Ji-Eun Chang

Anticancer efficacy of photodynamic therapy with hematoporphyrin-modified, doxorubicin-loaded nanoparticles in liver cancer.

Photodynamic therapy (PDT) in combination with chemotherapy has great potential for cancer treatment. However, there have been very few attempts to developing cancer-targeted co-delivered systems of photosensitizers and anticancer drugs. We developed hematoporphyrin (HP)-modified doxorubicin (DOX)-loaded nanoparticles (HP-NPs) to improve the therapeutic effect of PDT in treating liver cancer. HP is not only a ligand for low density lipoprotein (LDL) receptors on the hepatoma cells but also a well-known photosensitizer for PDT. In vitro phototoxicity in HepG2 (human hepatocellular carcinoma) cells and in vivo anticancer efficacy in HepG2 tumor-bearing mice of free HP and HP-NPs were evaluated. The in vitro phototoxicity in HepG2 cells determined by MTT assay, annexin V-FITC staining and FACS analysis was enhanced in HP-NPs compared with free HP. Furthermore, compared with free HP-based PDT, in vivo anticancer efficacy in HepG2 tumor-bearing mice was markedly improved by HP-NPs-based PDT. Moreover, in both cases, the therapeutic effect was increased according to the irradiation time and number of PDT sessions. In conclusion, the HP-NPs prepared in this study represent a potentially effective co-delivery system of photosensitizer (HP) and anticancer drug (DOX) which improved the effects of PDT in liver cancer.

Upregulation of COX-2 in the lung cancer promotes overexpression of multidrug resistance protein 4 (MRP4) via PGE2-dependent pathway

It is apparent that lung cancer is associated with inflammation, with accompanying hallmark elevations of cyclooxygenase 2 (COX-2) and prostaglandin E2 (PGE2) levels. However, the effects of these changes on MRP efflux transporters have not been thoroughly investigated before. Here, we report that upregulation of COX-2 can induce overexpression of MRP4 in both A549 non-small-cell lung cancer cell lines and mouse lung cancer models. In A549 cells, phorbol 12-myristate 13-acetate (PMA) treatment induced upregulation of COX-2 and MRP4 together, but not other MRP transporters. Transient overexpression of human COX-2 cDNA also specifically increased COX-2 and MRP4. Moreover, COX inhibitor treatment and COX-2-specific siRNA significantly inhibited the upregulation of MRP4. Additionally, PMA-treatment increased extracellular PGE2 levels, likely due to increased MRP4 function. Likewise, COX-2-specific siRNA reduced extracellular PGE2 levels. Furthermore, COX-2 upregulation resulted in an increase in mPGES-1, an enzyme responsible for PGE2 production. Finally, metastasized lung cancer model mice exhibited increased expression levels of COX-2 and MRP4, as well as mPGES-1. In conclusion, the present study suggests that overexpression of MRP4 in lung cancer may be attributable to COX-2 upregulation via a PGE2-dependent pathway.

Hypocrellin B and paclitaxel-encapsulated hyaluronic acid-ceramide nanoparticles for targeted photodynamic therapy in lung cancer.

To increase the therapeutic efficacy of photodynamic therapy (PDT) in treating lung cancer, we developed both photosensitizer and anticancer drug encapsulated hyaluronic acid-ceramide nanoparticles. Based on our previous study, a co-delivery system of photosensitizers and anticancer agents greatly improves the therapeutic effect of PDT. Furthermore, hyaluronic acid-ceramide-based nanoparticles are ideal targeting carriers for lung cancer. In vitro phototoxicity in A549 (human lung adenocarcinoma) cells and in vivo antitumor efficacy in A549 tumor-bearing mice treated with hypocrellin B (HB)-loaded nanoparticles (HB-NPs) or hypocrellin B and paclitaxel loaded nanoparticles (HB-P-NPs) were evaluated. Cell viability assay, microscopic analysis and FACS analysis were performed for the in vitro studies and HB-P-NPs showed enhanced phototoxicity compared with HB-NPs. In the animal study, the tumor volume change and the histological analysis was studied and the anticancer efficacy improved in the order of free HB<HB-NPs<HB-P-NPs. In conclusion, the combination therapy of PDT and chemotherapy, and hyaluronic acid-ceramide nanoparticle-based targeted delivery improved the effects of PDT in lung cancer in mice.

Clinical outcome of photodynamic therapy in esophageal squamous cell carcinoma

The aim of this study was to evaluate the feasibility and safety of photodynamic therapy (PDT) as a curative treatment option or as palliative therapy for esophageal squamous cell carcinoma. Medical records of patients who received PDT for esophageal squamous cell carcinoma, including carcinoma in situ, were reviewed retrospectively. Survival analysis was performed using the Kaplan-Meier method. A total of 31 cases were treated with PDT between 2003 and 2013. Treatment was for palliative purposes in 11 cases (35.5%) and for therapeutic purposes in 20 cases (64.5%). We achieved 15 cases (48.4%) of complete remission and 16 (51.6%) cases of partial remission during the follow-up period. There were 6 fatalities, 5 of which were related to disease progression. Complications, including benign strictures, occurred in 11 cases (35.5%) but there was only 1 complication-related death. Recurrence occurred in 2 patients with complete remission. Overall survival was 31.9 months for patients with complete remission and 28.2 months for those with partial remission. Disease-free survival of patients with complete remission was 21.9 months. Our data suggest that photodynamic therapy is a reasonable palliative treatment option with acceptable complication rates for esophageal cancer and could be performed for therapeutic purposes in cases of early esophageal cancer.

Tumor Size-Dependent Anticancer Efficacy of Chlorin Derivatives for Photodynamic Therapy

Photodynamic therapy (PDT) with a suitable photosensitizer molecule is a promising anticancer treatment. We evaluated two chlorin molecules as potential photosensitizers, methyl pyropheophorbide a (MPPa) and N-methoxyl purpurinimide (NMPi), against A549 human lung adenocarcinoma cells in vitro as well as in A549 tumor-bearing mice in vivo. Cell viability, microscopy, and fluorescence-activated cell sorting (FACS) analyses were performed for the in vitro studies. MPPa and NMPi showed high phototoxicity in vitro, which was dependent on the concentration of the photosensitizers as well as the light irradiation time. In the animal study, tumor volume change, tumor surface alterations, and hematoxylin & eosin (H&E) and terminal deoxyribonucleotidyl transferse-mediated dUTP nick-end labelling (TUNEL) staining analyses were performed and compared between small (tumor volume of <50 mm3) and large (tumor volume of >50 mm3) size of initial tumors. MPPa and NMPi showed high anticancer efficacy against small-size tumors, indicating that early treatment with PDT is effective. Especially, repeated two times PDT with NMPi allowed almost complete eradication against small-size tumors. However, MPPa and NMPi were not effective against large-size tumors. In conclusion, the two chlorin derivatives, MPPa and NMPi, show good anticancer efficacy as promising photosensitizers for PDT in vitro and in vivo. Moreover, their activity in vivo was significantly dependent on the initial tumor size in mice, which confirms the importance of early cancer treatment.

Anticancer Efficacy of Photodynamic Therapy with Lung Cancer-Targeted Nanoparticles.

Photodynamic therapy (PDT) is a non-invasive and non-surgical method representing an attractive alternative choice for lung cancer treatment. Photosensitizers selectively accumulate in tumor tissue and lead to tumor cell death in the presence of oxygen and the proper wavelength of light. To increase the therapeutic effect of PDT, we developed both photosensitizer- and anticancer agent-loaded lung cancer-targeted nanoparticles. Both enhanced permeability and retention (EPR) effect-based passive targeting and hyaluronic-acid-CD44 interaction-based active targeting were applied. CD44 is a well-known hyaluronic acid receptor that is often introduced as a biomarker of non-small cell lung cancer. In addition, a combination of PDT and chemotherapy is adopted in the present study. This combination concept may increase anticancer therapeutic effects and reduce adverse reactions. We chose hypocrellin B (HB) as a novel photosensitizer in this study. It has been reported that HB causes higher anticancer efficacy of PDT compared to hematoporphyrin derivatives1. Paclitaxel was selected as the anticancer drug since it has proven to be a potential treatment for lung cancer2. The antitumor efficacies of photosensitizer (HB) solution, photosensitizer encapsulated hyaluronic acid-ceramide nanoparticles (HB-NPs), and both photosensitizer- and anticancer agent (paclitaxel)-encapsulated hyaluronic acid-ceramide nanoparticles (HB-P-NPs) after PDT were compared both in vitro and in vivo. The in vitro phototoxicity in A549 (human lung adenocarcinoma) cells and the in vivo antitumor efficacy in A549 tumor-bearing mice were evaluated. The HB-P-NP treatment group showed the most effective anticancer effect after PDT. In conclusion, the HB-P-NPs prepared in the present study represent a potential and novel photosensitizer delivery system in treating lung cancer with PDT.

Clinical results of photodynamic therapy in tracheobronchial malignancy.

Photodynamic therapy (PDT) has been adopted as an alternative therapy for lung cancer patients who could not receive surgery due to their poor condition. It also has expanded its roles in lung cancer treatment for palliative treatment for increasing symptoms. We retrospectively reviewed medical records of patients of tracheobronchial cancers who received photodynamic therapy in our institute. Outcomes of the treatment results were evaluated, and survival analysis was performed via Kaplan-Meier analysis. We performed 25 cases of photodynamic therapy for tracheobronchial cancer patients between 2003 and 2013. A total of 21 patients were involved. Average ages at the time of treatment were 68.1. In those 25 cases, 8 cases achieved complete remission, and 15 cases remained partial remission. There were 2 cases of no response. Seven patients died during the follow-up periods, but none of these were related with complications. Only two minor complications were observed during the follow-up periods. One was granulation at the site of PDT, and the other was hemoptysis. Average overall survival periods for the therapeutic group were 50.1 months and those of the palliative group were 29.3 months. Photodynamic therapy was safe and feasible for palliative therapy in tracheobronchial cancer with acceptable complication rates. Also, it could be a treatment option for double primary lung cancer in inoperable patients.

The potential application of photodynamic therapy in drug-resistant tuberculosis

Tuberculosis (TB) is an infectious bacterial disease that has historically created a high global health burden. Unfortunately, the emergence of drug-resistant TB (DR-TB), which includes multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), has greatly affected the treatment of TB. Anti-TB chemotherapy drugs are classified into five groups to facilitate application of effective guidelines for the treatment regimen. However, chemotherapy has a limited ability to treat DR-TB, and therefore a novel alternative treatment for DR-TB is required. In this review, we focused on photodynamic therapy (PDT) as potential treatment for DR-TB. PDT is a widely used cancer treatment that combines photosensitizers and harmless laser light to produce reactive oxygen species that selectively damage the target cells. Initially, PDT was originally developed to target pathogenic microorganisms but fell into disuse because of adverse reactions. Recently, photodynamic antimicrobial chemotherapy is attracting attention again as an alternative treatment for bacterial infections. In our previous study, we suggested that PDT could be a novel option to treat MDR- and XDR-TB in vitro. Despite the limited previous studies regarding PDT in TB models, fast-developing bronchoscopic technologies and clinician experience will soon facilitate the clinical application of safe and minimally invasive PDT for TB.

Synchrotron tomographic images from human lung adenocarcinoma: Three-dimensional reconstruction and histologic correlations

High‐resolution tomographic images using synchrotron X‐rays are expected to provide detailed reflection of microstructures, thereby allowing for the examination of histologic structures without destruction of the specimen. This study aims to evaluate the synchrotron tomographic images of mixed ground‐glass opacity excised on 5‐mm sections in comparison to pathologic examination. The Institutional Review Board of our institute approved this retrospective study, and written informed consent was obtained from each patient whose lung tissue would be used. Obtained lung cancer specimens were brought to the multiple Wiggler 6C beam line at the Pohang Light Source (PLS‐II) in Korea, and phase contrast X‐ray images were obtained in November 2016. The X‐ray emanated from a bending magnet of the electron storage ring with electron energy of 3 GeV, and a typical beam current was 320 mA. Reconstructed tomographic images were compared with images from histologic slides obtained from the same samples. Pulmonary microstructures including terminal bronchioles, alveolar sacs, and vasculature were identified with phase contrast X‐ray images. Images from normal lung tissue and mixed ground‐glass opacity were clearly distinguishable. Hyperplasia of the interalveolar septum and dysplasia of microstructure were clearly identified. The imaging findings correlated well with hematoxylin‐eosin stained specimens. Tomographic images using synchrotron radiation have the potential for clinical applications. With refinement, this technique may become a diagnostic tool for detection of lung cancer.

Association of MAGE A1-6 Expression with Lung Cancer Progression

The melanoma-associated antigen (MAGE) genes are known to be expressed in various kinds of tumors including lung cancer. Although they are studied as targets for immunotherapy and tools for early detection of lung cancer, the correlation between MAGE expression and the prognosis in lung cancer has not been clarified. In this study, we evaluated the relationship between MAGE A1-6 gene expression and the clinical prognosis in lung cancer. Bone marrow aspirations were performed in 60 patients who were diagnosed as lung cancer and underwent lung cancer surgery between 2007 and 2008. Each bone marrow was examined using nested reverse transcription- polymerase chain reaction (RT-PCR) with the MAGE common primer to detect MAGE A1-6. Overall survival rate, disease-free survival rate, recurrence, and distant metastasis were reviewed retrospectively. Survival periods were analyzed using SPSS ver. 20.0. Of the total 60 lung cancer patients, 9 patients (15%) had MAGE A1-6. MAGE A1-6-positive patients showed poor overall survival and overall disease-free survival rates (43.8 ± 26.1, 43.2 ± 26.9 months, respectively) compared with MAGE A1-6-negative patients (54.4 ± 17.2, 44.8 ± 22.1 months, respectively). No significant difference was shown in either survival rates. In conclusion, MAGE A1-6 expression of bone marrow in lung cancer patients correlated with poor survival rates. We suggest that MAGE A1-6 may be considered as a novel prognostic factor for lung cancer which leads to effective follow-up and treatment.