Polymeric photosensitizer-embedded self-expanding metal stent for repeatable endoscopic photodynamic therapy of cholangiocarcinoma.
Bae Byoung-chan,Yang Su-Geun,Jeong Seok,Lee Don Haeng,Na Kun,Kim Joon Mee,Costamagna Guido,Kozarek Richard A,Isayama Hiroyuki,Deviere Jacques,Seo Dong Wan,Nageshwar Reddy D
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.
Temoporfin improves efficacy of photodynamic therapy in advanced biliary tract carcinoma: A multicenter prospective phase II study.
Wagner Andrej,Denzer Ulrike W,Neureiter Daniel,Kiesslich Tobias,Puespoeck Andreas,Rauws Erik A J,Emmanuel Klaus,Degenhardt Nora,Frick Ulrich,Beuers Ulrich,Lohse Ansgar W,Berr Frieder,Wolkersdörfer Gernot W
Hepatology (Baltimore, Md.)
UNLABELLED:Photodynamic therapy using porfimer (P-PDT) improves palliation and survival in nonresectable hilar bile duct cancer. Tumoricidal penetration depth of temoporfin-PDT (T-PDT) is twice that of P-PDT. In a single-arm phase II study we investigated the safety, efficacy, survival time, and adverse events of T-PDT compared with previous data on P-PDT. Twenty-nine patients (median 71 [range 47-88] years) with nonresectable hilar bile duct cancer were treated with T-PDT (median 1 [range 1-4] sessions) plus stenting and followed up every 3 months. The PDT was well tolerated. In patients with occluded segments at baseline (n=28) a reopening of a median of 3 (range 1-7) segments could be achieved: n=16 local response and n=11 stable local disease, one progressive disease. Cholestasis and performance significantly improved when impaired at baseline. Time to local tumor progression was a median of 6.5 (2.7-41.0) months. Overall survival time was a median of 15.4 (range 4.4-62.4) months. Patients died from tumor progression (55%), cholangitis (18%), pneumonia (7%), hemobilia (7%), esophagus variceal hemorrhage (3%), and vascular diseases (10%). Adverse events were cholangitis (n=4), liver abscess (n=2), cholecystitis (n=2), phototoxic skin (n=5), and injection site reactions (n=7). Compared to previous P-PDT, T-PDT shows prolonged time to local tumor progression (median 6.5 versus 4.3 months, P<0.01), fewer PDT treatments needed (median 1 versus 3, P<0.01), a higher 6-month survival rate (83% versus 70%, P<0.01), and a trend for longer overall median survival (15.4 versus 9.3 months, P=0.72) yet not significantly different. The risk of adverse events is not increased except for (avoidable) subcutaneous phototoxicity at the injection site. CONCLUSION:Temoporfin-PDT can safely be delivered to hilar bile duct cancer patients and results in prolonged patency of hilar bile ducts, a trend for longer survival time, and similar palliation as with P-PDT.
Indwelling Stent Embedded with Light-Emitting Diodes for Photodynamic Therapy of Malignant Biliary Obstruction.
Baran Timothy M,Mironov Oleg,Sharma Ashwani K,Foster Thomas H
Cardiovascular and interventional radiology
PURPOSE:We describe the design and preliminary characterization of a stent incorporating light-emitting diodes (LEDs) for photodynamic therapy (PDT) of malignant biliary obstruction. METHODS:A prototype was constructed with red (640 nm) LEDs embedded in a 14.5 French polyurethane tube. The device was evaluated for optical power and subjected to physical and electrical tests. PDT-induced reactive oxygen species were imaged in a gel phantom. RESULTS:The stent functioned at a 2.5-cm bend radius and illuminated for 6 months in saline. No stray currents were detected, and it was cool after 30 minutes of operation. Optical power of 5-15 mW is applicable to PDT. Imaging of a reactive oxygen indicator showed LED-stent activation of photosensitizer. CONCLUSIONS:The results motivate biological testing and design optimization.
Photodynamic Therapy Plus Chemotherapy Compared with Photodynamic Therapy Alone in Hilar Nonresectable Cholangiocarcinoma.
Wentrup Robert,Winkelmann Nicola,Mitroshkin Andrey,Prager Matthias,Voderholzer Winfried,Schachschal Guido,Jürgensen Christian,Büning Carsten
Gut and liver
BACKGROUND/AIMS:Standard treatments are not available for hilar nonresectable cholangiocarcinoma (NCC). It is unknown whether combination therapy of photodynamic therapy (PDT) plus systemic chemotherapy is superior to PDT alone. METHODS:We retrospectively reviewed 68 patients with hilar NCC treated with either PDT plus chemotherapy (PTD-C) or PDT monotherapy (PDT-M). The primary endpoint was the mean overall survival rate. Secondary endpoints included the 1-year survival rate, risk of cholangitic complications, and outcomes, which were evaluated according to the chemotherapy protocol. RESULTS:More than 90% of the study population had advanced hilar NCC Bismuth type III or IV. In the PDT-M group (n=35), the mean survival time was 374 days compared with 520 days in the PDT-C group (n=33, p=0.021). The 1-year survival rate was significantly higher in the PDT-C group compared with the PDT-M group (88% vs 58%, p=0.001) with a significant reduction of mortality (hazard ratio, 0.20; 95% confidence interval, 0.07 to 0.58; p=0.003). Gemcitabine monotherapy resulted in a shorter survival time compared with the gemcitabine combination therapy (mean, 395 days vs 566 days; p=0.09). Cholangitic complications were observed at a similar frequency in the PDT-C and PDT-M groups. CONCLUSIONS:Combining repeated PDT with a gemcitabine-based combination therapy might offer a significant survival benefit in patients with hilar NCC.
Photodynamic Therapy in Patients with Advanced Hilar Cholangiocarcinoma: Percutaneous Cholangioscopic Versus Peroral Transpapillary Approach.
Lee Tae Yoon,Cheon Young Koog,Shim Chan Sup
Photomedicine and laser surgery
OBJECTIVE:This study aimed to compare the clinical outcomes of patients with advanced hilar cholangiocarcinoma (CC) who underwent photodynamic therapy (PDT) with either percutaneous transhepatic cholangioscopy (PTCS) or endoscopic retrograde cholangiopancreatography (ERCP). BACKGROUND DATA:PDT has been proposed as a promising therapy for treatment of unresectable hilar CC that is resistant to conventional standard treatment. However, few studies have compared the delivery methods of PDT in unresectable hilar CC patients. METHODS:Thirty-seven adult patients with advanced hilar CC were included in this study. Twenty-four patients treated with PTCS-directed PDT and 13 patients treated with ERCP-directed PDT were analyzed retrospectively. RESULTS:The PTCS- and ERCP-directed PDT groups were comparable with respect to age, gender, health status, pretreatment bilirubin levels, Bismuth type, and hilar CC stage. The length of hospital stay differed significantly (p < 0.001) between the two groups, with a median hospital stay of 37 days (range, 13-77 days) in the ERCP-directed PDT group versus 63 days (range, 23-125 days) in the PTCS-directed group. PTCS-directed PDT patients demonstrated an overall survival similar to that of ERCP-directed PDT patients, with a median survival of 11.6 versus 9.5 months, respectively (p = 0.96). Only lower pre-PDT bilirubin levels (p = 0.002) were a significant predictor of improved survival in all patients who underwent PDT, as determined by multivariate analysis. Median metal stent patency was similar between the groups [PTCS-directed PDT group (n = 8), 6.2 months; ERCP-directed PDT group (n = 7), 7.2 months; p = 0.642]. Survival after PTCS- or ERCP-directed PDT was not statistically different in patients with advanced hilar CC. CONCLUSIONS:Lower pre-PDT bilirubin levels were associated with longer survival in all patients.
Treatment of unresectable extrahepatic cholangiocarcinoma using hematoporphyrin photodynamic therapy: A prospective study.
Yang Jianfeng,Shen Hongzhang,Jin Hangbin,Lou Qifeng,Zhang Xiaofeng
Photodiagnosis and photodynamic therapy
BACKGROUND:The available evidence of Photodynamic therapy (PDT) combined with stent placement treatment for unresectable extrahepatic cholangiocarcinoma (EHCC) is still insufficient. It also remains unclear whether PDT influences systemic inflammatory response. AIM:To explore the clinical efficacy and safety of the combination treatment and the systemic inflammatory response in patients with EHCC. METHODS:Patients with unresectable EHCC underwent either the combined treatment using Hematoporphyrin PDT and stent placement (PDT+stent group, n=12) or stent-only (stent group, n=27). The primary end-point was overall survival. Tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels were measured. Quality of life was assessed using the Karnofsky performance scale (KPS) every 3 months. RESULTS:Average survival time (13.8 vs. 9.6 months), and 6-month (91.7% vs. 74.1%), and 1-year (58.3% vs. 3.7%) survival rates of PDT+stent group were significantly increased compared with the stent group. KPS scores in the PDT+stent group were significantly improved. TNF-α and IL-6 levels were significantly increased in the PDT+stent group. CONCLUSION:Hematoporphyrin-PDT combined with stent placement is an effective and safe treatment for EHCC. The treatment might promote systemic inflammatory response.
Success of photodynamic therapy in palliating patients with nonresectable cholangiocarcinoma: A systematic review and meta-analysis.
Moole Harsha,Tathireddy Harsha,Dharmapuri Sirish,Moole Vishnu,Boddireddy Raghuveer,Yedama Pratyusha,Dharmapuri Sowmya,Uppu Achuta,Bondalapati Naveen,Duvvuri Abhiram
World journal of gastroenterology
AIM:To perform a systematic review and meta-analysis on clinical outcomes of photodynamic therapy (PDT) in non-resectable cholangiocarcinoma. METHODS:Included studies compared outcomes with photodynamic therapy and biliary stenting (PDT group) biliary stenting only (BS group) in palliation of non-resectable cholangiocarcinoma. Articles were searched in MEDLINE, PubMed, and EMBASE. Pooled proportions were calculated using fixed and random effects model. Heterogeneity among studies was assessed using the statistic. RESULTS:Ten studies ( = 402) that met inclusion criteria were included in this analysis. The for χ heterogeneity for all the pooled accuracy estimates was > 0.10. Pooled odds ratio for successful biliary drainage (decrease in bilirubin level > 50% within 7days after stenting) in PDT BS group was 4.39 (95%CI: 2.35-8.19). Survival period in PDT and BS groups were 413.04 d (95%CI: 349.54-476.54) and 183.41 (95%CI: 136.81-230.02) respectively. The change in Karnofsky performance scores after intervention in PDT and BS groups were +6.99 (95%CI: 4.15-9.82) and -3.93 (95%CI: -8.63-0.77) respectively. Odds ratio for post-intervention cholangitis in PDT BS group was 0.57 (95%CI: 0.35-0.94). In PDT group, 10.51% (95%CI: 6.94-14.72) had photosensitivity reactions that were self-limiting. Subgroup analysis of prospective studies showed similar results, except the incidence of cholangitis was comparable in both groups. CONCLUSION:In palliation of unresectable cholangiocarcinoma, PDT seems to be significantly superior to BS alone. PDT should be used as an adjunct to biliary stenting in these patients.
One-Step Formulation of Targeted Aggregation-Induced Emission Dots for Image-Guided Photodynamic Therapy of Cholangiocarcinoma.
Li Min,Gao Yang,Yuan Youyong,Wu Yuzhe,Song Zifang,Tang Ben Zhong,Liu Bin,Zheng Qi Chang
Photodynamic therapy (PDT) is a palliative technique that can improve median survival with minimal invasion for cholangiocarcinoma (CC) patients. An ideal photosensitizer (PS) is critical to guarantee the efficacy of PDT. However, conventional PSs have some obvious drawbacks, such as lack of specificity and easy aggregation in aqueous media that limit their further application in the clinic. We herein fully take advantage of a red emissive aggregation-induced emission (AIE) PS to fabricate integrin αβ targeted organic AIE dots for image-guided PDT via a simple and straightforward one-step strategy. The obtained AIE dots exhibit high specificity to CC as well as excellent antitumor effect both in vitro and in vivo. Different from conventional PSs and previously reported PS-loaded nanostructures, the AIE dots do not suffer from aggregation-caused fluorescence quenching and reduction in reactive oxygen species production when the AIE PS molecules are in an aggregated state. The significant antitumor effect, as well as good biocompatibility and negligible toxicity, makes the AIE dots promising for future translational research in CC diagnosis and therapy.
A novel photodynamic therapy-based drug delivery system layered on a stent for treating cholangiocarcinoma.
Liang Po-Chin,Huang Kai-Wen,Tung Chien-Chih,Chang Ming-Chu,Chang Fuh-Yu,Wong Jau-Min,Chang Yu-Ting
This study aimed to investigate the drug delivery efficacy and bio-effectiveness of a novel photodynamic therapy (PDT)-matrix drug delivery system for cholangiocarcinoma (CCA). Metallic stents were coated with polyurethane (PU) as the first layer. A 2-hydroxyethyl methacrylate (2-HEMA)/ethylene glycol dimethacrylate (EGDMA)/benzoyl peroxide (BPO) layer and a poly(ethylene-co-vinyl acetate) (PEVA)/poly(n-butyl methacrylate) (PBMA)/polyvinylpyrrolidone K30 (K30) layer containing various concentrations of Photofrin were then incorporated onto the stent as the second and third layers. After incubating the layered membranes with cultured CCA cell line, the release of Photofrin, cell viability, the intracellular uptake of Photofrin, reactive oxygen species (ROS) generation, and apoptosis were determined. Using a single-layer diffusion model, the maximum release of Photofrin from the 5 to 10% K30 formulas was 80 and 100%, respectively, after 24 h. When using the multiple-layer diffusion model, the released Photofrin showed an initial burst of the loading dose from the PEVA/PBMA/K30 layer. In the immobilized model, less than 5% of the Photofrin from the 2-HEMA/EGDMA/BPO layer was released over the 24-h period. Cell viability decreased linearly with increasing Photofrin concentrations, and ROS generation and apoptosis were shown to increase significantly with increasing Photofrin concentrations, until the concentration of Photofrin reached a saturation point of 1.5 μg/ml. This new, multiple-layered, PDT-based stent with dual-release mechanisms is a promising treatment for CCA and cancer-related ductal stenosis.
Gemcitabine-loaded DSPE-PEG-PheoA liposome as a photomediated immune modulator for cholangiocarcinoma treatment.
Kim Da Hye,Im Byeong Nam,Hwang Hee Sook,Na Kun
To improve the therapeutic efficacy of gemcitabine (GEM) as an anticancer drug for bile duct cancer, GEM-loaded liposomes (GDPPL) prepared from a photosensitizer-conjugated lipid were investigated regarding the drug release kinetics, photodynamic therapy (PDT) efficacy, and immunomodulatory effects. The release rate of GEM from the liposomes was improved approximately 2-fold compared to non-laser irradiation groups due to lipid disruption by reactive oxygen species produced from the activated photosensitizer upon laser irradiation. Through in vitro testing using a human liver bile duct carcinoma cell line (HuCCT-1), the cytotoxicity of GDPPL with laser irradiation was enhanced due to rapid GEM release and PDT effects. Furthermore, the results of in vivo tests using a HuCCT-1 tumor-bearing xenograft mice model showed that GDPPL exhibited approximately 3-fold antitumoral effects compared to control group. Additionally, immunohistochemical analysis demonstrated the recruitment of immunostimulatory cells in tumor tissues. IHC tests in BALB/c mice indicated that GDPPL under laser irradiation dramatically enhanced the quantities of various immune cells for effective antitumoral immunotherapy against biliary tract cancer. From these results, it was concluded that GDPPL with rapid drug release behavior, PDT efficacy, and immunomodulatory effects upon laser irradiation has potential as an antitumor therapeutic agent for biliary tract cancer.
Combined treatment of nonresectable cholangiocarcinoma complicated by obstructive jaundice.
Shiryaev A A,Musaev G Kh,Levkin V V,Reshetov I V,Loshchenov M V,Alekseeva P M,Volkov V V,Linkov K G,Makarov V I,Shchekoturov I O,Borodkin A V,Loschenov V B
Photodiagnosis and photodynamic therapy
BACKGROUND:The five-year survival rate for successful surgical treatment of cholangiocellular cancer is only 20-40%, and in the case of an unresectable tumor, the life expectancy does not usually exceed 6 months. Survival decreases with the presence of jaundice, due to the spread of the tumor process along the bile ducts, leading to their obstruction. We report outcomes of patients with nonresectable bile duct carcinoma complicated by obstructive jaundice treated with Photodynamic Therapy (PDT). METHODS:Combined diagnosis and treatment included percutaneous cholangiostomy, intraductal video fluorescence diagnostics, photodynamic therapy, and bile duct stenting. All patients were treated at the Sechenov University Oncology Center in Moscow. The results of treatment of 33 patients have been presented. The intraductal diagnosis of malignant bile duct lesions was performed after cholangiostomy using the endovideofluorescence module for minimally invasive surgery and endoscopy. With the use of this method, it is the first time in Russia that it has become possible to obtain a videofluorescent image of the tumor and to determine the high level of photosensitizer accumulation in all cholangiocarcinoma patients. The preparations Photolon, Radachlorin, and Photosens were employed as photosensitizers (PS). Intraductal photodynamic therapy was used to achieve the antitumor effect. Laser power density was about 200 mW/cm. RESULTS:We present initial results, improved the diagnostic possibilities in this difficult localization of carcinoma, and demonstrated the feasibility of prolongation of life without significant deterioration of its quality. The average survival time in the treatment group is 9.5 months. CONCLUSION:The treatment of patients with nonresectable cholangiocarcinoma with Photodynamic Therapy should be an available option. In this context, the additional use of intraductal endovideofluorescence diagnostics is a highly specific technique that allows reliable detection of the photosensitizer accumulation predominantly by the tumor tissue and appears promising. As shown by our experience, flourescent localization followed by Photodynamic Therapy, enabled us to improve diagnostic techniques and treat the tumor with improved outcome.