Potential of photodynamic therapy in the management of infectious oral diseases

Photodynamic therapy(PDT)can take place in the presence of three elements:Light with an appropriate wavelength;a photosensitizer;and the presence of oxygen.This type of treatment is very effective overall against bacterial,viral and mycotic cells.In the last 10 years many papers have been published on PDT with different types of photosensitizers(e.g.,methylene blue,toluidine blue,indocyanine green,curcumin-based photosensitizers),different wavelengths(e.g.,460 nm,630 nm,660 nm,810 nm)and various parameters(e.g.,power of the light,time of illumination,number of sessions).In the scientific literature all types of PDT seem very effective,even if it is difficult to find a standard protocol for each oral pathology.PDT could be an interesting way to treat some dangerous oral infections refractory to common pharmacological therapies,such as candidiasis from multidrug-resistant Candida spp.

Antitumor effects of a novel photosensitizer-mediated photodynamic therapy and its influence on the cell transcriptome

Photodynamic therapy(PDT)is a promising cancer treatment.This study investigated the antitumor effects and mechanisms of a novel photosensitizer meso-5-[ρ-diethylene triamine pentaacetic acid-aminophenyl]−10,15,20-triphenyl-porphyrin(DTP)mediated PDT(DTP-PDT).Cell viability,reactive oxygen species(ROS),and apoptosis were measured with a Cell Counting Kit-8 assay,DCFH-DA fluorescent probe,and Hoechst staining,respectively.Cell apoptosis-and autophagy-related proteins were examined using western blotting.RNA sequencing was used to screen differentially expressed mRNAs(DERs),and bioinformatic analysis was performed to identify the major biological events after DTP-PDT.Our results show that DTP-PDT inhibited cell growth and induced ROS generation in MCF-7 and SGC7901 cells.The ROS scavenger N-acetyl-L-cysteine(NAC)and the P38 MAPK inhibitor SB203580 alleviated DTP-PDT-induced cytotoxicity.DTP-PDT induced cell apoptosis together with upregulated Bax and downregulated Bcl-2,which could also be inhibited by NAC or SB203580.The level of LC3B-Ⅱ,a marker of autophagy,was increased by DTP-PDT.A total of 3496 DERs were obtained after DTP-PDT.Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that DERs included those involved in cytosolic ribosomes,the nuclear lumen,protein binding,cell cycle,protein targeting to the endoplasmic reticulum,and ribosomal DNA replication.Disease Ontology and Reactome enrichment analyses indicated that DERs were associated with a variety of cancers and cell cycle checkpoints.Protein-protein interaction results demonstrated that cdk1 and rps27a ranked in the top 10 interacting genes.Therefore,DTP-PDT could inhibit cell growth and induce cell apoptosis and autophagy,partly through ROS and the P38 MAPK signaling pathway.Genes associated with the cell cycle,ribosomes,DNA replication,and protein binding may be the key changes in DTP-PDT-mediated cytotoxicity.

Enhancing the Photosensitivity of Hypocrellin A by Perylene Diimide Metallacage‑Based Host–Guest Complexation for Photodynamic Therapy

The development of supramolecular hosts which can efficiently encapsulate photosensitizers to improve the photodynamic efficacy holds great promise for cancer therapy.Here,we report two perylene diimide-based metallacages that can form stable host–guest complexes with planar conjugated molecules including polycyclic aromatic hydrocarbons and photosensitizers(hypocrellin A).Such host–guest complexation not only prevents the aggregation of photosensitizers in aqueous environments,but also offers fluorescence resonance energy transfer(FRET)from the metallacage to the photosensitizers to further improve the singlet oxygen generation(Φ_(Δ)=0.66).The complexes are further assembled with amphiphilic polymers,forming nanoparticles with improved stability for anticancer study.Both in vitro and in vivo studies indicate that the nanoparticles display excellent anticancer activities upon light irradiation,showing great potential for cancer photodynamic therapy.This study provides a straightforward and effective approach for enhancing the photosensitivity of conventional photosensitizers via host–guest complexation-based FRET,which will open a new avenue for host–guest chemistry-based supramolecular theranostics.

Anti-PD1 antibody and not anti-LAG-3 antibody improves the antitumor effect of photodynamic therapy for treating metastatic breast cancer

Photodynamic therapy(PDT)has limited effects in treating metastatic breast cancer.Immune checkpoints can deplete the function of immune cells;however,the expression of immune checkpoints after PDT is unclear.This study investigates whether the limited e±cacy of PDT is due to upregulated immune checkpoints and tries to combine the PDT and immune checkpoint inhibitor to observe the e±cacy.A metastatic breast cancer model was treated by PDT mediated by hematoporphyrin derivatives(HpD-PDT).The anti-tumor effect of HpD-PDT was observed,as well as CD4þT,CD8þT and calreticulin(CRT)by immunohistochemistry and immunofluorescence.Immune checkpoints on T cells were analyzed byflow cytometry after HpD-PDT.When combining PDT with immune checkpoint inhibitors,the antitumor effect and immune effect were assessed.For HpD-PDT at 100 mW/cm2 and 40,60 and 80 J/cm2,primary tumors were suppressed and CD4þT,CD8þT and CRT were elevated;however,distant tumors couldn't be inhibited and survival could not be prolonged.Immune checkpoints on T cells,especially PD1 and LAG-3 after HpD-PDT,were upregulated,which may explain the reason for the limited HpD-PDT effect.After PDT combined with anti-PD1 antibody,but not with anti-LAG-3 antibody,both the primary and distant tumors were signi-cantly inhibited and the survival time was prolonged,additionally,CD4þT,CD8þT,IFN-þCD4þT and TNF-þCD4þT cells were signi-cantly increased compared with HpD-PDT.HpD-PDT could not combat metastatic breast cancer.PD1 and LAG-3 were upregulated after HpD-PDT.Anti-PD1 antibody,but not anti-LAG-3 antibody,could augment the antitumor effect of HpD-PDT for treating metastatic breast cancer.

Tissue optical clearing enhances efficacy of vascular targeted photodynamic therapy of mouse dorsal skin

Vascular-targeted photodynamic therapy(V-PDT)is an effective treatment for port wine stains(PWS).However,repeated treatment is usually needed to achieve optimal treatment outcomes,possibly due to the limited treatment light penetration depth in the PWS lesion.The optical clearing technique can increase light penetration in depth by reducing light scattering.This study aimed to investigate the V-PDT in combination with an optical clearing agent(OCA)for the therapeutic enhancement of V-PDT in the rodent skinfold window chamber model.Vascular responses were closely monitored with laser speckle contrast imaging(LSCI),optical coherence tomography angiography,and stereo microscope before,during,and after the treatment.We further quantitatively demonstrated the effects of V-PDT in combination with OCA on the blood flow and blood vessel size of skin microvasculature.The combination of OCA and V-PDT resulted in significant vascular damage,including vasoconstriction and the reduction of blood flow.Our results indicate the promising potential of OCA for enhancing V-PDT for treating vascular-related diseases,including PWS.

Nanoparticle-mediated synergistic anticancer effect of ferroptosis and photodynamic therapy:Novel insights and perspectives

Current antitumor monotherapy has many limitations,highlighting the need for novel synergistic anticancer strategies.Ferroptosis is an iron-dependent form of nonapoptotic cell death that plays a pivotal regulatory role in tumorigenesis and treatment.Photodynamic therapy(PDT)causes irreversible chemical damage to target lesions and is widely used in antitumor therapy.However,PDT’s effectiveness is usually hindered by several obstacles,such as hypoxia,excess glutathione(GSH),and tumor resistance.Ferroptosis improves the anticancer efficacy of PDT by increasing oxygen and reactive oxygen species(ROS)or reducing GSH levels,and PDT also enhances ferroptosis induction due to the ROS effect in the tumor microenvironment(TME).Strategies based on nanoparticles(NPs)can subtly exploit the potential synergy of ferroptosis and PDT.This review explores recent advances and current challenges in the landscape of the underlyingmechanisms regulating ferroptosis and PDT,as well as nano delivery system-mediated synergistic anticancer activity.These include polymers,biomimetic materials,metal organic frameworks(MOFs),inorganics,and carrier-free NPs.Finally,we highlight future perspectives of this novel emerging paradigm in targeted cancer therapies.

Innovative strategies for photodynamic therapy against hypoxic tumor

Photodynamic therapy(PDT)is applied as a robust therapeutic option for tumor,which exhibits some advantages of unique selectivity and irreversible damage to tumor cells.Among which,photosensitizer(PS),appropriate laser irradiation and oxygen(O_(2))are three essential components for PDT,but the hypoxic tumor microenvironment(TME)restricts the O_(2) supply in tumor tissues.Even worse,tumor metastasis and drug resistance frequently happen under hypoxic condition,which further deteriorate the antitumor effect of PDT.To enhance the PDT efficiency,critical attention has been received by relieving tumor hypoxia,and innovative strategies on this topic continue to emerge.Traditionally,the O_(2) supplement strategy is considered as a direct and effective strategy to relieve TME,whereas it is confronted with great challenges for continuous O_(2) supply.Recently,O_(2)-independent PDT provides a brand new strategy to enhance the antitumor efficiency,which can avoid the influence of TME.In addition,PDT can synergize with other antitumor strategies,such as chemotherapy,immunotherapy,photothermal therapy(PTT)and starvation therapy,to remedy the inadequate PDT effect under hypoxia conditions.In this paper,we summarized the latest progresses in the development of innovative strategies to improve PDT efficacy against hypoxic tumor,which were classified into O_(2)-dependent PDT,O_(2)-independent PDT and synergistic therapy.Furthermore,the advantages and deficiencies of various strategies were also discussed to envisage the prospects and challenges in future study.

Photodynamic therapy with TBZPy regulates the PI3K/AKT and endoplasmic reticulum stress-related PERK/eIF2α pathways in HeLa cells

Background:((1-triphenylaminebenzo[c][1,2,5]thiadiazole-4-yl)styryl)-1-methylpyridin methylpyridin-1-ium iodide salt(TBZPy)is a novel photosensitizer that displays excellent photodynamic properties.However,There are few reports on the mechanism of action of the TBZPy photodynamic.Previous studies revealed that photodynamic therapy(PDT)could induce endoplasmic reticulum stress by acting on the endoplasmic reticulum.Therefore,in this study,we investigated the effects of endoplasmic reticulum stress induced by TBZPy-PDT in treating High-risk human papillomavirus(HR-HPV)infection and their underlying mechanisms.Methods:The human cervical cancer cell line HeLa(containing whole genome of HR-HPV18)was treated with TBZPy-PDT.Cell migration,invasion,and colony-forming ability were evaluated using wound-healing,Transwell invasion,and colonyforming assays,respectively.Through western blot analysis,we determined the level of expression of the PI3K/AKT and PERK/eIF2αpathway proteins and the proteins associated with calcium trafficking and apoptosis.The calcium levels in the cytoplasm were detected via flow cytometry.Results:The result shows that TBZPy-PDT could inhibite the migration,invasion,and colony forming ability of infected HeLa cells by downregulating the PI3K/AKT pathway in vitro.And we found that TBZPy-PDT induced endoplasmic reticulum stress-specific apoptosis via the PERK/eIF2αpathway.Moreover,TBZPy-PDT increased the levels of calcium and calmodulin,while decreasing the levels of endoplasmic reticulum calcium-binding proteins.Conclusions:TBZPy-PDT is effective on treating human papillomavirus-infected cells.Targeting the PI3K/AKT and PERK/eIF2αpathways and the endoplasmic reticulum stress process may help improve the effects of TBZPy-PDT for treating high-risk human papillomavirus infection.

Advances in photodynamic therapy for port-wine stain and our experience

Port-wine stain(PWS)is a congenital capillary malformation that occurs in 0.3%–0.5%of newborns.The pulsed dye laser is the current gold standard treatment for PWS;however,its efficacy is poor.Photosensitizer photodynamic therapy(PDT)is considered a promising treatment for PWS.Here we provide a comprehensive overview of PDT.

Clinical Study of Photodynamic Therapy for Upper Gastrointestinal Tract Cancers

Objective： To evaluate the clinical effectiveness and adverse effects of photodynamic therapy （PDT） for the upper gastrointestinal tract cancers. Methods： 56 patients with upper gastrointestinal cancers in different clinical stages were treated with PDT. Diode laser （630 nm） was used as the light source and the parameters were as follows： power density 200 to 400 mW/cm, energy density 100 to 300 J/cm. PHOTOFRIN was used as photosensitizer, which was given in a dose of 2 mg/kg intravenously 12-24 h before irradiation. Results： Evaluation of the 56 patients＇ therapeutic effectiveness showed that 6 patients （10.7%） had a complete response （CR）, 33 patients （58.9%） partial response （PR）, 12 patients （21.4%） mild response （MR）, and 5 patients （8.9%） no response （NR）. The total response rate （CR＋PR） was 69.6%. No patients had severe adverse effects in this group. Conclusion： PDT is an effective and safe palliative modality for upper gastrointestinal tract cancers.

Low-fluence photodynamic therapy combinations in the treatment of exudative age-related macular degeneration

AIM:To compare the efficacy of low-fluence photodynamic therapy(PDT) combinations in the treatment of age-related macular degeneration(AMD).· METHODS:Forty-five previously untreated eyes of 45 patients with exudative AMD whose best-corrected visual acuity(BCVA) was ≥0.3(Snellen) were enrolled.15 patients in Group I underwent low-fluence PDT(25J/cm2-300mW/cm2-83sec) and intravitreal pegaptanib combination,15 patients in Group II underwent PDT(50J/cm2-600mW/cm2-83sec) and intravitreal pegaptanib combination while,15 patients in Group III underwent intravitreal pegaptanib monotherapy.Complete ophthalmologic examinations were performed in pre and post treatment visits,and the results were statistically analised.A clinical activity score(CAS) was calculated by using changes in lesion size,amount of hemorrhage,staining pattern in FA and OCT measurement of intra/subretinal fluid.≤3 logMAR lines of decrease in BCVA and decrease in CAS were considered as successful treatment.· RESULTS:The mean age of 19 female(42.2%) and 26 male(57.8%) patients was(72.82±8.02) years.Mean follow-up was(13.93±5.87) months.Lesion type was occult in 28 eyes(62.2%).Treatment success rates according to BCVA assessments were 86.7%,80%,60% and mean BCVA decrease were 0.3,1.0,2.2 logMAR lines in Group I,II and III,respectively(P >0.05).According to the changes in central macular thickness and CAS,no difference was found among the study groups(P =0.850 and P =0.811,respectively).Patients treated with combination regimens had lower intravitreal injection frequencies(P =0.015).· CONCLUSION:Combination regimen with intravitreal pegaptanib and low-fluence PDT seems to be safe and effective in stabilizing the clinical activity and BCVA in exudative AMD.·

Recent Advances in Tumor Microenvironment Hydrogen Peroxide-Responsive Materials for Cancer Photodynamic Therapy

Photodynamic therapy(PDT),as one of the noninvasive clinical cancer phototherapies,suffers from the key drawback associated with hypoxia at the tumor microenvironment(TME),which plays an important role in protecting tumor cells from damage caused by common treatments.High concentration of hydrogen peroxide(H2O2),one of the hallmarks of TME,has been recognized as a double-edged sword,posing both challenges,and opportunities for cancer therapy.The promising perspectives,strategies,and approaches for enhanced tumor therapies,including PDT,have been developed based on the fast advances in H2O2-enabled theranostic nanomedicine.In this review,we outline the latest advances in H2O2-responsive materials,including organic and inorganic materials for enhanced PDT.Finally,the challenges and opportunities for further research on H2O2-responsive anticancer agents are envisioned.

Success of photodynamic therapy in palliating patients with nonresectable cholangiocarcinoma: A systematic review and meta-analysis

To perform a systematic review and meta-analysis on clinical outcomes of photodynamic therapy (PDT) in non-resectable cholangiocarcinoma.METHODSIncluded studies compared outcomes with photodynamic therapy and biliary stenting (PDT group) vs 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 I2 statistic.RESULTSTen studies (n = 402) that met inclusion criteria were included in this analysis. The P for χ2 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 vs 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 vs 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.CONCLUSIONIn 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.

Human natural killer cells for targeting delivery of gold nanostars and bimodal imaging directed photothermal/photodynamic therapy and immunotherapy

Objective:To construct a novel nanoplatform GNS@CaCO3/Ce6-NK by loading the CaCO3-coated gold nanostars(GNSs)with Chlorin e6 molecules(Ce6)into human peripheral blood mononuclear cells(PBMCs)-derived NK cells for tumor targeted therapy.Methods:GNS@CaCO3/Ce6 nanoparticles were prepared and characterized by TEM and UV-vis.The cell surface markers and cytokines secretion of NK cells before and after loading the GNS@CaCO3/Ce6 nanoparticles were detected by Flow Cytometry(FCM)and ELISA.Effects of the GNS@CaCO3/Ce6-NK cells on A549 cancer cells was determined by FCM and CCK-8.Intracellular fluorescent signals of GNS@CaCO3/Ce6-NK cells were detected via Confocal laser scanning microscopic(CLSM)and FCM at different time points.Intracellular ROS generation of GNS@CaCO3/Ce6-NK cells under laser irradiation were examined by FCM.The distribution of GNS@CaCO3/Ce6-NK in A549 tumor-bearing mice were observed by fluorescence imaging and PA imaging.The combination therapy of GNS@CaCO3/Ce6-NK under laser irradiation were investigated on tumor-bearing mice.Results:The coated CaC03 shell on the surface of GNSs exhibited prominent delivery and protection effect of Ce6 during the cellular uptake process.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells possessed bimodal functions of fluorescence imaging and photoacoustic imaging.The as-prepared multifunctional GNS@CaCO3/Ce6-NK cells could actively target tumor tissues with the enhanced photothermal/photodynamic therapy and immunotherapy.Conclusions:The GNS@CaCO3/Ce6-NK shows effective tumor-targeting ability and prominent therapeutic efficacy toward lung cancer A549 tumor-bearing mice.Through fully utilizing the features of GNSs and NK cells,this new nanoplatform provides a new synergistic strategy for enhanced photothermal/photodynamic therapy and immunotherapy in the field of anticancer development in the near future.

Photodynamic therapy prolongs metal stent patency in patients with unresectable hilar cholangiocarcinoma

AIM:To evaluate the effect of photodynamic therapy (PDT) on metal stent patency in patients with unresectable hilar cholangiocarcinoma (CC). METHODS:This was a retrospective analysis of patients with hilar CC referred to our institution from December, 1999 to January, 2011. Out of 232 patients, thirty-three patients with unresectable hilar CC were treated. Eighteen patients in the PDT group were treated with uncovered metal stents after one session of PDT. Fifteen patients in the control group were treated with metal stents alone. Porfimer sodium (2 mg/kg) was administered intravenously to PDT patients. Fortyeight hours later, PDT was administered using a diffusing fiber that was advanced across the tumor by either endoscopic retrograde cholangiopancreatography or percutaneous cholangiography. After performance of PDT, uncovered metal stents were inserted to ensure adequate decompression and bile drainage. Patient survival rates and cumulative stent patency were calculated using Kaplan-Meier analysis with the log-rank test. RESULTS:The PDT and control patients were comparable with respect to age, gender, health status, pretreatment bilirubin, and hilar CC stage. When compared to control, the PDT group was associated with significantly prolonged stent patency (median 244 ± 66 and 177 ± 45 d, respectively, P = 0.002) and longer patient survival (median 356 ± 213 and 230 ± 73 d, respectively, P = 0.006). Early complication rates were similar between the groups (PDT group 17%, control group 13%) and all patients were treated conservatively. Stent malfunctions occurred in 14 PDT patients (78%) and 12 control patients (80%). Of these 26 patients, twenty-two were treated endoscopically and four were treated with external drainage. CONCLUSION:Metal stenting after one session of PDT may be safe with acceptable complication rates. The PDT group was associated with a significantly longer stent patency than the control group in patients with unresectable hilar CC.

Combined therapy with bevacizumab and photodynamic therapy for myopic choroidal neovascularization: A oneyear follow-up controlled study

AIMTo evaluate the efficacy and safety of a combined treatment for myopic choroidal neovascularization (CNV) using photodynamic therapy (PDT) and intravitreal bevacizumab and to compare it with intravitreal bevacizumab monotherapy.

Safety and efficacy of photodynamic therapy using BCECF-AM compared to mitomycin C in controlling post-operative fibrosis in a rabbit model of subscleral trabeculectomy

AIM： To evaluate the safety and efficacy of cellular photoablation using BCECF-AM [2, T-bis-（2-carboxyethyl） -5-（and-6）-carboxyfluorescein, acetoxymethyl ester mixed isomersl as a method to control postoperative fibrosis in subscleral trabeculectomy （SST） compared to mitomycin C （MMC） in a rabbit model. METHODS： A comparative prospective case-control animal study was conducted. Fourteen rabbits were subjected to SST with intraoperaUve use of wound modulating agents （MMC or BCECF-AM） of the right eye （study groups I and II respectively） and SST without use of intraoperative wound modulating agents for the left eye （control group II）. Two rabbits 4 eyes were considered as control group I with no surgical intervention. BCECF-AM was injected subconjunctivally 30min before surgery followed by intraoperative illumination with diffuse blue light for 10min. Antifibrotic efficacy was established by clinical response and histological examination. Clinical response was assessed by measuring intraocular pressure （lOP） at day 1, 3, 5, 7, 14, 21 postoperatively, Success was defined by 〉20.0% reduction in lOP from the preoperative values without anti-glaucoma medications. RESULTS： The mean percentage of reduction was 35.0% in the study group I with only one eye （14.3%） had 12.5% reduction. The mean percentage of reduction was 28.0% in the study group U with two eyes （28.6%） in study group II had 14.2% reduction each. Regarding the control group II, the mean percentage of reduction was 14.3% with 64.3% eyes had 〈20.0% reduction. There was a highly statistically significant difference between each of the study groups （right eyes） and the corresponding control group II （left eyes） as regards the mean postoperative lOP values started from day 5 in both study groups and this highly significant difference remained so till the end of the follow up period. Histologically, MMC treated blebs showed thinning of conjunctival epithelium with marked reduction of the goblet cells relative to control. Marked sub-epithelial edema was seen along with variable collagen dispersion. Mild cellularity was noted in sub-epithelial tissue. BCECF-AM treated blebs showed normal conjunctival epithelial thickness with abundant goblet cells. Mild sub- epithelial edema was noted along with moderate collagen dispersion. No histological abnormality was noted in the ciliary body or the cornea in any of the studied groups. CONCLUSION： Cellular photoablation using BCECF-AM is a safe and effective wound modulating agent to control postoperative fibrosis in trabeculectomy. However MMC considered as a more potent adjuvant to trabeculectomy than BCECF-AM in promoting IOP reduction.

Combination of ranibizumab with photodynamic therapy vs ranibizumab monotherapy in the treatment of age-related macular degeneration: a systematic review and meta-analysis of randomized controlled trials

AIM:To compare the efficacy and safety of combination of ranibizumab with photodynamic therapy(PDT)vs ranibizumab monotherapy in the treatment of age-related macular degeneration(AMD).METHODS:The Cochrane Central Register of Controlled Trials(CENTRAL)in the Cochrane Library,Pubmed,and Embase were searched.There were no language or data restrictions in the search for trials.Only randomized controlled trials(RCTs)were included.Methodological quality of the literatures was evaluated according to the Jadad Score.RevMan 5.2.6 software was used to do the meta-analysis.RESULTS:Seven studies were included in our systematic review,among which four of them were included in quantitative analysis.The result shows that the ranibizumab monotherapy group had a better mean best corrected visual acuity(BCVA)change vs baseline at month 12 compared with that of the combination treatment group,and the statistical difference was significant(WMD,-2.61;95%CI,-5.08 to-0.13;P=0.04).However,after the removal of one study,the difference between the two groups showed no significant difference(WMD,-2.29;95%CI,-4.81 to 0.23;P=0.07).Meanwhile,no significant central retinal thickness(CRT)reduction was found in the combination treatment group and the ranibizumab monotherapy group at 12 months follow-up.Nevertheless,the combination group tended to have a greater reduction in CRT(WMD,-4.13μm;95%CI,-25.88to 17.63,P=0.71).The proportion of patients gaining more than 3 lines at month 12 in the ranibizumab group was higher than in the combination group and there was a significant difference(RR,0.72;95%CI,0.54 to 0.95;P=0.02).Whereas there was no significant difference for the proportion of patients gaining more than 0 line at month12 between the two groups(RR,0.93;95%CI,0.76 to1.15;P=0.52).The general tendency shows a reduction in ranibizumab retreatment number in the combination treatment group compared with the ranibizumab monotherapy group.As major adverse events,the differences in the number of eye pain,endophthalmitis,hypertension and arterial thromboembolic events were not significant between the two groups,and the incidence of serious adverse events in the two groups was very low.CONCLUSION:For the maintenance of vision,the comparison of the combination of ranibizumab with PDT vs ranibizumab monotherapy shows no apparent difference.Compared with the combination of ranibizumab and PDT,patients treated with ranibizumab monothearpy may gain more visual acuity(VA)improvement.The combination treatment group had a tendency to reduce the number of ranibizumab retreatment.Both the two treatment strategies were well tolerated.

Synergetic anticancer effect of combined gemcitabine and photodynamic therapy on pancreatic cancer in vivo

AIM： To investigate the anti-tumor effects of combined cytotoxic drug （gemcitabine） and photodynamic therapy （PDT） on human pancreatic cancer xenograft in nude mice.METHODS： Human pancreatic cancer cell line SW1990 was used in the investigation of the in vivo effect of combined gemcitabine and PDT on human pancreatic cancer xenograft in mice. Sixty mice were randomly allocated into a control group （without treatment）, photosensitizer treatment group （2 mg/kg photosan, without illumination）, chemotherapy group （50 mg/kg gemcitabine i.p.）, PDT group （2 mg/kg photosan ＋ laser irradiation） and combined treatment group （photosan ＋ chemotherapy）, with 12 mice in each group. Tumor size was measured twice every week. Anti-tumor activity in different groups was evaluated by tumor growth inhibition （TGI）RESULTS： No significant anti-tumor effect was observed either in photosensitizer treatment group or in chemotherapy group. PDT led to necrosis in cancer lesions and significantly reduced tumor volume compared with photosensitizer on day 6 and at the following time points after initialization of therapy （0.24 ± 0.15-0.49 ± 0.08 vs 0.43 ± 0.18-1.25± 0.09, P 〈 0.05）. PDT significantly reduced tumor volume in combined treatment group compared with photosensitizer treatment group （0.12 ± 0.07-0.28 ± 0.22 vs 0.39 ± 0.15-2.20 ± 0.12, P 〈 0.05）, small dose chemotherapy group （0.12 ± 0.07-0.28 ± 0.12 vs 0.32 ± 0.14-1.16 ± 0.08, P 〈 0.05） and control group （0.12 ± 0.07-0.28 ± 0.12 vs 0.43 ± 0.18-1.25 ± 0.09, P 〈 0.05）. TGI was higher in the combined treatment group （82.42%） than in the PDT group （58.18%）.CONCLUSION： PDT has a significant anti-tumor effect, which is maintained for a short time and can be significantly enhanced by small doses of gemcitabine.

Effects of Photodynamic Therapy on the Ultrastructure of Glioma Cells

To study the change in ultrastructure of C6 glioma cells after photodynamic therapy （PDT）, to compare morphological differences in necrosis and apoptosis before and after PDT treatment, and to evaluate the effect of photodynamic therapy on the blood brain tumor barrier （BTB） of C6 glioma. Methods The model was produced by transplanting C6 glioma cells cultured in vitro using Peterson method into the caudate nuclei of Wister rats. The experiment group received PDT for two weeks after the operation. The sub-cellular structure, blood-brain-barrier （BBB） and BTB in both groups were observed under electron microscope. Results Apoptosis in different phases and necrosis could be observed in some C6 glioma cells. Swelling occurred on the ultrastructure of cellular organs such as mitochondria and endoplasmic reticulum in most of the cells. Damage to the BTB, reduction of the number of cellular organs in endothelial cells of the capillary blood vessels, stretch of the tight junction, and enlargement of the gaps between endothelial cells were also seen in the experiment group. Meanwhile, limited impact on the normal sub-ceUular structures and BBB was observed. Conclusion PDT could induce apoptosis and necrosis of C6 glioma cells due to the damage to the ultrastructure of mitochondria and endoplasmic reticulum. The weakened function of C6 glioma BTB initiated by PDT makes it possible to perform a combined therapy of PDT and chemotherapy for glioma.