Byung-Heon Lee

Kyungpook National University, Daikyū, Daegu, South Korea

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Publications (50)238.07 Total impact

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    ABSTRACT: Biopanning of phage displayed-peptide library was performed against myoglobin, a marker for the early assessment of acute myocardial infarction (AMI), to identify peptides that selectively bind to myoglobin. Using myoglobin-conjugated magnetic beads, phages that bound to myoglobin were collected and amplified for the next round of screening. A 148-fold enrichment of phage titer was observed after five rounds of screening relative to the first round. After phage binding ELISA, three phage clones were selected (3R1, 3R7 and 3R10) and the inserted peptides were chemically synthesized. The analysis of binding affinity showed that the 3R7 (CPSTLGASC) peptide had higher binding affinity (Kd=57nM) than did the 3R1 (CNLSSSWIC) and 3R10 (CVPRLSAPC) peptide (Kd=125nM and 293nM, respectively). Cross binding activity to other proteins, such as bovine serum albumin, troponin I, and creatine kinase-MB, was minimal. In a peptide-antibody sandwich ELISA, the selected peptides efficiently captured myoglobin. Moreover, the concentrations of myoglobin in serum samples measured by a peptide-peptide sandwich assay were comparable to those measured by a commercial antibody-based kit. These results indicate that the identified peptides can be used for the detection of myoglobin and may be a cost effective alternative to antibodies.
    Journal of biotechnology. 07/2014;
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    ABSTRACT: Effective anticancer therapy can be achieved by designing a targeted drug-delivery system with high stability during circulation and efficient uptake by the target tumour cancer cells. We report here a novel nano-assembled drug-delivery system, formed by multivalent host-guest interactions between a polymer-cyclodextrin conjugate and a polymer-paclitaxel conjugate. The multivalent inclusion complexes confer high stability to the nano-assembly, which efficiently delivers paclitaxel into the targeted cancer cells via both passive and active targeting mechanisms. The ester linkages between paclitaxel and the polymer backbone permit efficient release of paclitaxel within the cell by degradation. This novel targeted nano-assembly exhibits significant antitumour activity in a mouse tumour model. The strategy established in this study also provides knowledge for the development of advanced anticancer drug delivery.
    Nature Communications 01/2014; 5:3702. · 10.74 Impact Factor
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    ABSTRACT: Early decision on tumor response after anti-cancer treatment is still an unmet medical need. Here we investigated whether in vivo imaging of apoptosis using linear and cyclic (disulfide-bonded) form of ApoPep-1, a peptide that recognizes histone H1 exposed on apoptotic cells, at an early stage after treatment could predict tumor response to the treatment later. Treatment of stomach tumor cells with cistplatin or cetuximab alone induced apoptosis, while combination of cisplatin plus cetuximab more efficiently induced apoptosis, as detected by binding with linear and cyclic form of ApoPep-1. However, the differences between the single agent and combination treatment were more remarkable as detected with the cyclic form compared to the linear form. In tumor-bearing mice, apoptosis imaging was performed 1 week and 2 weeks after the initiation of treatment, while tumor volumes and weights were measured 3 weeks after the treatment. In vivo fluorescence imaging signals obtained by the uptake of ApoPep-1 to tumor was most remarkable in the group injected with cyclic form of ApoPep-1 at 1 week after combined treatment with cisplatin plus cetuximab. Correlation analysis revealed that imaging signals by cyclic ApoPep-1 at 1 week after treatment with cisplatin plus cetuximab in combination were most closely related with tumor volume changes (r2 = 0.934). These results demonstrate that in vivo apoptosis imaging using Apopep-1, especially cyclic ApoPep-1, is a sensitive and predictive tool for early decision on stomach tumor response after anti-cancer treatment.
    PLoS ONE 01/2014; 9(6):e100341. · 3.53 Impact Factor
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    ABSTRACT: During acute myocardial infarction (AMI), both apoptosis and necrosis of myocardial cells could occur and lead to left ventricular (LV) functional decline. Here we determined whether in vivo imaging signals of myocardial cell death by ApoPep-1 (CQRPPR), a peptide probe that binds to apoptotic and necrotic cells through histone H1, at an early stage after AMI showed correlation with the long-term heart function. AMI was induced using a rat model of ischemia and reperfusion (I/R) injury. Fluorescence-labeled ApoPep-1 was administered by intravenous injection into rats 2h after reperfusion. Ex vivo imaging of hearts isolated 2h after peptide injection showed higher levels of near-infrared fluorescence (NIRF) signals at hearts of I/R rats than those of sham-operated rats. The fluorescent peptide was rapidly cleared from the blood and did not bind to red and white blood cells. Localization of fluorescent ApoPep-1 at the area of cell death was demonstrated by co-staining of myocardial tissue with TUNEL. The intensity of in vivo NIRF imaging signals by homing of ApoPep-1 to injured myocardium of I/R rats obtained 2h after peptide injection (equivalent to 4h after injury) showed strong and moderate correlation with the change in the LV ejection fractions (r(2)=0.82) and the size of the fibrotic area (r(2)=0.64), respectively, observed at four weeks after injury. These results suggest that ApoPep-1-mediated in vivo imaging signals of myocardial cell death, including both apoptosis and necrosis, at an early stage of AMI could be a potential biomarker for assessment of long-term outcome of heart function.
    Journal of Controlled Release 09/2013; · 7.63 Impact Factor
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    ABSTRACT: Protein-cage nanoparticles are promising multifunctional platforms for targeted delivery of imaging and therapeutic agents owing to their biocompatibility, biodegradability, and low toxicity. The major advantage of protein-cage nanoparticles is the ability to decorate their surfaces with multiple functionalities through genetic and chemical modification to achieve desired properties for therapeutic and/or diagnostic purposes. Specific peptides identified by phage display can be genetically fused onto the surface of cage proteins to promote the association of nanoparticles with a particular cell type or tissue. Upon symmetrical assembly of the cage, peptides are clustered on the surface of the cage protein in bunches. The resulting PBNC (Peptide Bunches on NanoCage) offers the potential of synergistic increasing the avidity of the peptide ligands, thereby enhancing their blocking ability for therapeutic purposes. Here, we demonstrated proof-of-principle of PBNCs, fusing the interleukin-4 receptor (IL-4R)-targeting peptide, AP-1, identified previously by phage display, with ferritin-L-chain (FTL), which undergoes 24-subunit assembly to form highly stable AP-1-containing nanocage proteins (AP1-PBNC). AP1-PBNCs bound specifically to the IL-4R-expressing cell line, A549, and their binding and internalization were specifically blocked by anti-IL-4R antibody. AP1-PBNCs exhibited dramatically enhanced binding avidity to IL-4R compared with AP-1 peptide, measured by surface plasmon resonance spectroscopy. Furthermore, treatment with AP1-PBNCs in a murine model of experimental asthma diminished airway hyper-responsiveness and eosinophilic airway inflammation along with decreased mucus hyperproduction. These findings hold great promise that various PBNCs containing ligand specific peptides could be applied for therapeutics indifferent diseases, such as cancer.
    ACS Nano 08/2013; · 12.03 Impact Factor
  • Byung-Heon Lee, Tae-Hwan Kwon
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    ABSTRACT: In vitro phage display represents an emerging and innovative technology for the rapid isolation of high-affinity peptide ligands. Phage display technologies using phages comprising a vast library of peptides have become fundamental to the isolation of high-affinity binding ligands for diagnostic and therapeutic applications, e.g., ligand proteomics, discovery of novel protein-protein interactions, antibody engineering, targeted delivery of therapeutic agents, and development of imaging probes. This chapter describes the procedures for phage display selection of peptide ligands that selectively bind to aquaporin-2-expressing membrane fractions of rat kidney.
    Methods in molecular biology (Clifton, N.J.) 01/2013; 1023:181-9. · 1.29 Impact Factor
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    ABSTRACT: Various human solid tumors highly express IL-4 receptors which amplify the expression of some of anti-apoptotic proteins, preventing drug-induced cancer cell death. Thus, IL-4 receptor targeted drug delivery can possibly increase the therapeutic efficacy in cancer treatment. Macromolecular carriers with multivalent targeting moieties offered great advantages in cancer therapy as they not only increase the plasma half-life of the drug but also allow delivery of therapeutic drugs to the cancer cells with higher specificity, minimizing the deleterious effects of the drug on normal cells. In this study we designed a library of elastin like polypeptide (ELP) polymers containing tumor targeting AP1 peptide using recursive directional ligation method. AP1 was previously discovered as an atherosclerotic plaque and breast tumor tissue homing peptide using phage display screening method, and it can selectively bind to the interleukin 4 receptor (IL-4R). The fluorescently labeled [AP1-V12]6, an ELP polymer containing six AP1 enhanced tumor-specific targeting ability and uptake efficiency in H226 and MDA-MB-231 cancer cell lines in vitro. Surface plasmon resonance analysis showed that multivalent presentation of the targeting ligand in the ELP polymer increased the binding affinity towards IL-4 receptor compared to free peptide. The binding of [AP1-V12]6 to cancer cells was remarkably reduced when IL-4 receptors were blocked by antibody against IL-4 receptor further confirmed its binding. Importantly, the Cy5.5-labeled [AP1-V12]6 demonstrated excellent homing and longer retention in tumor tissues in MDA-MB-231 xenograft mouse model. Immunohistological studies of tumor tissues further validated the targeting efficiency of [AP1-V12]6 to tumor tissue. These results indicate that designed [AP1-V12]6 can serve as a novel carrier for selective delivery of therapeutic drugs to tumors.
    PLoS ONE 01/2013; 8(12):e81891. · 3.53 Impact Factor
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    ABSTRACT: Various angiogenesis inhibitors and apoptosis-targeting agents have been therapeutically applied in preclinical cancer models, some of which have been tested in clinical trials. In a previous study, we demonstrated that LHT7, a low molecular weight heparin (LMWH)-taurocholate conjugate, has strong antiangiogenic and tumor-suppressive activity and diminished anticoagulant properties. In this study, we developed LHT7-ApoPep-1, an apoptosis-homing peptide-conjugated variant of LHT7. LHT7-ApoPep-1 exhibited antiangiogenic activity in endothelial cell tube-formation assays and apoptotic cell-targeting ability in tumor cell binding assays; it also showed little toxicity toward healthy cells. Administration of LHT7-ApoPep-1 in mouse xenograft models of breast carcinoma delayed tumor growth compared to LHT7-only, and histological evaluations revealed decreased vessel formation and increased apoptotic area in tumor tissues. Moreover, an examination of LHT7-ApoPep-1-Cy7.5 localization within the body using in vivo live imaging showed accumulation at the tumor site of tumor-bearing mice, with a more prolonged circulation time and enhanced intensity compared to LHT7-Cy7.5. Inspection of the tumor microenvironment revealed that Cy5.5-labeled LHT7-ApoPep-1 was located on and near CD31-positive vessels in tumor tissue. We conclude that LHT7-ApoPep-1 has antiangiogenic and apoptosis-targeting properties and exerts antitumor effects by suppressing tumor vessel growth and homing to apoptotic cells within the tumor.
    Biomaterials 12/2012; · 8.31 Impact Factor
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    ABSTRACT: Chemotherapy-induced apoptosis of tumor cells enhances the antigen presentation and sensitizes tumor cells to T cell-mediated cytotoxicity. Here we harnessed the apoptosis of tumor cells as a homing signal for the delivery of T cells to tumor. Jurkat T cells were anchored with ApoPep-1, an apoptosis-targeted peptide ligand, using the biocompatible anchor for membrane (BAM), an oleyl acid derivative. The ApoPep-1-BAM conjugate was efficiently anchored to cell membrane, while little anchoring was obtained with ApoPep-1 alone. The retention period of the ApoPep-1-BAM conjugate on cell membrane was approximately 80 and 40min in the absence and presence of serum, respectively. ApoPep-1 was resistant to degradation in serum until 2h. The apoptosis-targeted T cells that were anchored with the ApoPep-1-BAM preferentially bound to apoptotic tumor cells over living cells. When intravenously injected into tumor-bearing mice, the number of apoptosis-targeted T cells and in vivo fluorescence signals by the homing of the cells to doxorubicin-treated tumor were higher than those of untargeted T cells. Accumulation of apoptosis-targeted T cells at other organs such as liver was not detected. These results suggest that the chemotherapy-induced apoptosis and subsequent enhancement of T cell delivery to tumor by the membrane anchoring of the apoptosis-targeted peptide could be a novel strategy for cancer immunotherapy.
    Journal of Controlled Release 07/2012; 162(3):521-8. · 7.63 Impact Factor
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    ABSTRACT: It is known that VEGF receptors (VEGFR) and integrins interact with each other to regulate angiogenesis. We reported previously that the fasciclin 1 (FAS1) domain-containing protein, TGFBIp/βig-h3 (TGF-β-induced protein) is an angiogenesis regulator that inhibits both endothelial cell migration and growth via αvβ3 integrin. In an attempt to target the interaction between VEGFR-2 and αvβ3 integrin, we determined whether the FAS1 domain region of TGFBIp/βig-h3 (FAS1 domain protein) can block the interaction between the two receptors, leading to the suppression of angiogenesis. In this study, we showed that FAS1 domain protein inhibits VEGF165-induced endothelial cell proliferation and migration via αvβ3 integrin, resulting in the inhibition of VEGF165-induced angiogenesis. We also defined a molecular mechanism by which FAS1 domain protein blocks the association between αvβ3 integrin and VEGFR-2, showing that it binds to αvβ3 integrin but not to VEGFR-2. Blocking the association of these major angiogenic receptors with FAS1 domain protein inhibits signaling pathways downstream of VEGFR-2. Collectively, our results indicate that FAS1 domain protein, in addition to its inhibitory effect on αvβ3 integrin-mediated angiogenesis, also inhibits VEGF165-induced angiogenesis. Thus, FAS1 domain protein can be further developed into a potent anticancer drug that targets two principal angiogenic pathways.
    Molecular Cancer Research 06/2012; 10(8):1010-20. · 4.35 Impact Factor
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    ABSTRACT: Bladder cancer is the second most common cancer of the urinary tract, however the invasive cystoscopy is still the standard technique for diagnosis and surveillance of bladder cancer. Herein, we radiolabel bladder cancer specific peptide with radioactive iodine ((131/124)I) and evaluate its potential as a new radiopharmaceutical for the non-invasive diagnosis of bladder cancer. A 9-mer bladder cancer specific peptide (BP) was conjugated with tyrosine and cyclized by disulfide bond formation to give Y-BP, which was further radioiodinated to give [(131/124)I]Y-BP in good radiochemical yield. The biodistribution data showed the high selectivity of [(124)I]Y-BP in HT1376 human bladder cancer xenograft models with a tumor-to-muscle ratio of 6.2. This tumor targeting was not observed in control B16F10 melanoma tumor models. In microPET studies, while the control scrambled peptide, [(124)I]Y-sBP, did not accumulate in either the bladder cancer or melanoma, [(124)I]Y-BP showed high tumor uptake only in animals with HT1376 bladder cancer cells. Furthermore, [(124)I]Y-BP showed superior bladder cancer uptake even compared to most commonly used cancer imaging tracer, [(18)F]FDG. The experimental results suggest the potential of [(124)I]Y-BP as a new radiopharmaceutical for the non-invasive diagnosis of bladder cancer with high binding affinity and selectivity.
    Bioorganic & medicinal chemistry 05/2012; 20(14):4330-5. · 2.82 Impact Factor
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    ABSTRACT: Macromolecular nanoparticles can extravasate and accumulate within tumor tissues via the passive targeting system, reflecting enhanced permeability and the retention effect. However, the unsatisfactory tumor therapeutic efficacy of the passive-targeting system, attributable to the retention of extravasated nanoparticles in the vicinity of tumor vessels, argues that a new system that facilitates intracellular delivery of nanoparticles within tumors is needed. Here, we developed hydrophobically modified glycol chitosan (HGC) nanoparticles conjugated with interleukin-4 receptor (IL-4R) binding peptides, termed I4R, and tested them in mice bearing IL-4R-positive tumors. These HGC-I4R nanoparticles exhibited enhanced IL-4R-dependent cellular uptake in tumors compared to nonconjugated nanoparticles, leading to better therapeutic and imaging efficacy. We conclude that I4R facilitates and enhances cellular uptake of nanoparticles in tumor tissues. This study suggests that the intracelluar uptake of nanoparticles in tumors is an essential factor to consider in designing nanoparticles for tumor-targeted drug delivery and imaging.
    Journal of Controlled Release 09/2011; 157(3):493-9. · 7.63 Impact Factor
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    ABSTRACT: Many cells, including macrophages, accumulate in atherosclerotic lesions, destabilizing plaques and driving plaque disruption. Therefore, macrophages serve as useful targets for atherosclerosis treatment and imaging. Stabilin-2 is a transmembrane protein expressed predominantly in macrophages and endothelial cells. In the present study, we found that stabilin-2 was widely expressed in atherosclerotic plaques than in normal vessel walls, and was present not only in macrophages but also in endothelial and smooth muscle cells in plaques. We used phage display technology to identify peptides that specifically bound to stabilin-2. After four rounds of selection, the most commonly isolated peptide had the sequence CRTLTVRKC, and was named S2P. We confirmed that this peptide specifically bound to stabilin-2-expressing cells in vitro and sinus endothelial cells in the spleen and lymph nodes in vivo. A FITC-conjugated synthetic CRTLTVRKC peptide was shown to home to atherosclerotic plaques in Ldlr-/- mice and to co-localize with endothelial cells, macrophages, and smooth muscle cells in such plaques. S2P conjugated to hydrophobically modified glycol chitosan nanoparticles was efficiently delivered to atherosclerotic plaques. These results show that the CRLTLTVRKC peptide homes to plaques by targeting stabilin-2; the peptide shows promise as a drug delivery moiety for, and an aid to molecular imaging of, atherosclerosis and other inflammatory diseases.
    Journal of Controlled Release 07/2011; 155(2):211-7. · 7.63 Impact Factor
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    ABSTRACT: When tumor cells undergo apoptosis in response to chemotherapy, the levels of apoptotic biomarkers such as histone H1 are increased at the tumor. This would amplify in situ homing signals and thus drug delivery by apoptosis-targeted drugs. To examine this possibility, we prepared apoptosis-targeted liposomes containing doxorubicin by labeling them with the CQRPPR peptide (ApoPep-1) that recognizes apoptotic cells by binding to histone H1. ApoPep-1-labeled liposomes, but not folate-labeled liposomes, inhibited tumor growth in mice more efficiently than untargeted liposomes, although in vitro cytotoxicities of those liposomes were similar. Fluorescence imaging signals at tumor were increased by the homing of ApoPep-1-labeled, fluorescent liposomes, which was correlated with the increase of apoptosis and the amount of doxorubicin at the tumor and, conversely, with the decrease of tumor volume. These results demonstrate that the apoptosis-targeted drug delivery enables in situ dose amplification and, when combined with imaging of apoptosis, provides a real-time monitoring of treatment response for cancer theragnosis.
    Journal of Controlled Release 07/2011; 154(3):214-7. · 7.63 Impact Factor
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    ABSTRACT: We used a novel apoptosis-targeting peptide called ApoPep-1 in order to evaluate whether ApoPep-1 can be used as a diagnostic indicator in a model of Parkinson's disease (PD). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was given to mice to produce the PD model. Cy7.5-labeled ApoPep-1 was given intravenously and optical imaging was taken at 1, 2, and 3 weeks after MPTP treatment. Immunohistochemical study was performed with brain sections. Increased ApoPep-1 signal was observed in the brain of MPTP-treated mice by in vivo and ex vivo imaging study. With histological evaluation, ApoPep-1 signal demonstrated a strong correlation with loss of dopaminergic neurons or increase of apoptotic cells. Moreover, the neuroprotective effect of amantadine in the MPTP model was effectively evaluated using optical imaging of ApoPep-1. We conclude that ApoPep-1 is the effective probe for imaging of apoptosis in the MPTP model and can be applied in brain diseases with apoptosis.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 05/2011; 14(2):147-55. · 2.47 Impact Factor
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    ABSTRACT: Laminar shear stress (LSS) is known to increase endothelial nitric oxide (NO) production, which is essential for vascular health, through expression and activation of nitric oxide synthase 3 (NOS3). Recent studies demonstrated that LSS also increases the expression of argininosuccinate synthetase 1 (ASS1) that regulates the provision of L-arginine, the substrate of NOS3. It was thus hypothesized that ASS1 might contribute to vascular health by enhancing NO production in response to LSS. This hypothesis was pursued in the present study by modulating NOS3 and ASS1 levels in cultured endothelial cells. Exogenous expression of either NOS3 or ASS1 in human umbilical vein endothelial cells increased NO production and decreased monocyte adhesion stimulated by tumor necrosis factor-α (TNF-α). The latter effect of overexpressed ASS1 was reduced when human umbilical vein endothelial cells were co-treated with small interfering RNAs (siRNAs) for ASS1 or NOS3. SiRNAs of NOS3 and ASS1 attenuated the increase of NO production in human aortic endothelial cells stimulated by LSS (12 dynes·cm(-2)) for 24 h. LSS inhibited monocyte adhesion to human aortic endothelial cells stimulated by TNF-α, but this effect of LSS was abrogated by siRNAs of NOS3 and ASS1 that recovered the expression of vascular cell adhesion molecule-1. The current study suggests that the expression of ASS1 harmonized with that of NOS3 may be important for the optimized endothelial NO production and the prevention of the inflammatory monocyte adhesion to endothelial cells.
    Journal of Biological Chemistry 01/2011; 286(4):2536-42. · 4.65 Impact Factor
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    ABSTRACT: Targeted delivery of imaging agents and therapeutics to tumors would provide early detection and increased therapeutic efficacy against cancer. Here we have screened a phage-displayed peptide library to identify peptides that selectively bind to lung tumor cells. Evaluation of individual phage clones after screening revealed that a phage clone displaying the CSNIDARAC peptide bound to H460 lung tumor cells at higher extent than other phage clones. The synthetic CSNIDARAC peptide strongly bound to H460 cells and was efficiently internalized into the cells, while little binding of a control peptide was seen. It also preferentially bound to other lung tumor cell lines as compared to cells of different tumor types. In vivo imaging of lung tumor was achieved by homing of fluorescence dye-labeled CSNIDARAC peptide to the tumor after intravenous injection into mice. Ex vivo imaging and microscopic analysis of isolated organs further demonstrated the targeting of CSNIDARAC peptide to tumor. The CSNIDARAC peptide-targeted and doxorubicin-loaded liposomes inhibited the tumor growth more efficiently than untargeted liposomes or free doxorubicin. In vivo imaging of fluorescence dye-labeled liposomes demonstrated selective homing of the CSNIDARAC-liposomes to tumor. In the same context, higher levels of doxorubicin and apoptosis in tumor tissue were observed when treated with the targeted liposomes than untargeted liposomes or free doxorubicin. These results suggest that the CSNIDARAC peptide is a promising targeting probe that is able to direct imaging agents and therapeutics to lung tumor.
    Molecular Pharmaceutics 01/2011; 8(2):430-8. · 4.57 Impact Factor
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    ABSTRACT: In vivo imaging of apoptosis could allow monitoring of tumor response to cancer treatments such as chemotherapy. Using phage display, we identified the CQRPPR peptide, named ApoPep-1(Apoptosis-targeting Peptide-1), that was able to home to apoptotic and necrotic cells in tumor tissue. ApoPep-1 also bound to apoptotic and necrotic cells in culture, while only little binding to live cells was observed. Its binding to apoptotic cells was not dependent on calcium ion and not competed by annexin V. The receptor for ApoPep-1 was identified to be histone H1 that was exposed on the surface of apoptotic cells. In necrotic cells, ApoPep-1 entered the cells and bound to histone H1 in the nucleus. The imaging signals produced during monitoring of tumor apoptosis in response to chemotherapy was enhanced by the homing of a fluorescent dye- or radioisotope-labeled ApoPep-1 to tumor treated with anti-cancer drugs, whereas its uptake of the liver and lung was minimal. These results suggest that ApoPep-1 holds great promise as a probe for in vivo imaging of apoptosis, while histone H1 is a unique molecular signature for this purpose.
    Journal of Controlled Release 12/2010; 148(3):283-91. · 7.63 Impact Factor
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    ABSTRACT: This study was conducted to determine the association between single-nucleotide polymorphisms (SNPs) in apoptosis-related genes and survival outcomes of patients with early-stage non-small-cell lung cancer (NSCLC). Three hundred ten consecutive patients with surgically resected NSCLC were enrolled. Twenty-five SNPs in 17 apoptosis-related genes were genotyped by a sequenome mass spectrometry-based genotyping assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were analyzed. Three SNPs (TNFRSF10B rs1047266, TNFRSF1A rs4149570, and PPP1R13L rs1005165) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased as the number of bad genotypes increased (P (trend) for OS and DFS = 7 × 10(-5) and 1 × 10(-4), respectively). Patients with one bad genotype, and patients with two or three bad genotypes had significantly worse OS and DFS compared with those with no bad genotypes [adjusted hazard ratio (aHR) for OS = 2.27, 95% confidence interval (CI) = 1.22-4.21, P = 0.01, aHR for DFS = 1.74, 95% CI = 1.08-2.81, P = 0.02; aHR for OS = 4.11, 95% CI = 2.03-8.29, P = 8 × 10(-5); and aHR for DFS = 2.89, 95% CI = 1.64-5.11, P = 3 × 10(-4), respectively]. Three SNPs in apoptosis-related genes were identified as possible prognostic markers of survival in patients with early-stage NSCLC. The SNPs, and particularly their combined genotypes, can be used to identify patients at high risk for poor disease outcome.
    Annals of Surgical Oncology 10/2010; 17(10):2608-18. · 4.12 Impact Factor
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    ABSTRACT: Herein, we prepared tumor-targeting peptide (AP peptide; CRKRLDRN) conjugated pH-responsive polymeric micelles (pH-PMs) in cancer therapy by active and pH-responsive tumor targeting delivery systems, simultaneously. The active tumor targeting and tumoral pH-responsive polymeric micelles were prepared by mixing AP peptide conjugated PEG-poly(d,l-lactic acid) block copolymer (AP-PEG-PLA) into the pH-responsive micelles of methyl ether poly(ethylene glycol) (MPEG)-poly(beta-amino ester) (PAE) block copolymer (MPEG-PAE). These mixed amphiphilic block copolymers were self-assembled to form stable AP peptide-conjugated and pH-responsive AP-PEG-PLA/MPEG-PAE micelles (AP-pH-PMs) with an average size of 150 nm. The AP-pH-PMs containing 10 wt % of AP-PEG-PLA showed a sharp pH-dependent micellization/demicellization transition at the tumoral acid pH. Also, they presented the pH-dependent drug release profile at the acidic pH of 6.4. The fluorescence dye, TRITC, encapsulated AP-pH-PMs (TRITC-AP-pH-PMs) presented the higher tumor-specific targeting ability in vitro cancer cell culture system and in vivo tumor-bearing mice, compared to control pH-responsive micelles of MPEG-PAE. For the cancer therapy, the anticancer drug, doxorubicin (DOX), was efficiently encapsulated into the AP-pH-PMs (DOX-AP-pH-PMs) with a higher loading efficiency. DOX-AP-pH-PMs efficiently deliver anticancer drugs in MDA-MB231 human breast tumor-bearing mice, resulted in excellent anticancer therapeutic efficacy, compared to free DOX and DOX encapsulated MEG-PAE micelles, indicating the excellent tumor targeting ability of AP-pH-PMs. Therefore, these tumor-targeting peptide-conjugated and pH-responsive polymeric micelles have great potential application in cancer therapy.
    Bioconjugate Chemistry 02/2010; 21(2):208-13. · 4.58 Impact Factor

Publication Stats

807 Citations
238.07 Total Impact Points

Institutions

  • 2003–2014
    • Kyungpook National University
      • • Department of Biochemistry and Cell Biology
      • • School of Medicine
      Daikyū, Daegu, South Korea
  • 2002–2005
    • Kyungpook National University Hospital
      • Department of Pathology
      Sŏul, Seoul, South Korea
    • Dongguk University
      • Department of Biochemistry
      Seoul, Seoul, South Korea