phytochlorin and Pancreatic-Neoplasms

Pancreatic tumor are a deadly malignancy with high aggressiveness, and photodynamic therapy (PDT) is a prospective remedy. Nevertheless, the cells in the peripheral tissues of large tumors are often subjected to low-dose illumination and tend to survive after sublethal PDT exposure. Thus, it is of critical importance to determine the metastatic influence of PDT on pancreatic neoplasms. (17R, 18R)-2-(1-Hexyloxyethyl)-2-devinyl chlorine E6 trisodium salt (YLG-1) is a novel chlorine derivative photosensitizer, and we previously demonstrated potent growth inhibition of pancreatic neoplasms by YLG-1-mediated PDT (YLG-1-PDT). In this study, we assessed the metastatic effect of low-dose PDT with YLG-1 on pancreatic tumors and its combination with simvastatin. We found that sublethal YLG-1-PDT promoted MMP-2/9 expression in residual pancreatic tumor cells as well as tumor cell motility/invasion and liver metastasis. Since simvastatin was reported to improve the survival of patients with pancreatic tumors at an early stage and suppress the metastasis of most cancers, we utilized it during YLG-1-PDT and discovered alleviated migration/invasion, metastasis and MMP-2/9 expression. Collectively, our study results raise the concern that PDT could also be a Janus-like treatment owing to its prometastatic potential provoked by a low dosage. Concomitant use of simvastatin during PDT might be an effective method to attenuate such adverse reactions.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Chlorophyllides; Collagenases; Combined Modality Therapy; Female; Humans; Low-Level Light Therapy; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Simvastatin; Treatment Outcome

Pancreatic cancer has a very poor prognosis, and early diagnosis is a way to increase the survival rate of patients. The purpose of this study was to develop pancreatic cancer-specific peptides for imaging studies.. Three pancreatic cancer cell lines, MIA PaCa-2, UACC-462, and BxPC-3, and a control cell line, CCD841, were used. Biopannings were performed on MIA PaCa-2 using a phage display library. After this, the peptides were synthesized and labeled with fluorescein isothiocyanate (FITC). Immunocytochemistry (ICC), enzyme-linked immunosorbent assay (ELISA), and fluorescence- activated cell sorter (FACS) were performed to examine the specific binding. To examine its therapeutic applications, a photosensitizer, chlorin e6 (Ce6), was conjugated on the peptide and photodynamic therapy was performed. Cell survival was investigated using a [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] assay.. After three biopannings, the phages were amplified from 1.4×10. This study showed that the noble peptide, M5, binds specifically to the pancreatic cancer cell line, MIA PaCa-2. The M5 peptide has potential use in future optical diagnostic and therapeutic purposes.

Topics: Animals; Cell Line, Tumor; Cell Surface Display Techniques; Cell Survival; Chlorophyllides; Fluorescein-5-isothiocyanate; Humans; Light; Mice; Mice, Nude; Optical Imaging; Pancreatic Neoplasms; Peptides; Photochemotherapy; Photosensitizing Agents; Porphyrins

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Chlorophyllides; Curcumin; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Structure-Activity Relationship

Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used, and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between chlorin e6 (Ce6) and cationic photosensitizer-encapsulated polymeric nanoparticle (PS-pNP), which is comprised with Ce6, polyethylene glycol, and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS-pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1 xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison with that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which was related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells.

Topics: Animals; Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 2; Cell Line, Tumor; Cell Survival; Chlorophyllides; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Polymers; Porphyrins; Singlet Oxygen; Xenograft Model Antitumor Assays

New methods for the endoscopic selective ablation of locally advanced pancreaticobiliary malignancies as a minimally invasive approach are needed. Our aim was to examine the feasibility and safety of endoscopic ultrasonography (EUS)-guided photodynamic therapy (PDT) for local tumor control in patients with locally advanced pancreaticobiliary malignancies.. A chlorin e6 derivative and a flexible laser-light catheter were used to perform EUS-guided PDT in four patients with locally advanced pancreaticobiliary malignancies.. EUS-guided PDT was technically feasible in all four patients with locally advanced pancreaticobiliary malignancies (two in the caudate lobe of the liver, one in the far distal bile duct, and one in the tail of the pancreas). No treatment-related complications occurred. The median volume of necrosis produced by PDT was 4.0 cm(3) (range 0.7 - 11.3). Disease remained stable in all four patients during a median follow-up of 5 months (range 3 - 7).. These preliminary data suggest that EUS-guided PDT with a second-generation photosensitizer and a flexible laser probe is feasible and safe.

Topics: Aged; Bile Duct Neoplasms; Catheters; Chlorophyllides; Cholangiocarcinoma; Endosonography; Feasibility Studies; Follow-Up Studies; Humans; Male; Middle Aged; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Pilot Projects; Porphyrins; Treatment Outcome; Ultrasonography, Interventional

Lack of effective treatment results in the low survival for patients with pancreatic cancer, and photodynamic therapy (PDT) with photosensitizers has emerged as an effective therapeutic option for treatment of various tumors by light-generated cytotoxic reactive oxygen species (ROS) to induce cell apoptosis or necrosis. However, the poor solubility, rapid blood clearance, and weak internalization of the photosensitizer seriously inhibit its anticancer efficacy. To overcome these obstacles, a polyphosphoester-based nanocarrier (NP-PPE) is employed as the carrier of the hydrophobic photosensitizer, chlorin e6 (Ce6), for photodynamic therapy. The Ce6-encapsulated nanocarrier (NP-PPE/Ce6) significantly promoted the cellular internalization of Ce6, enhanced the generation of ROS in the tumor cells after irradiation. Therefore, the cellular phototoxicity of NP-PPE/Ce6 against BxPC-3 pancreatic cancer cells was markedly enhanced than that of free Ce6 in vitro. Furthermore, NP-PPE/Ce6 improved accumulation of Ce6 in tumor tissue and treatment with NP-PPE/Ce6 significantly enhanced antitumor efficacy in human BxPC-3 pancreatic cancer xenografts. These results suggest that using a polyphosphoester-based nanocarrier as the delivery system for a photosensitizer has great potential for PDT of pancreatic cancer.

Topics: Animals; Cell Line, Tumor; Cell Survival; Chlorophyllides; Drug Carriers; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred ICR; Mice, Nude; Nanostructures; Pancreatic Neoplasms; Photosensitizing Agents; Porphyrins; Reactive Oxygen Species; Tissue Distribution; Transplantation, Heterologous

Recently it has been suggested that quantum dots could be used in the photodynamic therapy of cancer as resonant energy donors for conventional porphyrin type photosensitizers. Here we summarize our results obtained by studying a non-covalent complex formed between quantum dots and a second generation photosensitizer, chlorin e6, in aqueous medium and in live pancreatic MiaPaCa2 cancer cells. Spectral changes in the absorption and photoluminescence of quantum dots and chlorin e6, as well as changes in the photoluminescence lifetime of quantum dots, revealed the formation of quantum dot-chlorin e6 complex. Fluorescence confocal microscopy with spectral imaging unit showed uptake of quantum dot-chlorin e6 complex in live cancer cells: the complex localized in plasma membrane and endocytic vesicles. Fluorescence lifetime imaging revealed Forster resonance energy transfer from quantum dots to chlorin e6 within live cells. Finally, a light-induced damage to cancer cells by the quantum dot-chlorin e6 complex was achieved.

Topics: Apoptosis; Cell Line, Tumor; Cell Survival; Chlorophyllides; Humans; Pancreatic Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Quantum Dots