Self-assembled PEGylated albumin nanoparticles (SPAN) as a platform for cancer chemotherapy and imaging

Lee, Jung Eun,Kim, Myung Goo,Jang, Yeon Lim,Lee, Min Sang,Kim, Nak Won,Yin, Yue,Lee, Jong Han,Lim, Su Yeon,Park, Ji Won,Kim, Jaeyun,Lee, Doo Sung,Kim, Sun Hwa,Jeong, Ji Hoon TaylorFrancis 2018 DRUG DELIVERY Vol.25 No.1

<P><B>Abstract</B></P><P>Paclitaxel (PTX) is used as a major antitumor agent for the treatment of recurrent and metastatic breast cancer. For the clinical application of PTX, it needs to be dissolved in an oil/detergent-based solvent due to its poor solubility in an aqueous medium. However, the formulation often causes undesirable complications including hypersensitivity reactions and limited tumor distribution, resulting in a lower dose-dependent antitumor effect. Herein, we introduce a facile and oil-free method to prepare albumin-based PTX nanoparticles for efficient systemic cancer therapy using a conjugate of human serum albumin (HSA) and poly(ethyleneglycol) (PEG). PTX were efficiently incorporated in the self-assembled HSA-PEG nanoparticles (HSA-PEG/PTX) using a simple film casting and re-hydration procedure without additional processes such as application of high pressure/shear or chemical crosslinking. The spherical HSA-PEG nanoparticle with a hydrodynamic diameter of ca. 280 nm mediates efficient cellular delivery, leading to comparable or even higher cytotoxicity in various breast cancer cells than that of the commercially available Abraxane<SUP>®</SUP>. When systemically administered in a mouse xenograft model for human breast cancer, the HSA-PEG-based nanoparticle formulation exhibited an extended systemic circulation for more than 96 h and enhanced intratumoral accumulation, resulting in a remarkable anticancer effect and prolonged survival of the animals.</P>

Targeted cellular delivery of robust enzyme nanoparticles for the treatment of drug-induced hepatotoxicity and liver injury

Lee, Min Sang,Kim, Nak Won,Lee, Jung Eun,Kim, Myung Goo,Yin, Yue,Kim, Sun Young,Ko, Bo Sung,Kim, Aeseon,Lee, Jong Han,Lim, Su Yeon,Lim, Dong Woo,Kim, Sun Hwa,Park, Ji Won,Lim, Yong Taik,Jeong, Ji Hoon Elsevier 2018 Acta Biomaterialia: structure-property-function re Vol.81 No.-

<P><B>Abstract</B></P> <P>Direct delivery of proteins into cells has been considered an effective approach for treating the protein-related diseases. However, clinical use of proteins has still been limited due to their instability in the blood and poor membrane permeability. To achieve an efficient cellular delivery of the protein to target cells via a systemic administration, a multifunctional carrier system having desirable stability both in the blood stream and the cells, specific cell-targeting property and endosomal escape functions may be required. In this study, we prepared a catalytic nanoparticle containing an active enzyme by cross-tethering multiple superoxide dismutase (SOD) molecules with catechol-derivatized hyaluronic acid (HA). The permeable shell of hydrophilic HA chains effectively protects the enzyme from degradation in the blood after intravenous administration and provides an additional function for targeting hepatocytes expressing HA receptor (CD44). The structure and catalytic activity of the enzyme molecules in the nanoparticle were not significantly compromised in the nanoparticle. In addition, ultra-small calcium phosphate nanoparticles (USCaP, 2–5 nm) were crystalized and decorated on the surface of the nanoparticle for the efficient endosomal escape after cellular uptake. The SOD-containing nanoparticle fortified with USCaP was used for the treatment of acetaminophen (APAP)-induced fulminant hepatotoxicity and liver injury. The nanoparticle achieved the efficient hepatic cellular delivery of SOD via a systemic administration and resulted in efficient removal of reactive oxygen species (ROS) in the liver and remarkable improvement of APAP-induced hepatotoxicity and liver injury in animals.</P> <P><B>Statement of Significance</B></P> <P>Despite the enormous therapeutic potential, the intracellular delivery of proteins has been limited due to their poor membrane permeability and stability. In this study, we demonstrated an active enzyme-containing nanoparticle functionalized by hyaluronic acid and ultra-small size calcium phosphate nanoparticles (2–5 nm) for targeted cellular delivery of superoxide dismutase (SOD). The nanoparticle was designed to integrate all the essential functions, including serum stability, target specificity, and endosomal escape capability, for a systemic delivery of a therapeutic protein to the cells of the liver tissue. The intravenous administration of the nanoparticle efficiently removes reactive oxygen species (ROS) in the liver and remarkably improves the drug-induced hepatotoxicity and the progress of fulminant liver injury in an acetaminophen-overdose animal model.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Copolymerization of Ethylene and Norbornene via Polymethylene Bridged Dinuclear Constrained Geometry Catalysts

Yin Bang Zhu,Eun Gyeong Jeong,Bae Wook Lee,Bong Shik Kim,Seok Kyun Noh,Won Seok Lyoo,Dong Ho Lee,Yong Man Kim 한국고분자학회 2007 Macromolecular Research Vol.15 No.5

Genetic Diversity and Fitness of Fusarium graminearum Populations from Rice in Korea

Lee, Jungkwan,Chang, In-Young,Kim, Hun,Yun, Sung-Hwan,Leslie, John F.,Lee, Yin-Won American Society for Microbiology 2009 Applied and environmental microbiology Vol.75 No.10

<B>ABSTRACT</B><P><I>Fusarium graminearum</I> is an important fungal pathogen of cereal crops and produces mycotoxins, such as the trichothecenes nivalenol and deoxynivalenol. This species may be subdivided into a series of genetic lineages or phylogenetic species. We identified strains of <I>F. graminearum</I> from the Republic of Korea to lineage, tested their ability to produce nivalenol and deoxynivalenol, and determined the genetic composition and structure of the populations from which they were recovered. Based on amplified fragment length polymorphism (AFLP), PCR genotyping, and chemical analyses of trichothecenes, all 249 isolates from southern provinces belonged to lineage 6, with 241 having the nivalenol genotype and 8 having the deoxynivalenol genotype. In the eastern Korea province, we recovered 84 lineage 6 isolates with the nivalenol genotype and 23 lineage 7 isolates with the deoxynivalenol genotype. Among 333 lineage 6 isolates, 36% of the AFLP bands were polymorphic, and there were 270 multilocus haplotypes. Genetic identity among populations was high (>0.972), and genotype diversity was low (30 to 58%). To test the adaptation of lineage 6 to rice, conidial mixtures of strains from lineages 3, 6, and 7 were inoculated onto rice plants and then recovered from the rice grains produced. Strains representing lineages 6 and 7 were recovered from inoculated spikelets at similar frequencies that were much higher than those for the strain representing lineage 3. Abundant perithecia were produced on rice straw, and 247 single-ascospore isolates were recovered from 247 perithecia. Perithecia representing lineage 6 (87%) were the most common, followed by those representing lineage 7 (13%), with perithecia representing lineage 3 not detected. These results suggest that <I>F. graminearum</I> lineage 6 may have a host preference for rice and that it may be more fit in a rice agroecosystem than are the other lineages present in Korea.</P>

Rosa hybrida extract suppresses vascular smooth muscle cell responses by the targeting of signaling pathways, cell cycle regulation and matrix metalloproteinase-9 expression

LEE, SE-JUNG,WON, SE YEON,PARK, SUNG LYEA,SONG, JUN-HUI,NOH, DAE-HWA,KIM, HONG-MAN,YIN, CHANG SHIK,KIM, WUN-JAE,MOON, SUNG-KWON UNKNOWN 2016 INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE Vol.37 No.4

<P>The pharmacological effects of Rosa hybrida are well known in the cosmetics industry. However, the role of Rosa hybrida in cardiovascular biology had not previously been investigated, to the best of our knowledge. The aim of the present study was to elucidate the effect of water extract of Rosa hybrida (WERH) on platelet-derived growth factor (PDGF)-stimulated vascular smooth muscle cells (VSMCs). VSMC proliferation, which was stimulated by PDGF, was inhibited in a non-toxic manner by WERH treatment, which also diminished the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT. Treatment with WERH also induced G1-phase cell cycle arrest, which was due to the decreased expression of cyclins and cyclin-dependent kinases (CDKs), and induced p21WAF1 expression in PDGF-stimulated VSMCs. Moreover, WERH treatment suppressed the migration and invasion of VSMCs stimulated with PDGF. Treatment with WERH abolished the expression of matrix metalloproteinase-9 (MMP-9) and decreased the binding activity of nuclear factor-kappa B (NF-kappa B), activator protein-1 (AP-1), and specificity protein 1 (Sp1) motifs in PDGF-stimulated VSMCs. WERH treatment inhibited the proliferation of PDGF-stimulated VSMCs through p21WAF1-mediated G1-phase cell cycle arrest, by decreasing the kinase activity of cyclin/CDK complexes. Furthermore, WERH suppressed the PDGF-induced phosphorylation of ERK1/2 and AKT in VSMCs. Finally, treatment with WERH impeded the migration and invasion of VSMCs stimulated by PDGF by downregulating MMP-9 expression and a reduction in NF-kappa B, AP-1 and Sp1 activity. These results provide new insights into the effects of WERH on PDGF-stimulated VSMCs, and we suggest that WERH has the potential to act as a novel agent for the prevention and/or treatment of vascular diseases.</P>

Variation in 8-ketotrichothecenes and zearalenone production by Fusarium graminearum isolates from corn and barley in Korea

( Yin Won Lee,Jeong Ah Seo ) 한국균학회 1997 97 KOREA CHINA JOINT SYMPOSIUM Vol.- No.-

Development of a three-dimensionally printed scaffold grafted with bone forming peptide-1 for enhanced bone regeneration with <i>in vitro</i> and <i>in vivo</i> evaluations

Lee, Sang Jin,Won, Jong-Eun,Han, Changhak,Yin, Xiang Yun,Kim, Hyung Keun,Nah, Haram,Kwon, Il Keun,Min, Byoung-Hyun,Kim, Chul-Ho,Shin, Yoo Seob,Park, Su A Elsevier 2019 JOURNAL OF COLLOID AND INTERFACE SCIENCE - Vol.539 No.-

<P><B>Abstract</B></P> <P>Defects in bone are some of the most difficult injuries to treat. Biomimetic scaffolds represent a promising approach for successful bone tissue regeneration. In this study, a three-dimensional (3D) scaffold with osteo-inductive functionality was designed and assayed both in-vitro and in-vivo. Bone formation peptide-1 (BFP1), an osteo-promoting specific peptide, was covalently bound to a 3D printed polycaprolactone (PCL) scaffold using polydopamine (DOPA). The amount of BFP1 immobilized on the surface was found to increase depending on the BFP1 concentration of the loading solution. To observe the biological effects of the 3D scaffolds, human tonsil-derived mesenchymal stem cells (hTMSCs) were isolated. The cells were cultured on the scaffolds and observed to rapidly differentiate into osteoblast-like cells with osteo-promoting capabilities. The scaffolds were implanted in a rabbit calvarial defect model for 8 weeks and successfully stimulated both vessel and bone regeneration. Osteo-promoting 3D scaffolds may provide a safer and more efficient approach for bone repair and remodelling in regenerative medicine.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Role of soluble CD14 in cerebrospinal fluid as a regulator of glial functions

Yin, Guo Nan,Jeon, Hyejin,Lee, Shinrye,Lee, Ho Won,Cho, Je-Yoel,Suk, Kyoungho Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of neuroscience research Vol.87 No.11

<P>Proteomic analysis of cerebrospinal fluid (CSF) samples derived from patients with Alzheimer's disease (AD) or Parkinson's disease (PD) was performed. On the basis of liquid chromatography–tandem mass spectrometry, two-dimensional gel electrophoresis analysis, and Western blot validation, it was found that the level of soluble form of monocyte differentiation antigen CD14 precursor was elevated in CSF from AD or PD patients compared with normal subjects. The soluble CD14 protein and mRNA expression was detected in microglia cells, indicating that microglia may be a cellular source of soluble CD14 in CSF. Next, the role of soluble CD14 in the regulation of glial functions was investigated. Soluble CD14 inhibited lipopolysaccharide (LPS)- or LPS/interferon-gamma-induced nitric oxide production and cell death of microglia and astrocytes. Soluble CD14 suppressed glial neurotoxicity in a coculture of glia/neuroblastoma. In addition, soluble CD14 moderately enhanced phagocytic activity of microglia. These results suggest that microglia-derived soluble CD14 is a candidate CSF biomarker for AD and PD, and the soluble CD14 may inhibit glial activation by interfering with LPS effects. © 2009 Wiley-Liss, Inc.</P>

Estrogenic Compounds Compatible with a Conditional Gene Expression System for the Phytopathogenic Fungus Fusarium graminearum

Lee, Jung-Kwan,Son, Ho-Kyoung,Lee, Yin-Won The Korean Society of Plant Pathology 2011 Plant Pathology Journal Vol.27 No.4

The ascomycete fungus Fusarium graminearum is an important plant pathogen responsible for Fusarium head blight in small grains and ear rot on maize. This fungus also produces the estrogenic metabolite, zearalenone (ZEA) that causes estrogenic disorders in humans and animals. Previously, we developed a conditional gene expression system for this fungus using a ZEA-inducible promoter (Pzear). In the present study, four other estrogenic compounds, including ${\beta}$-estradiol, estriol, estrone, and secoisolariciresinol, were screened as possible substitutes for ZEA in this system. Among them, ${\beta}$-estradiol was able to successfully induce the expression of a gene controlled by Pzear, while estrone was only able to partially induce its expression but the other two compounds were not effective. In combination, these results demonstrate that ${\beta}$-estradiol can replace ZEA in this conditional gene expression system, thereby eliminating the need to use the more expensive reagent, ZEA, and facilitating high-throughput functional analyses of F. graminearum in future studies.

Development of a Conditional Gene Expression System Using a Zearalenone-Inducible Promoter for the Ascomycete Fungus Gibberella zeae

Lee, Jungkwan,Son, Hokyoung,Lee, Seunghoon,Park, Ae Ran,Lee, Yin-Won American Society for Microbiology 2010 Applied and environmental microbiology Vol.76 No.10

<B>ABSTRACT</B><P>The ascomycete fungus <I>Gibberella zeae</I> is an important plant pathogen that causes fusarium head blight on small grains. Molecular studies of this fungus have been performed extensively to uncover the biological mechanisms related to pathogenicity, toxin production, and sexual reproduction. Molecular methods, such as targeted gene deletion, gene overexpression, and gene fusion to green fluorescent protein (GFP), are relatively easy to perform with this fungus; however, conditional expression systems have not been developed. The purpose of this study was to identify a promoter that could be induced by zearalenone (ZEA) for the development of a conditional expression system in <I>G. zeae</I>. Through microarray analysis, we isolated one zearalenone response gene (<I>ZEAR</I>) whose expression was increased more than 50 times after ZEA treatment. Northern blot analysis showed that the <I>ZEAR</I> transcript dramatically increased after 1 h of ZEA treatment. To determine the utility of the <I>ZEAR</I> promoter, called Pzear, in a conditional expression system, we transformed a <I>Pzear</I>::<I>GFP</I> fusion construct into <I>G. zeae</I>. Our data showed a ZEA concentration-dependent increase in GFP expression. We also replaced the promoter of <I>G. zeae metE</I> (<I>GzmetE)</I>, an essential gene for methionine biosynthesis, with the Pzear promoter. The growth of the <I>Pzear-GzmetE</I> mutant on minimal medium was dependent on the ZEA concentration supplemented in the medium and showed that GzMetE expression was induced by ZEA. This study is the first report of an inducible promoter in <I>G. zeae.</I> Our system will be useful for the characterization of essential gene functions in this fungus through differential and ZEA-dependent gene expression. In addition, the Pzear promoter may be applicable as a biosensor for the detection of ZEA contamination in agricultural products.</P>