Publications by authors named "Su-Geun Yang"

46 Publications

Retinoic acid-conjugated chitosan/manganese porphyrin ionic-complex nanoparticles for improved T contrast MR imaging of hepatic fibrosis.

J Biomed Mater Res B Appl Biomater 2021 Jul 26. Epub 2021 Jul 26.

Department of Biomedical Science, BK21 FOUR Program in Biomedical Science and Engineering, Inha University College of Medicine, Incheon, South Korea.

Noninvasive and precise diagnosis of hepatic fibrosis is very important for the preventive therapeutic regimen of hepatic cirrhosis and cancer. In this study, we fabricated T contrast Mn-porphyrin (MnTPPS )/retinoic acid-chitosan ionic-complex nanoparticles (MRC NPs). The functional properties of MRC NPs were evaluated via transmission electron microscopy (TEM) imaging, release study, cytotoxicity assay, hepatocyte-specific uptake assay, and magnetic resonance (MR) imaging study. TEM images confirmed the typical structure of an ionic-complex NPs with around 100-200 nm of diameter. MnTPPS is released from MRC NPs for up to 24 hr in controlled pattern which implies that more reliable and convenient hepatic MR imaging is possible using of MRC NPs in clinical practice. Hepatocytes uptake assay proved retinoic acid-specific targeting of MRC NPs. The same results were observed in animal pharmacokinetic studies. In vitro MR phantom study, MRC NPs showed an increased T relaxivity (r  = 6.772 mM  s ) in comparison with 3.242 mM  s of MnTPPS . The result was confirmed again in vivo MR imaging studies. Taken together, MRC NPs displayed a potential for noninvasive diagnostic T MR imaging of hepatic fibrosis with improved target specificity and prolonged MR imaging time window.
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http://dx.doi.org/10.1002/jbm.b.34914DOI Listing
July 2021

Acetazolamide-eluting biodegradable tubular stent prevents pancreaticojejunal anastomotic leakage.

J Control Release 2021 Jul 10;335:650-659. Epub 2021 Jun 10.

Biomedical Engineering Research Center, Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea; Division of Hepatobiliary Pancreas Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea; Asan Medical Institute of Convergence Science and Technology (AMIST), Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea. Electronic address:

Postoperative pancreatic fistula at the early stage can lead to auto-digestion, which may delay the recovery of the pancreaticojejunal (PJ) anastomosis. The efficacy and safety of an acetazolamide-eluting biodegradable tubular stent (AZ-BTS) for the prevention of self-digestion and intra-abdominal inflammatory diseases caused by pancreatic juice leakage after PJ anastomosis in a porcine model were investigated. The AZ-BTS was successfully fabricated using a multiple dip-coating process. Then, the drug amount and release profile were analyzed. The therapeutic effects of AZ were examined in vitro using two kinds of pancreatic cancer cell lines, AsPC-1 and PANC-1. The efficacy of AZ-BTS was assessed in a porcine PJ leakage model, with animals were each assigned to a leakage group, a BTS group and an AZ-BTS group. The overall mortality rates in these three groups were 44.4%, 16.6%, and 0%, respectively. Mean α-amylase concentrations were significantly higher in the leakage and BTS groups than in the AZ-BTS group on day 2-5 (p < 0.05 each all). The luminal diameters and areas of the pancreatic duct were significantly larger in the leakage group than in the BTS and AZ-BTS groups (p < 0.05 each all). These findings indicate that AZ-BTS can significantly suppress intra-abdominal inflammatory diseases caused by pancreatic juice leakage and also prevent late stricture formation at the PJ anastomotic site in a porcine model.
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http://dx.doi.org/10.1016/j.jconrel.2021.06.010DOI Listing
July 2021

Improved effect of a mitochondria-targeted antioxidant on hydrogen peroxide-induced oxidative stress in human retinal pigment epithelium cells.

BMC Pharmacol Toxicol 2021 01 20;22(1). Epub 2021 Jan 20.

Inha Research Institute for Aerospace Medicine, Inha University, Incheon, 22212, South Korea.

Background: Oxidative damage to retinal pigment epithelial (RPE) cells contributes to the development of age-related macular degeneration, which is among the leading causes of visual loss in elderly people. In the present study, we evaluated the protective role of triphenylphosphonium (TPP)-Niacin against hydrogen peroxide (HO)-induced oxidative stress in RPE cells.

Methods: The cellular viability, lactate dehydrogenase release, reactive oxygen species (ROS) generation, and mitochondrial function of retinal ARPE-19 cells were determined under treatment with HO or pre-treatment with TPP-Niacin. The expression level of mitochondrial related genes and some transcription factors were assessed using real-time polymerase chain reaction (RT-qPCR).

Results: TPP-Niacin significantly improved cell viability, reduced ROS generation, and increased the antioxidant enzymes in HO-treated ARPE-19 cells. Mitochondrial dysfunction from the HO-induced oxidative stress was also considerably diminished by TPP-Niacin treatment, along with reduction of the mitochondrial membrane potential (MMP) and upregulation of the mitochondrial-associated gene. In addition, TPP-Niacin markedly enhanced the expression of transcription factors (PGC-1α and NRF2) and antioxidant-associated genes (especially HO-1 and NQO-1).

Conclusion: We verified the protective effect of TPP-Niacin against HO-induced oxidative stress in RPE cells. TPP-Niacin is believed to protect against mitochondrial dysfunction by upregulating antioxidant-related genes, such as PGC-1α, NRF2, HO-1, and NQO-1, in RPE cells.
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http://dx.doi.org/10.1186/s40360-020-00471-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819191PMC
January 2021

T-Positive Mn-Doped Multi-Stimuli Responsive poly(L-DOPA) Nanoparticles for Photothermal and Photodynamic Combination Cancer Therapy.

Biomedicines 2020 Oct 14;8(10). Epub 2020 Oct 14.

Department of Biomedical Science, Inha University College of Medicine, 366 Seohae-Daero, Jung-gu, Incheon 22332, Korea.

In this study, we designed near-infrared (NIR)-responsive Mn-doped melanin-like poly(L-DOPA) nanoparticles (MNPs), which act as multifunctional nano-platforms for cancer therapy. MNPs, exhibited favorable π-π stacking, drug loading, dual stimuli (NIR and glutathione) responsive drug release, photothermal and photodynamic therapeutic activities, and T-positive contrast for magnetic resonance imaging (MRI). First, MNPs were fabricated via KMnO oxidation, where the embedded Mn acted as a T-weighted contrast agent. MNPs were then modified using a photosensitizer, Pheophorbide A, via a reducible disulfide linker for glutathione-responsive intracellular release, and then loaded with doxorubicin through π-π stacking and hydrogen bonding. The therapeutic potential of MNPs was further explored via targeted design. MNPs were conjugated with folic acid (FA) and loaded with SN38, thereby demonstrating their ability to bind to different anti-cancer drugs and their potential as a versatile platform, integrating targeted cancer therapy and MRI-guided photothermal and chemotherapeutic therapy. The multimodal therapeutic functions of MNPs were investigated in terms of T-MR contrast phantom study, photothermal and photodynamic activity, stimuli-responsive drug release, enhanced cellular uptake, and in vivo tumor ablation studies.
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http://dx.doi.org/10.3390/biomedicines8100417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656312PMC
October 2020

Effect of expanding nanocellulose sponge on nasal mucosal defects in an animal model.

Regen Biomater 2020 Feb 3;7(1):47-52. Epub 2020 Mar 3.

Department of Otorhinolaryngology, Inha University, College of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Republic of Korea.

Nanocellulose has emerged for a wide range of applications in biomedical engineering because of its water absorption capacity, appropriate elasticity. We investigated the hemostatic and regenerative abilities of an expanding polyvinyl alcohol (PVA)-nanocellulose sponge on nasal mucosal defects. A 3 mm-diameter nasal defect was made in experimental rabbits. Rabbits were divided into four groups with control, vaseline, PVA and PVA-nanocellulose packing groups. After the defect was created, bleeding times and amounts were monitored. Packing materials were removed on experimental day (ED) 2. On ED 3, 7 and 14, histological analysis and immunohistochemical study for neutrophils were performed. Inflammatory cells were counted and epithelial thicknesses were evaluated. Bleeding amounts and times in the vaseline packing group were smaller than in the PVA groups. PVA-nanocellulose group showed less neutrophils than in the other groups on ED 7. Average epithelium thickness in the PVA-nanocellulose group was significantly smaller than in the control group at ED 7, but at ED 14, there was no significant intergroup difference. PVA-nanocellulose group had a significant lower inflammatory cell count than the control group on ED 7. PVA-nanocellulose sponge applied to nasal mucosal defects can significantly enhance mucosal regeneration during early wound healing.
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http://dx.doi.org/10.1093/rb/rbz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053266PMC
February 2020

Effects of Helix Geometry on Magnetic Guiding of Helical Polymer Composites on a Gastric Cancer Model: A Feasibility Study.

Materials (Basel) 2020 Feb 24;13(4). Epub 2020 Feb 24.

Division of Gastroenterology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon 22332, Korea.

This study investigates the effects of soft-robot geometry on magnetic guiding to develop an efficient helical mediator on a three-dimensional (3D) gastric cancer model. Four different magnetically active helical soft robots are synthesized by the inclusion of 5-μm iron particles in polydimethylsiloxane matrices. The soft robots are named based on the diameter and length (D2-L15, D5-L20, D5-L25, and D5-L35) with samples having varied helical pitch and weight values. Then, the four samples are tested on a flat surface as well as a stomach model with various 3D wrinkles. We analyze the underlying physics of intermittent magnetomotility for the helix on a flat surface. In addition, we extract representative failure cases of magnetomotility on the stomach model. The D5-L25 sample was the most suitable among the four samples for a helical soft robot that can be moved to a target lesion by the magnetic-flux density of the stomach model. The effects of diameter, length, pitch, and weight of a helical soft robot on magnetomotility are discussed in order for the robot to reach the target lesion successfully via magnetomotility.
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http://dx.doi.org/10.3390/ma13041014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078772PMC
February 2020

Doxycycline-Eluting Core-Shell Type Nanofiber-Covered Trachea Stent for Inhibition of Cellular Metalloproteinase and Its Related Fibrotic Stenosis.

Pharmaceutics 2019 Aug 19;11(8). Epub 2019 Aug 19.

Department of Biomedical Science, Inha University College of Medicine, Incheon 22332, Korea.

In this study, we fabricated a doxycycline (doxy)-eluting nanofiber-covered endotracheal stent for the prevention of stent intubation-related tissue fibrosis and re-stenosis. The nanofiber was deposited directly on the outer surface of the stent using a coaxial electrospinning method to form a doxy-eluting cover sleeve. Poly(d,l-lactide) was used as the shell-forming polymer and dedicated drug release-control membrane. Polyurethane was selected as the drug-loading core polymer. The compositional ratio of the core to shell was adjusted to 1:0, 1:2, and 1:4 by changing the electro-spray rate of each polymeric solution and microscopic observation of nanofibers using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and the fluorescence microscopy proved core-shell structure of nanofibers. The in vitro release study suggested that the release of doxy could be controlled by increasing the compositional ratio of the shell. The growth of HT1080 fibrosarcoma cells was inhibited by the 10% doxy-containing nanofiber. The real-time polymerase chain reaction (PCR) in HT1080 cells and xenografted tissue models indicated that the doxy-releasing nanofiber inhibited mRNA expression of metalloproteinases (MT1-MMP, MMP-2, and MMP-9). Overall, our study demonstrates that a doxy-eluting core-shell nanofiber stent can be successfully fabricated using coaxial electrospinning and displays the potential to prevent fibrotic re-stenosis, which is the most problematic clinical complication of tracheal stent intubation.
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http://dx.doi.org/10.3390/pharmaceutics11080421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723391PMC
August 2019

NIR-responsive ROS generating core and ROS-triggered 5'-Deoxy-5-fluorocytidine releasing shell structured water-swelling microgel for locoregional combination cancer therapy.

J Control Release 2019 07 13;305:120-129. Epub 2019 May 13.

Department of New Drug Development, Inha University College of Medicine, B-308, Chungsuk Bldg., 366, Seohae-Daero, Jung-Gu, Incheon 22332, Republic of Korea.. Electronic address:

Combination chemotherapy now becomes the most standard cancer treatment protocol. Here, we present a core-shell type polymeric microgel (CSPM) which combines photodynamic and chemo therapeutic modalities in one-pot system. CSPM localizes in the malignant lesion after intratumoral injection, releases reactive oxygen species (ROS) and anticancer drug (5'-deoxy-5-fluorocytidine; DFCR) under the near-infrared (NIR) laser treatment. Pheophorbide A (PheoA)-linked poly(hydroxyethyl methacrylate) (poly-HEMA) was designated to a ROS-generating core, and chemically covered with a chitosan shell. In addition, phenylboronic acid was employed in chitosan shells and linked to DFCR to form an ROS cleavable boronic ester. The core-shell structure of CSPM was determined by transmission electron microscopy. NIR-responsive photodynamic ROS generation was confirmed by the oxidative reduction of 9,10-dimethylanthracene (a fluorescent dye), and the cascadic release of DFCR by ROS was confirmed by a release study and a live and dead cell imaging study. Typically, poly-HEMA cored microgel increased its volume by 48.9-fold after absorption of body fluid. This swelling property ensured CSPM was retained in tumor tissues after subtumoral injection and the suitability of CSPM for locoregional phototherapy. The therapeutic effect of CSPM was attributed to the combined, cascadic deliveries of cytotoxic ROS and DFCR and confirmed by growth inhibition studies in in vitro pancreatic cancer cells and in vivo colon cancer mouse model.
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http://dx.doi.org/10.1016/j.jconrel.2019.05.016DOI Listing
July 2019

Multifunctional spiky branched gold-silver nanostars with near-infrared and short-wavelength infrared localized surface plasmon resonances.

J Colloid Interface Sci 2019 Apr 7;542:308-316. Epub 2019 Feb 7.

Department of Energy and Materials Engineering, Dongguk University, Seoul, Republic of Korea. Electronic address:

We report a one-pot seedless green method for the synthesis of gold-silver (AuAg) spiky branched nanostars, with gold (90%) being the major component. Here, the zwitterionic surfactant lauryl sulfobetaine (LSB) is employed in the synthesis of bimetallic nanostars. The concentration of LSB plays an important role in determining the shape of nano-objects. A minimum LSB concentration of 50 mM is required for the formation of spiky branched nanostars, the size of which is controlled by increasing the LSB concentration. Two distinct intense localized surface plasmon resonances in the near-infrared (NIR) and short-wavelength infrared ranges are observed. The molecular structure of LSB causes LSB molecules to assemble into spherical micelles that act as a soft template for the growth of the nano-objects. An analysis of the mechanisms behind the formation of the nanostars suggests that there is a rapid growth of spikes followed by the formation of a spherical core at the center. AuAg nanostars with evenly spaced spikes and low branching demonstrate great potential as efficient nanocatalysts, surface-enhanced Raman scattering-active substrates and for photothermal therapy, active in both the visible and NIR regions.
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http://dx.doi.org/10.1016/j.jcis.2019.01.132DOI Listing
April 2019

Clinical development of photodynamic agents and therapeutic applications.

Biomater Res 2018 26;22:25. Epub 2018 Sep 26.

World Class Smart Lab, Department of New Drug Development, Inha University College of Medicine, 366, Seohae-daero, Jung-gu, Incheon, 22332 Republic of Korea.

Background: Photodynamic therapy (PDT) is photo-treatment of malignant or benign diseases using photosensitizing agents, light, and oxygen which generates cytotoxic reactive oxygens and induces tumour regressions. Several photodynamic treatments have been extensively studied and the photosensitizers (PS) are key to their biological efficacy, while laser and oxygen allow to appropriate and flexible delivery for treatment of diseases.

Introduction: In presence of oxygen and the specific light triggering, PS is activated from its ground state into an excited singlet state, generates reactive oxygen species (ROS) and induces apoptosis of cancer tissues. Those PS can be divided by its specific efficiency of ROS generation, absorption wavelength and chemical structure.

Main Body: Up to dates, several PS were approved for clinical applications or under clinical trials. Photofrin® is the first clinically approved photosensitizer for the treatment of cancer. The second generation of PS, Porfimer sodium (Photofrin®), Temoporfin (Foscan®), Motexafin lutetium, Palladium bacteriopheophorbide, Purlytin®, Verteporfin (Visudyne®), Talaporfin (Laserphyrin®) are clinically approved or under-clinical trials. Now, third generation of PS, which can dramatically improve cancer-targeting efficiency by chemical modification, nano-delivery system or antibody conjugation, are extensively studied for clinical development.

Conclusion: Here, we discuss up-to-date information on FDA-approved photodynamic agents, the clinical benefits of these agents. However, PDT is still dearth for the treatment of diseases in specifically deep tissue cancer. Next generation PS will be addressed in the future for PDT. We also provide clinical unmet need for the design of new photosensitizers.
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http://dx.doi.org/10.1186/s40824-018-0140-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158913PMC
September 2018

In Vivo Fluorescence Microendoscopic Monitoring of Stent-Induced Fibroblast Cell Proliferation in an Esophageal Mouse Model.

J Vasc Interv Radiol 2018 12 26;29(12):1756-1763. Epub 2018 Sep 26.

Department of Biomedical Engineering Research Center, and Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88, Olymic-ro 43-gil, Songpa-gu, Seoul, Republic of Korea. Electronic address:

Purpose: To evaluate the feasibility of self-expanding metal stent (SEMS) placement and fluorescence microendoscopic monitoring for determination of fibroblast cell proliferation after stent placement in an esophageal mouse model.

Materials And Methods: Twenty fibroblast-specific protein (FSP)-1 green fluorescent protein (GFP) transgenic mice were analyzed. Ten mice (Group A) underwent SEMS placement, and fluoroscopic and fluorescence microendoscopic images were obtained biweekly until 8 weeks thereafter. Ten healthy mice (Group B) were used for control esophageal values.

Results: SEMS placement was technically successful in all mice. The relative average number of fibroblast GFP cells and the intensities of GFP signals in Group A were significantly higher than in Group B after stent placement. The proliferative cellular response, including granulation tissue, epithelial layer, submucosal fibrosis, and connective tissue, was increased in Group A. FSP-1-positive cells were more prominent in Group A than in Group B.

Conclusions: SEMS placement was feasible and safe in an esophageal mouse model, and proliferative cellular response caused by fibroblast cell proliferation after stent placement was longitudinally monitored using a noninvasive fluorescence microendoscopic technique. The results have implications for the understanding of proliferative cellular response after stent placement in real-life patients and provide initial insights into new clinical therapeutic strategies for restenosis.
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http://dx.doi.org/10.1016/j.jvir.2018.06.024DOI Listing
December 2018

Ramalin, an antioxidant compound derived from Antarctic lichen, prevents progression of liver fibrosis induced by dimethylnitrosamine (DNM) in rats.

Biochem Biophys Res Commun 2018 09 30;504(1):25-33. Epub 2018 Aug 30.

World Class Smart Lab, Department of New Drug Development, College of Medicine, Inha University, Incheon, 22332, Republic of Korea. Electronic address:

Hepatic fibrosis is characterized by the excessive accumulation of extracellular matrix (ECM), primarily collagen, within the liver. Because reactive oxygen species (ROS) has been implicated in its pathogenesis, the use of antioxidants as a potential treatment has been broadly explored. Here, we investigated the hepatoprotective properties of ramalin (RM), a compound extracted from the Antarctic lichen Ramalina terebrata, against hepatic fibrosis in vitro and in vivo. RM suppressed hepatic stellate cell (HSC) activation in vitro without any significant signs of adverse effects on the cells tested, and the accumulation of ECM was dramatically reduced in the liver tissue. Oral administration of RM in rats noticeably improved the gross appearance of the liver with increased body and liver weight relative to the DMN injected rats, and all of the serum biochemical markers returned to the normal range. RM treatment have ameliorated hepatic fibrosis in rats induced by DMN by repressing α-smooth muscle actin (α-SMA) and upregulating heme oxygenase-1 (HO-1). In addition, RM significantly reduced collagen accumulation, and levels of malondialdehyde (MDA) and hydroxyproline (HP) in the liver tissue of DMN injected rats. The efficacy exerted by RM was through erythroid 2-related factor 2 (Nrf2) mediated antioxidant response proteins such as HO-1 and NAD(P)H quinone dehydrogenase 1 (NQO-1). Our results show the beneficial effect of RM against the progression of hepatic fibrosis.
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http://dx.doi.org/10.1016/j.bbrc.2018.08.103DOI Listing
September 2018

Tumor-suppressing miR-141 gene complex-loaded tissue-adhesive glue for the locoregional treatment of hepatocellular carcinoma.

Theranostics 2018 24;8(14):3891-3901. Epub 2018 Jun 24.

World Class Smart Lab, Department of New Drug Development, Inha University College of Medicine, Incheon, Republic of Korea.

microRNAs (miRNAs) regulate gene expression post-transcriptionally and have been extensively tested as therapeutic molecules against several human diseases. delivery of miRNAs needs to satisfy the following conditions: safety, efficiency, and long-term therapeutic effectiveness. To satisfy these conditions, we developed a tissue-adhesive nucleotide-polymer complex (NPX-glue) for vo delivery of miRNAs to treat hepatocellular carcinoma (HCC). : Polyallylamine (PAA), a cationic polymer, was mixed with tumor-suppressing miR-141 to form NPX and then mixed with partially oxidized alginate (OA) to form NPX-glue. Delivery efficiency of miR-141:NPX-glue was determined in cultured HCC cells and in an implanted HCC tumor model. tumor-suppressive effects of miR-141 on HCC were examined in mice upon intratumoral injection of miR-141:NPX-glue. NPX-glue was generated by mixing of NPX with OA, which eliminated the inherent cytotoxic effect of NPX. NPX-glue led to the efficient delivery of miR-141 and plasmid to cultured cells and solid tumors in mice, where their expression was maintained for up to 30 days. Upon intratumoral injection of miR-141:NPX-glue, the growth of the tumors was dramatically retarded in comparison with the negative control, NCmiR:NPX-glue, ( < 0.05). Molecular examination proved miR-141:NPX-glue efficiently regulated the target genes including , , , , and and finally induced apoptosis of cancer tissues. Here, we show that NPX-glue delivers therapeutic miR-141 to solid tumors in a safe, stable, and long-term manner and prove that locoregional treatment of HCC is possible using the NPX-glue system.
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http://dx.doi.org/10.7150/thno.24056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071529PMC
August 2019

EW-7197 eluting nano-fiber covered self-expandable metallic stent to prevent granulation tissue formation in a canine urethral model.

PLoS One 2018 15;13(2):e0192430. Epub 2018 Feb 15.

Department of Radiology, Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Purpose: To evaluate an EW-7197-eluting nanofiber-covered stent (NFCS) for suppressing granulation tissue formation after stent placement in a canine urethral model.

Materials And Methods: All experiments were approved by the committee of animal research. A total of 12 NFCSs were placed in the proximal and distal urethras of six dogs. Dogs were divided into two groups with 3 dogs each. The control stent (CS) group received NFCSs and the drug stent (DS) group received EW-7197 (1000 μg)-eluting NFCSs. All dogs were sacrificed 8 weeks after stent placement Histologic findings of the stented urethra were compared using the Mann-Whitney U test.

Results: Stent placement was technically successful in all dogs without procedure-related complications. On urethrographic analysis, the mean luminal diameter was significantly larger in the DS group than in the CS group at 4 and 8 weeks after stent placement (all p < 0.001). On histological examination, mean thicknesses of the papillary projection, thickness of submucosal fibrosis, number of epithelial layers, and degree of collagen deposition were significantly lower in the DS group than in the CS group (all p < 0.001), whereas the mean degree of inflammatory cell infiltration was not significantly different (p > 0.05).

Conclusion: The EW-7197-eluting NFCS is effective and safe for suppressing granulation tissue formation after stent placement in a canine urethral model.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192430PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813937PMC
April 2018

Prevention of tracheal inflammation and fibrosis using nitinol stent coated with doxycycline.

Laryngoscope 2018 07 20;128(7):1558-1563. Epub 2017 Dec 20.

Department of New Drug Development, Inha University College of Medicine, Jung-gu, Incheon, Republic of Korea.

Objectives: This study was conducted to determine whether a nitinol stent coated with doxycycline prevents tracheal inflammation and fibrosis in a rabbit.

Methods: A nitinol stent coated with doxycycline was designed by us. Twelve rabbits were divided into three groups: normal, control (nondoxycycline-coated stent), and doxycycline-coated stent group. The stents were inserted into the tracheal lumen through the oral cavity. Tracheal granulation was evaluated and graded by laryngoscopy. Histological examinations evaluated the inflammatory response and fibrosis. Real-time polymerase chain reaction (PCR) and Western blot assessed the changes to the extracellular matrix (ECM).

Results: Endoscopic findings showed that the nitinol stent coated with doxycycline resulted in lesser granulation tissue in the trachea than the noncoated stent. Histologic examination further revealed that the doxycycline-coated stent was associated with decreased inflammatory cells and reduced fibrosis, compared to the noncoated stent. In PCR and Western blot, the doxycycline-coated stent showed lower expression of ECM components inducing fibrosis.

Conclusion: A nitinol stent coated with doxycycline showed favorable effects in reducing tracheal inflammation and fibrosis in a rabbit model. Further research is required to study the beneficial effects of local application of doxycycline for prevention of tracheal stenosis.

Level Of Evidence: NA. Laryngoscope, 128:1558-1563, 2018.
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http://dx.doi.org/10.1002/lary.27028DOI Listing
July 2018

Fabrication of Eudragit polymeric nanoparticles using ultrasonic nebulization method for enhanced oral absorption of megestrol acetate.

Pharm Dev Technol 2018 Apr 20;23(4):407-413. Epub 2017 Nov 20.

a World Class Smart Lab, Department of New Drug Development, College of Medicine , Inha University , Incheon , Republic of Korea.

Megestrol acetate (MGA) is used as a progestagen to treat advanced cancers in the breast or uterus and anorexia-cachexia syndrome in cancer patients. Due to its low solubility (BCS class II), MGA bioavailability needs to be enhanced for efficacy and safety. We developed MGA-encapsulated Eudragit L100 (EUD) nanoparticles (MGA-EUD (1:1) and MGA-EUD (2:1)) using an ultrasonic nebulization method. MGA-EUD (1:1) and MGA-EUD (2:1) consisted of MGA and EUD at the mass ratios of 1:1 and 2:1. Their physicochemical properties, i.e. particle size, loading efficiency, morphology, and crystallinity were determined. Dissolution tests were performed using USP method II. For pharmacokinetics, they were orally administered at 50 mg/kg to mice. Microcrystalline MGA suspension (MGA-MC, Megace, BMS) was used as control. MGA-EUD (1:1) and MGA-EUD (2:1) had a smooth and spherical shape of 0.70 and 1.05 µm in diameter with loading efficiencies of 93 and 95% showing amorphous states of MGA. They significantly enhanced the dissolution potential of MGA. Oral bioavailability of MGA-EUD (1:1) and MGA-EUD (2:1) increased 2.0- and 1.7-fold compared to that of MGA-MC. It suggests that ultrasonic nebulization method for the fabrication of polymeric nanoparticles is a promising approach to improve the bioavailability of poorly soluble drugs.
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http://dx.doi.org/10.1080/10837450.2017.1400049DOI Listing
April 2018

Calcium-Triggered Pulsatile Delivery of Parathyroid Hormone from Microbeads for Osteoporosis Treatment.

Biomacromolecules 2017 Oct 13;18(10):3099-3105. Epub 2017 Sep 13.

WCSL, Department of New Drug Development, Inha University College of Medicine , B-308, Chungsuk Bldg, 366, Seohae-Daero, Jung-Gu, Incheon 22332, Republic of Korea.

Recombinant human parathyroid hormone 1-34 (rhPTH 1-34) is the most potent anabolic drug recommended for patients with osteoporosis who do not respond to conventional treatment. However, subcutaneous intermittent injection is the only effective regimen due to its unusual action of mechanism. This regimen is inconvenient and is a big hurdle in clinical applications. In this study, we designed polyelectrolyte microbeads that can deliver rhPTH 1-34 in response to Ca concentration, which indicates the osteoporotic status. Dextran photopolymer was synthesized, mixed with anionic monoacrylate, and photopolymerized by passing through capillary microfluidics to obtain the microbeads. The anionic property of microbeads was confirmed by toluidine blue staining. One microbead, loaded with a 1 day dose of rhPTH 1-34 (23.4 ± 0.9 μg), released rhPTH 1-34 in a triggered manner following the addition of Ca ion. In vitro cell study demonstrated that rhPTH 1-34 released in a pulsatile manner from the microbeads induced osteogenic markers (ALP, RUNX2, and OPN) and precipitated mineral disposition more effectively.
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http://dx.doi.org/10.1021/acs.biomac.7b00750DOI Listing
October 2017

EW-7197, an activin-like kinase 5 inhibitor, suppresses granulation tissue after stent placement in rat esophagus.

Gastrointest Endosc 2017 Jul 27;86(1):219-228. Epub 2017 Jan 27.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background And Aims: Self-expanding metallic stent (SEMS) placement is a well-established method for treating malignant esophageal strictures; however, this procedure has not gained widespread acceptance for treating benign esophageal strictures because of granulation tissue formation. The aim of the present study was to investigate whether EW-7197, a novel per-oral transforming growth factor-β type I receptor kinase inhibitor, suppressed granulation tissue formation after SEMS placement in the rat esophagus.

Methods: Sixty rats underwent SEMS placement and were randomly divided into 4 groups. Group A (n = 20) received vehicle-treated control for 4 weeks. Group B (n = 20) received 20 mg/kg/day EW-7197 for 4 weeks. Group C (n = 10) received 20 mg/kg/day EW-7197 for 4 weeks followed by vehicle-treated control for 4 weeks. Group D (n = 10) received 20 mg/kg/day EW-7197 for 8 weeks.

Results: SEMS placement was technically successful in all rats. Eleven rats, however, were excluded because of stent migration (n = 9) and procedure-related death (n = 2). The luminal diameter in group A was significantly smaller than those in groups B, C, and D (all P < .001). The percentage of granulation tissue area, number of epithelial layers, thickness of submucosal fibrosis, percentage of connective tissue area, and degree of collagen deposition were significantly higher in group A than in groups B, C, and D (all P < .001); however, there were no significant differences among groups B, C, and D. EW-7197 decreased the expression levels of phospho-Smad 3, N-cadherin, fibronectin, α-smooth muscle actin, and transforming growth factor-β1 and increased the expression level of E-cadherin (all P < .01).

Conclusions: EW-7197 suppressed granulation tissue formation after SEMS placement in the rat esophagus.
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http://dx.doi.org/10.1016/j.gie.2017.01.013DOI Listing
July 2017

MT1-MMP Responsive Doxorubicin Conjugated Poly(lactic-co-glycolic Acid)/Poly(styrene-alt-maleic Anhydride) Core/Shell Microparticles for Intrahepatic Arterial Chemotherapy of Hepatic Cancer.

ACS Appl Mater Interfaces 2017 01 22;9(1):71-79. Epub 2016 Dec 22.

Department of New Drug Development, School of Medicine, Inha University , B-308, Chungsuk Bldg, 366, Seohae-Daero, Jung-Gu, Incheon 22332, Republic of Korea.

In this study, we demonstrated that the MT1-MMP-responsive peptide (sequence: GPLPLRSWGLK) and doxorubicin-conjugated poly(lactic-co-glycolic acid/poly(styrene-alt-maleic anhydride) core/shell microparticles (PLGA/pSMA MPs) can be applied for intrahepatic arterial injection for hepatocellular carcinoma (HCC). PLGA/pSMA MPs were prepared with a capillary-focused microfluidic device. The particle size, observed by scanning electron microscopy (SEM), was around 22 ± 3 μm. MT1-MMP-responsive peptide and doxorubicin (DOX) were chemically conjugated with pSMA segments on the shell of MPs to form a PLGA/pSMA-peptide-DOX complex, resulting in high encapsulation efficiency (91.1%) and loading content (2.9%). DOX was released from PLGA/pSMA-peptide-DOX MPs in a pH-dependent manner (∼25% at pH 5.4 and ∼8% at pH 7.4) and accumulated significantly in an MT1-MMP-overexpressing Hep3B cell line. An in vivo intrahepatic injection study showed localization of MPs on the hepatic vessels and hepatic lobes up to 24 h after the injection without any shunting to the lung. Moreover, MPs efficiently inhibited tumor growth of Hep3B hepatic tumor xenografted mouse models. We expect that PLGA/pSMA-peptide-DOX MPs can be utilized as an effective intrahepatic drug delivery system for the treatment of HCC.
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http://dx.doi.org/10.1021/acsami.6b08994DOI Listing
January 2017

Lipase-Sensitive Transfersomes Based on Photosensitizer/Polymerizable Lipid Conjugate for Selective Antimicrobial Photodynamic Therapy of Acne.

Adv Healthc Mater 2016 12 10;5(24):3139-3147. Epub 2016 Nov 10.

Center for Photomedicine, Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do, 420-743, South Korea.

Acne vulgaris is a common skin problem affecting nearly 90% of adolescents and its development is associated with a colonization of Propionibacterium acnes (P. acnes). Although antibiotics have commonly been used to treat acne, antibiotic resistance of P. acnes is an emerging issue to be solved. In this study, a new way of photodynamic acne therapy is developed using P. acnes lipase-sensitive transfersome (DSPE-PEG-Pheo A (DPP) transfersome). For enhanced selectivity and skin penetration efficiency, DPP transfersomes are prepared from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000], pheophorbide A (Pheo A), cholesterol, and Tween-80. Incorporation of Tween-80 as an edge activator increases the deformability of DPP transfersomes, enhancing skin penetration efficiency to four times that of free Pheo A. The photoactivity of Pheo A quenched by DPP transfersomes is gradually recovered by selective cleavage of the ester linkage in DPP transfersomes by P. acnes lipases. In vitro P. acnes-specific photoactivity and subsequent selective antimicrobial effect exhibit a greater than 99% loss of P. acnes viability. In vivo antiacne therapeutic effect is confirmed by reduction of swelling volume and thickness of P. acnes-induced nude mice skin. These results demonstrate that DPP transfersome-mediated photodynamic therapy can be used as an alternative method to treat bacterial skin infections.
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http://dx.doi.org/10.1002/adhm.201600815DOI Listing
December 2016

Bone morphogenetic protein-9 is a potent growth inhibitor of hepatocellular carcinoma and reduces the liver cancer stem cells population.

Oncotarget 2016 Nov;7(45):73754-73768

Protein Engineering Laboratory, Joint Center for Biosciences, Songdo Smart Valley, Yeonsu-gu, Incheon 406-840, South Korea.

The biological role of BMP-9 signaling in liver cancer remains dubious. To explore the potential use of BMP-9 signaling for anti-cancer therapy, we used recombinant human BMP-9, which we referred to as MB109, to study the effect on growth of fifteen hepatocellular carcinoma (HCC) cell lines. MB109 effectively inhibits the proliferation of nine HCC cells in vitro. The anti-proliferative effect was found to be induced by turning on p21 signaling, which caused survivin suppression and G0/G1 cell cycle arrest. ID3 was identified to be the mediator of the MB109-induced p21 expression. Blocking the activity of p38 MAPK diminished ID3 and p21 expression, indicating that MB109 signals through a p38 MAPK/ID3/p21 pathway to arrest cell cycle progression. Moreover, prolonged MB109 treatment suppressed the expression of five prominent liver cancer stem cell (LCSC) markers, including CD44, CD90, AFP, GPC3 and ANPEP. Xenograft model confirmed the anti-tumor and LCSC-suppression capability of MB109 in vivo. Contrary to ongoing efforts of suppressing BMP-9 signaling to inhibit angiogenesis of cancer tissue, these results demonstrate an unexpected therapeutic potential of MB109 to stimulate BMP-9 signaling for anti-cancer therapies.
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http://dx.doi.org/10.18632/oncotarget.12062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342011PMC
November 2016

Capillary microfluidics-derived doxorubicin-containing human serum albumin microbeads for transarterial chemoembolization of hepatic cancer.

Mater Sci Eng C Mater Biol Appl 2016 May 29;62:391-7. Epub 2016 Jan 29.

Department of New Drug Development, School of Medicine, Inha University, Incheon 400-712, Republic of Korea. Electronic address:

In this study, we prepared doxorubicin (DOXO)-loaded albumin microbeads (DOXO-MBs) using a capillary microfluidic device for transarterial chemoembolization of hepatic cancer. Albumin droplets were fabricated using the capillary microfluidic device and solidified by addition of glutaraldehyde. The acquired DOXO-MBs were homogeneous and the size was adjustable from 183.2 ± 12.2 μm to 351.5 ± 7.9 μm by changing the flow rate of fluidic solutions. The loading amount of DOXO was 9.7 ± 1.5 mg/g, and over 15.7% of DOXO was released over one month in pH7.2 buffer. Intra-portal injection of DOXO-MBs on normal liver of rats proved microbeads efficiently embolized hepatic vessels. Hepatic lobes, recovered 24 days after intra-portal injection, showed that the DOXO-MBs remained in hepatic vessels and released DOXO to surrounding hepatic tissues. In the hepatic tumor xenograft mouse model, DOXO-MBs inhibited tumor growth more efficiently than intravenous (I.V.) injection of free DOXO (p<0.01).
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http://dx.doi.org/10.1016/j.msec.2016.01.073DOI Listing
May 2016

Enhanced conjugation stability and blood circulation time of macromolecular gadolinium-DTPA contrast agent.

Mater Sci Eng C Mater Biol Appl 2016 Apr 7;61:659-64. Epub 2016 Jan 7.

Department of New Drug Development, School of Medicine, Inha University, 2F A-dong, Jeongseok Bldg., Sinheung-dong 3-ga, Jung-gu, Incheon 400-712, Republic of Korea. Electronic address:

In this study, we prepared macromolecular MR T1 contrast agent: pullulan-conjugated Gd diethylene triamine pentaacetate (Gd-DTPA-Pullulan) and estimated residual free Gd(3+), chelation stability in competition with metal ions, plasma and tissue pharmacokinetics, and abdominal MR contrast on rats. Residual free Gd(3+) in Gd-DTPA-Pullulan was measured using colorimetric spectroscopy. The transmetalation of Gd(3+) incubated with Ca(2+) was performed by using a dialysis membrane (MWCO 100-500 Da) and investigated by ICP-OES. The plasma concentration profiles of Gd-DTPA-Pullulan were estimated after intravenous injection at a dose 0.1 mmol/kg of Gd. The coronal-plane abdominal images of normal rats were observed by MR imaging. The content of free Gd(3+), the toxic residual form, was less than 0.01%. Chelation stability of Gd-DTPA-Pullulan was estimated, and only 0.2% and 0.00045% of Gd(3+) were released from Gd-DTPA-Pullulan after 2h incubation with Ca(2+) and Fe(2+), respectively. Gd-DTPA-Pullulan displayed the extended plasma half-life (t1/2,α=0.43 h, t1/2,β=2.32 h), much longer than 0.11h and 0.79 h of Gd-EOB-DTPA. Abdominal MR imaging showed Gd-DTPA-Pullulan maintained initial MR contrast for 30 min. The extended plasma half-life of Gd-DTPA-Pullulan probably allows the prolonged MR acquisition time in clinic with enhanced MR contrast.
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http://dx.doi.org/10.1016/j.msec.2016.01.008DOI Listing
April 2016

Nanomemulsion of megestrol acetate for improved oral bioavailability and reduced food effect.

Arch Pharm Res 2015 Oct 18;38(10):1850-6. Epub 2015 Apr 18.

Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, 400-712, South Korea.

Megestrol acetate (MGA) belongs to the BCS class II drugs with low solubility and high permeability, and its oral absorption in conventional dosage form MGA microcrystal suspension (MGA MS) is very limited and greatly affected by food. In this study, MGA nanoemulsion (MGA NE) was formulated based on solubility, phase-diagram and release studies. Then oral bioavailability of MGA NE and MGA MS was evaluated. A randomized two-way crossover trial was conducted on six male dogs under fed and fasting conditions. Blood concentrations of MGA were analyzed using LC-MS/MS. MGA NE yielded 5.00-fold higher oral bioavailability in fasting conditions and displayed more stable absorption profiles after food intake compared with MGA MS.
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http://dx.doi.org/10.1007/s12272-015-0604-9DOI Listing
October 2015

Hemostatic action of EGF-endospray on mucosectomy-induced ulcer bleeding animal models.

Biomed Mater Eng 2015 ;25(1):101-9

Department of New Drug Development and NCEED, School of Medicine, Inha University, Incheon, South Korea.

Gastric bleeding is one of the irritant problems in ulcer patients. In this study, we evaluated hemostatic action of ulcer-coating powder (EGF-endospray) on gastric ulcer animal models. EGF-endospray, containing epidermal growth factor, is designed to be applied through an endoscope. Hemostatic action of the EGF-endospray was evaluated on gastric hemorrhage models of rabbits and micro-pigs. The EGF-endospray was directly applied onto a mucosal resection (MR)-induced gastric bleeding focus in a rabbit model. In a porcine model, the EGF-endospray was applied once via an endoscopy to a bleeding lesion created by endoscopic submucosal dissection. The bleeding focus was then observed via an endoscope. In the rabbit model, EGF-endospray treatment significantly shortened mean bleeding time in comparison with other treatments (104.3 vs 548.0 vs 393.2 s for the EGF-endospray, the non-treated control and the epinephrine injection, respectively). In the micro-pig model, EGF-endospray showed immediate hemostatic action and prolonged covering of the bleeding focus for over 72 h. Histology proved mucosal thickness was more efficiently recovered in all EGF-endospray treated animals. The results of the present study suggest that the EGF-endospray is a promising hemostatic agent for GI bleeding.
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http://dx.doi.org/10.3233/BME-141236DOI Listing
October 2015

Paclitaxel-eluting nanofiber-covered self-expanding nonvascular stent for palliative chemotherapy of gastrointestinal cancer and its related stenosis.

Biomed Microdevices 2014 Dec;16(6):897-904

Utah-Inha DDS and Advanced Therapeutics Research Center, Incheon, 406-840, Republic of Korea.

Self-expanding non-vascular metal stents (SEMS) is now a choice of treatment for tumor-induced obstructive symptoms of gastrointestinal tract. But in-growing tumor causes re-stenosis. Here, we studied a paclitaxel-eluting nanofiber-covered stent for palliative chemotherapy of gastrointestinal cancer and its related stenosis. In vivo and in vitro feasibility of nanofiber-covered nonvascular stent was evaluated in this study. Nanofiber-covered stent released paclitaxel (PTX) in controlled manner for 30 days. PTX-NFM significantly inhibited the growth of CT-26 colon cancer in comparison with PTX injection. PTX maintained higher tumor concentrations over 1.0 μg/ml for more than 14 days without systemic exposure. TUNEL and H&E staining proved locally concentrated PTX induced the higher apoptosis than PTX injection. In this way, PTX-eluting nanofiber-covered stent possibly inhibits in-growth of cancer and extends patency of stent. Clinical feasibility of PTX-eluting nanofiber nonvascular stent for cholangiocarcinoma and gastrointestinal cancers will be investigated in further studies.
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http://dx.doi.org/10.1007/s10544-014-9894-9DOI Listing
December 2014

Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma.

Biomaterials 2014 Oct 17;35(30):8487-95. Epub 2014 Jul 17.

Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India.

Photodynamic therapy (PDT) is a new therapeutic approach for the palliative treatment of malignant bile duct obstruction. In this study, we designed photosensitizer-embedded self-expanding nonvascular metal stent (PDT-stent) which allows repeatable photodynamic treatment of cholangiocarcinoma without systemic injection of photosensitizer. Polymeric photosensitizer (pullulan acetate-conjugated pheophorbide A; PPA) was incorporated in self-expanding nonvascular metal stent. Residence of PPA in the stent was estimated in buffer solution and subcutaneous implantation on mouse. Photodynamic activity of PDT-stent was evaluated through laserexposure on stent-layered tumor cell lines, HCT-116 tumor-xenograft mouse models and endoscopic intervention of PDT-stent on bile duct of mini pigs. Photo-fluorescence imaging of the PDT-stent demonstrated homogeneous embedding of polymeric Pheo-A (PPA) on stent membrane. PDT-stent sustained its photodynamic activities at least for 2 month. And which implies repeatable endoscopic PDT is possible after stent emplacement. The PDT-stent after light exposure successfully generated cytotoxic singlet oxygen in the surrounding tissues, inducing apoptotic degradation of tumor cells and regression of xenograft tumors on mouse models. Endoscopic biliary in-stent photodynamic treatments on minipigs also suggested the potential efficacy of PDT-stent on cholangiocarcinoma. In vivo and in vitro studies revealed our PDT-stent, allows repeatable endoscopic biliary PDT, has the potential for the combination therapy (stent plus PDT) of cholangiocarcinoma.
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http://dx.doi.org/10.1016/j.biomaterials.2014.07.001DOI Listing
October 2014

Endoscopic application of EGF-chitosan hydrogel for precipitated healing of GI peptic ulcers and mucosectomy-induced ulcers.

J Mater Sci Mater Med 2014 Feb 14;25(2):573-82. Epub 2013 Dec 14.

Utah-Inha DDS and Advanced Therapeutics Research Center, Incheon, 400-712, South Korea.

The gastrointestinal (GI) endoscopy has become a standard diagnostic tool for GI ulcers and cancer. In this study we studied endoscopic application of epidermal growth factor-containing chitosan hydrogel (EGF-CS gel) for treatment of GI ulcer. We hypothesized that directional ulcer-coating using EGF-CS gel via endoscope would precipitate ulcer-healing. EGF-CS gel was directly introduced to the ulcer-region after ulceration in acetic acid-induced gastric ulcer (AAU) and mucosal resection-induced gastric ulcer (MRU) rabbit and pig models. The ulcer dimensions and mucosal thicknesses were estimated and compared with those in the control group. Healing efficacy was more closely evaluated by microscopic observation of the ulcer after histological assays. In the AAU model, the normalized ulcer size of the gel-treated group was 2.3 times smaller than that in the non-treated control group on day 3 after ulceration (P < 0.01). In the MRU model, the normalized ulcer size of the gel-treated group was 5.4 times smaller compared to that in the non-treated control group on day 1 after ulceration (P < 0.05). Histological analysis supported the ability of EGF-CS gel to heal ulcers. The present study suggests that EGF-CS gel is a promising candidate for treating gastric bleeding and ulcers.
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http://dx.doi.org/10.1007/s10856-013-5088-xDOI Listing
February 2014

Photo-cured PMMA/PEI core/shell nanoparticles surface-modified with Gd-DTPA for T1 MR imaging.

J Colloid Interface Sci 2014 Feb 17;415:70-6. Epub 2013 Oct 17.

Utah-Inha DDS and Advanced Therapeutics, B-403 Meet-You-All Tower, Songdo Technopark, 7-50, Songdo-dong, Yeonsu-gu, Incheon 406-840, Republic of Korea; Department of Chemistry, Faculty of Science, Mahidol University, Nakhon Pathom 73170, Thailand.

Herein, we introduced amine-functionalized core-shell nanoparticles (Polymethyl methacrylate/Polyethyleneimine; PMMA/PEI) with surface primary amines (3.15×10(5) groups/particle) and uniform size distribution (150-200nm) that were prepared by one-step photo-induced emulsion polymerization. Further PEI-surface was modified with diethylenetriamine pentaacetic acid (DTPA) and introduced with Gd(III). The modified particles possessing DTPA can entrap a high content of Gd(III) ions of over 5.5×10(4)Gd/particle with stable chelation (no release of free Gd) at least 7h. The Gd-DTPA-conjugated core-shell nanoparticles (PMMA/PEI-DTPA-Gd NPs) enhanced the MRI intensity more than Primovist (a commercial hepatic contrast agent). Moreover, the PMMA/PEI-DTPA-Gd NPs showed non-cytotoxicity up to 250μM in normal liver cells. Thus, in vitro data suggested the PMMA/PEI-DTPA-Gd NPs is promising delivery system as a superior MRI contrast agent, especially for hepatic lesion targeted MR imaging.
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http://dx.doi.org/10.1016/j.jcis.2013.09.049DOI Listing
February 2014

rhEGF-containing thermosensitive and mucoadhesive polymeric sol-gel for endoscopic treatment of gastric ulcer and bleeding.

J Biomater Appl 2014 Mar 13;28(7):1113-21. Epub 2013 Aug 13.

1Utah-Inha DDS and Advanced Therapeutics Research Center, Incheon, Korea.

Gastrointestinal endoscopy is a standard diagnostic tool for gastrointestinal ulcers and cancer. In this study, we have developed recombinant human epidermal growth factor-containing ulcer-coating polymeric sol-gel for endoscopic application. Chitosan and pluronic F127 were employed for their thermoresponsive and bioadhesive properties. At temperatures below 21, polymeric sol-gel remains liquid during endoscopic application and transforms to gel at body temperature after application on ulcers. In an in vitro cellular wounding assay, recombinant human epidermal growth factor sol-gel significantly enhanced the cell migration and decreased the wounding area (68%) compared to nontreated, recombinant human epidermal growth factor solution, and sol-gel without recombinant human epidermal growth factor (42, 49, and 32 % decreased at day 1). The in vivo ulcer-healing study was performed in an acetic acid-induced gastric ulcer rat model and proved that our recombinant human epidermal growth factor endoscopic sol-gel facilitated the ulcer-healing process more efficiently than the other treatments. Ulcer sizes in the recombinant human epidermal growth factor sol-gel group were decreased 2.9- and 2.1-fold compared with those in the nontreated group on days 1 and 3 after ulceration, respectively. The mucosal thickness in the recombinant human epidermal growth factor sol-gel group was significantly increased compared to that in the nontreated group (3.2- and 6.9-fold on days 1 and 3 after ulceration, respectively). In a gastric retention study, recombinant human epidermal growth factor sol-gel stayed on the gastric mucosa more than 2 h after application. The present study suggests that recombinant human epidermal growth factor sol-gel is a prospective candidate for treating gastric ulcers via endoscopic application.
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http://dx.doi.org/10.1177/0885328213499948DOI Listing
March 2014
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