carbonate substitution, which increased as the number of carboxyl groups increased. Scanning electron microscopy observations revealed morphological variation of the particles that occurred when the number of carboxyl groups was changed in the complexing agents. The changes in the morphology with the carboxyl group number were analyzed taking into account the driving force for HAp precipitation and the supersaturation level of Ca2+ and PO4 3− ions with respect to HAp. The analysis indicated that the supersaturation level of the reactants, especially the number of carboxyl groups in the complexing agent, played a predominant role in the precipitate morphology process of this reaction. Energy-dispersive X-ray spectroscopy (EDX) analysis showed that the Ca/P ratio increased as the number of carboxyl groups decreased. Keywordssintering-sol-gel-biomaterial-scanning electron microscopy-bone
    Metals and Materials International 04/2010; 16(2):333-338. DOI:10.1007/s12540-010-0426-8 · 1.22 Impact Factor
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    ABSTRACT: The work demonstrated the development of thermally cross-linked superparamagnetic nanomaterial which possessed polyethylene glycol moiety and covalently linked branched polyethylenimine (BPEI), and exhibited highly efficient magnetofection even under serum conditioned media. The study showed its high anti-biofouling, cell viability and serum stability and thus revealed a potential magnetic nanoparticle-mediated targeted gene delivery system. This superparamagnetic particle mediated rapid and efficient transfection in primary vascular endothelial cells (HUVEC) successfully inhibits expression of PAI-1 which is responsible for various vascular dysfunctions such as vascular inflammation and atherosclerosis and thereby provides a potential strategy to transfect highly sensitive HUVEC. The sequential steps for the enhanced magnetofection had been studied by monitoring cellular uptake with the aid of confocal microscopy.
    Biomaterials 02/2010; 31(14):4204-13. DOI:10.1016/j.biomaterials.2010.01.123 · 8.31 Impact Factor
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    ABSTRACT: Recent advances in the development of nanotechnology and devices now make it possible to accurately deliver drugs or genes to the lung. Magnetic nanoparticles can be used as contrast agents, thermal therapy for cancer, and be made to concentrate to target sites through an external magnetic field. However, these advantages may also become problematic when taking into account safety and toxicological factors. This study demonstrated the pulmonary toxicity and kinetic profile of anti-biofouling polymer coated, Cy5.5-conjugated thermally cross-linked superparamagnetic iron oxide nanoparticles (TCL-SPION) by optical imaging. Negatively charged, 36 nm-sized, Cy5.5-conjugated TCL-SPION was prepared for optical imaging probe. Cy5.5-conjugated TCL-SPION was intratracheally instilled into the lung by a non-surgical method. Cy5.5-conjugated TCL-SPION slightly induced pulmonary inflammation. The instilled nanoparticles were distributed mainly in the lung and excreted in the urine via glomerular filtration. Urinary excretion was peaked at 3 h after instillation. No toxicity was found under the concentration of 1.8 mg/kg and the half-lives of nanoparticles in the lung and urine were estimated to be about 14.4+/-0.54 h and 24.7+/-1.02 h, respectively. Although further studies are required, our results showed that Cy5.5-conjugated TCL-SPION can be a good candidate for use in pulmonary delivery vehicles and diagnostic probes.
    Toxicology and Applied Pharmacology 07/2009; 239(1):106-15. DOI:10.1016/j.taap.2009.05.026 · 3.63 Impact Factor
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    ABSTRACT: We report a combined chemoimmunotherapy vehicle consisting of plasmid loaded with doxorubicin and evaluate its efficacy in two different tumor models. A stable complex was formed with a 1300:1 ratio of doxorubicin bound to native plasmid via intercalation. Pharmacokinetics of the complex showed much slower clearance from plasma up to 3 h compared to 10 min for free doxorubicin. In mice bearing NCI-H358 xenografts, lower doses of complex (doxorubicin 0.5 mg/kg, plasmid 4 mg/kg) effectively reduced tumor growth compared to high doses (5 mg/kg) of free doxorubicin (68% versus 77%). Similar results were observed in mice bearing 4T1 murine allografts; the complex (doxorubicin 2 mg/kg, plasmid 8 mg/kg) was effective and caused similar reduction of tumor compared to free doxorubicin (4 mg/kg) (47% versus 46%). The complex showed no signs of severe systemic toxicity or cardiotoxicity compared to the free doxorubicin in mice as indicated by body weights and heart tissue histology. Elevated levels of cytokines (IL-12, IL-6, and IFN-gamma) were observed in serum as well as in tumor tissue after intravenous injection of complex when compared to plasmid or doxorubicin alone. This approach simultaneously delivers both chemotherapeutic and immunotherapeutic agents without time delay, improves pharmacokinetics of the free drug, lowers drug toxicity, upregulates a variety of cytokines, and is effective against different tumors.
    Molecular Pharmaceutics 05/2009; 6(3):1019-28. DOI:10.1021/mp800177f · 4.79 Impact Factor
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    ABSTRACT: Superparamagnetic iron oxide nanoparticles (SPIONs) are widely used as T2-contrast agents for magnetic resonance imaging (MRI). Herein we develop various antibiofouling amphiphilic polymer-coated SPIONs using a one-step nanoemulsion method. This methodology yielded ultrasmall polymer-coated SPIONs, of average diameter less than 30 nm, which were stable under physiological conditions. In vitro cell cytotoxicity tests revealed that no SPION showed toxicity even at relatively high concentrations. In vivo MRI with Lewis lung carcinoma (LLC) tumor-bearing mice resulted in an approximately 30% T2 signal drop in tumor tissues, indicating that the SPIONs reached such tissues via passive targeting. In summary, the ultrasmall, stable, amphiphilic polymer-coated SPIONs can be used as MRI contrast agents for cancer imaging.
    Journal of Materials Chemistry 01/2009; 19(35). DOI:10.1039/b902445j · 6.63 Impact Factor
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    Angewandte Chemie International Edition 07/2008; 47(29):5362-5. DOI:10.1002/anie.200800857 · 11.34 Impact Factor
  • Nanomedicine Nanotechnology Biology and Medicine 12/2007; 3(4):348-348. DOI:10.1016/j.nano.2007.10.056 · 5.98 Impact Factor

Publication Stats

1k Citations
137.83 Total Impact Points

Institutions

  • 2012
    • Korea Advanced Institute of Science and Technology
      • Department of Biological Sciences
      Sŏul, Seoul, South Korea
  • 2007–2012
    • Gwangju Institute of Science and Technology
      • Department of Life Sciences
      Gwangju, Gwangju, South Korea
    • Chonnam National University
      Gwangju, Gwangju, South Korea
  • 2011
    • Korea Basic Science Institute KBSI
      Sŏul, Seoul, South Korea
  • 2010
    • Chonbuk National University
      • College of Engineering
      Seoul, Seoul, South Korea