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Jung J.,University of Ulsan | Jung J.,Duksung Womens University | Jeong S.-Y.,University of Ulsan | Park S.S.,University of Ulsan | And 13 more authors.
International Journal of Oncology | Year: 2015

Radiotherapy (RT) is one of the major modalities for non-small cell lung cancer (NSCLC), but its efficacy is often compromised by cellular resistance caused by various mechanisms including the overexpression of epidermal growth factor receptor (EGFR). Although cis-diamminedichloroplatinum(II) (cisplatin, CDDP) has been well characterized as an effective radiosensitizer, its clinical application is limited by its severe nephrotoxic effects. In our current study, we developed a CDDP-incorporated liposome (LP) conjugated with EGFR antibodies (EGFR:LP-CDDP) and evaluated its potential to radiosensitize EGFR-overexpressing cells without exerting nephrotoxic effects. EGFR:LP-CDDP showed higher cytotoxicity than non-targeting liposomal CDDP (LP-CDDP) in the cells expressing EGFR in vitro. In an A549 cell-derived xenograft tumor mouse model, increased delays in tumor growth were observed in the mice treated with a combination of EGFR:LP-CDDP and radiation. Notably, the EGFR:LP-CDDP-treated animals showed no differences in body weight loss, survival rates of nephrotoxicity compared with untreated control mice. In contrast, the use of CDDP caused lower body weights and poorer survival outcomes accompanied by a significant level of nephrotoxicity [e.g., decreased kidney weight, increased blood urea nitrogen (BUN) and creatinine, and pathological change]. These findings suggest the feasibility of using EGFR:LP-CDDP to radiosensitize cells in a targeted manner without inducing nephrotoxic effects. This compound may therefore have clinical potential as part of a tailored chemoradiotherapy strategy. Source

Jung S.-Y.,Korea Institute of Radiological and Medical Sciences | Yi J.Y.,Korea Institute of Radiological and Medical Sciences | Kim M.-H.,Korea Institute of Radiological and Medical Sciences | Song K.-H.,Korea Institute of Radiological and Medical Sciences | And 5 more authors.
Oncology Reports | Year: 2015

Triple-negative breast cancer (TNBC) is an aggressive cancer with a poor prognosis due to its epithelial-to- mesenchymal transition (EMT) phenotype. Cancer patients often experience several detrimental effects of cancer treatment, such as chemoresistance, radioresistance and the maintenance of cancer stem cells due to EMT. Thus, EMT signaling is considered to be a valuable therapeutic target for cancer treatment, and its inhibition is being attempted as a new treatment option for TNBC patients. Previously, we showed that 3-(2-chlorobenzyl)-1,7-dimethyl-1H-imidazo[2,1- f]purine-2,4(3H,8H)-dione (IM-412) inhibits transforming growth factor-β (TGF-β)-induced differentiation of human lung fibroblasts through both Smad-dependent and -independent pathways. In the present study, we examined the inhibitory effect of IM-412 on EMT pathways and invasiveness in TNBC cells since the TGF-β signaling pathway is a typical signaling pathway that functions in EMT. IM-412 not only potently suppressed the migration and invasion of MDA-MB-231 cells, but also lowered the expression of mesenchymal markers and EMT-activating transcription factors in these cells. IM-412 inhibited the activation of several signaling proteins, including Smad2/Smad3, p38MAPK, Akt and JNK, and it also attenuated the phosphorylation of FGFR1 and FGFR3. Collectively, our findings suggest that the synthetic compound IM-412 suppressed the EMT process in MDA-MB-231 cells and thereby effectively inhibited the migration and invasion of these cancer cells. Thus, IM-412 could serve as a novel therapeutic agent for malignant cancers. Source

Woo H.N.,University of Ulsan | Chung H.K.,Center for Development and Commercialization of Anti cancer Therapeutics | Ju E.J.,University of Ulsan | Jung J.,University of Ulsan | And 12 more authors.
International Journal of Nanomedicine | Year: 2012

Nanoparticles are useful delivery vehicles for promising drug candidates that face obstacles for clinical applicability. Sirolimus, an inhibitor of mammalian target of rapamycin has gained attention for targeted anticancer therapy, but its clinical application has been limited by its poor solubility. This study was designed to enhance the feasibility of sirolimus for human cancer treatment. Polymeric nanoparticle (PNP)-sirolimus was developed as an injectable formulation and has been characterized by transmission electron microscopy and dynamic light scattering. Pharmacokinetic analysis revealed that PNP-sirolimus has prolonged circulation in the blood. In addition, PNP-sirolimus preserved the in vitro killing effect of free sirolimus against cancer cells, and intravenous administration displayed its potent in vivo anticancer efficacy in xenograft tumor mice. In addition, PNP-sirolimus enhanced the radiotherapeutic efficacy of sirolimus both in vitro and in vivo. Clinical application of PNP-sirolimus is a promising strategy for human cancer treatment. © 2012 Woo et al, publisher and licensee Dove Medical Press Ltd. Source

Choi J.,University of Ulsan | Woo H.-N.,University of Ulsan | Ju E.J.,University of Ulsan | Jung J.,University of Ulsan | And 11 more authors.
Journal of Nanomaterials | Year: 2012

Radiotherapy for cancer treatment has been used for primary or adjuvant treatment in many types of cancer, and approximately half of all cancer patients are undergoing radiation. However, ionizing radiation exposure induces genetic alterations in cancer cells and results in recruitment of monocytes/macrophages by triggering signals released from these cells. Using this characteristic of monocytes/macrophages, we have attempted to develop a biocarrier loading radiosensitizing anticancer agents that can lead to enhance the therapeutic effect of radiation in cancer treatment. The aim of this study is to demonstrate the proof of this concept. THP-1 labeled with Qdot 800 or iron oxide (IO) effectively migrated into tumors of subcutaneous mouse model and increased recruitment after ionizing radiation. Functionalized liposomes carrying a radiosensitizing anticancer agent, doxorubicin, are successfully loaded in THP-1 (THP-1-LP-Dox) with reduced cytotoxicity, and THP-1-LP-Dox also was observed in tumors after intravenous administration. Here, we report that monocytes/macrophages as a biocarrier can be used as a selective tool for amplification of the therapeutic effects on radiotherapy for human cancer treatment. Copyright © 2012 Jinhyang Choi et al. Source

Jung J.,University of Ulsan | Jung J.,Duksung Womens University | Kim M.S.,Sungkyunkwan University | Park S.-J.,University of Ulsan | And 11 more authors.
Journal of Nanomaterials | Year: 2012

Radiotherapy (RT) is a major modality for cancer treatment, but its efficacy is often compromised by the resistance caused by tumor-specific microenvironment including acidosis and hypoxia. For an effective RT, concurrent administration of radiosensitizer with RT has been emphasized. However, most anticancer agents enhancing radiotherapeutic efficacy have obstacles such as poor solubility and severe toxicity. Paclitaxel (PTX), a well-known radiosensitizer, is insoluble in water and needs toxic solvent like Cremophor EL. Nanomaterials in drug delivery systems have been utilized for improving the drawbacks of anti-cancer drugs. Solubilization, tumor accumulation, and toxicity attenuation of drug by nanomaterials are suitable for enhancement of radiotherapeutic efficacy. In this study, PTX was incorporated into pH-sensitive block copolymer micelle (psm-PTX), polyethylene glycol-graft-poly(β-amino ester), and preclinically evaluated for its effect on RT. The size of psm-PTX was 125.7±4.4 nm at pH 7.4. psm-PTX released PTX rapidly in the acidic condition (pH 6.5), while it was reasonably stable in the physiologic condition (pH 7.4). The clonogenic assay showed that psm-PTX greatly sensitized human non-small-cell lung cancer A549 cells to radiation. In the xenograft tumor model, the combination of psm-PTX and radiation significantly delayed the tumor growth. These results demonstrated the feasibility of psm-PTX to enhance the chemoradiotherapeutic efficacy. Copyright © 2012 Joohee Jung et al. Source

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