Combined Treatment Of Photodynamic Therapy Research Articles

Photodynamic Therapy and Its Synergism with Melittin Against Drug-Resistant Acinetobacter baumannii Isolates with High Biofilm Formation Ability.

Drug-resistant biofilm producer A. baumannii isolates are a global concern that warns researchers about the development of new treatments. This study was designed to analyze the effect of photodynamic therapy (PDT) as monotherapy and associated with melittin on multidrug-resistant A. baumannii isolates. Sub-lethal doses of photosensitizer, LED, and PDT were determined. The PDT effect on the biofilm and expression of biofilm-associated genes was evaluated by scanning electron microscopy and quantitative real-time PCR (qRT-PCR) methods, respectively. The synergistic effect of PDT and melittin on the survival of MDR/XDR strong biofilm producer isolates was evaluated by checkerboard assay. Survival rates were significantly decreased at the lowest concentration of 12.5-50μg/ml in 4min at an energy density of 93.75J/cm2 (P < 0.05). The optimized PDT method had a bactericidal effect against all tested groups, and the mean expression levels of csu, abaI, bap, and ompA genes in the strong biofilm producers were decreased significantly compared to the control group. The combined effect of LED and melittin successfully reduced the MDR/XDR A. baumannii strong biofilm producers' growth from 3.1 logs. MB-mediated aPDT and combined treatment of PDT with melittin, which has been investigated for the first time in this study, can be an efficient strategy against MDR/XDR A. baumannii isolates with strong biofilm production capacity.

Near-infrared light (NIR)-responsive nanoliposomes combining photodynamic therapy and chemotherapy for breast tumor control

Light-responsive carriers have been used for the controlled release of antitumor drugs in recent years. However, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug release, and ultraviolet light would cause cellular damage. Near-infrared light has a deeper tissue-penetration depths and minimal harm to tissues, but it is difficult to cleave the chemical bond directly. The aim of this study is to develop a novel near-infrared light-responsive carrier for local release of antitumor drugs. Unsaturated phospholipids can be oxidized by singlet oxygen to achieve liposomal drug release, and singlet oxygen can be produced by photosensitizer under light irradiation. A new near-infrared light-responsive nanoliposome was designed that imparts light-triggered local drug release. Nanoliposomes, which were composed of matrix phospholipids and unsaturated phospholipids, were prepared by ammonium sulfate gradient method, and loaded with antitumor drug doxorubicin (DOX) and photosensitizer 1,4,8,11,15,18,22,25-octabutoxypalladium phthalocyanine. Under near-infrared light, photosensitizers could produce singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the unsaturated phospholipids were oxidized by singlet oxygen and result in DOX release, causing sustained cell damage by chemotherapy. Near-infrared light-responsive nanoliposomes exhibit enhanced anticancer activity owing to combined treatment of photodynamic therapy and chemotherapy. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy.

Synergistic antimicrobial effect of photodynamic therapy and chitosan on the titanium-adherent biofilms of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa: An in vitro study.

To date, no studies on the combined use of photodynamic therapy (PDT) and chitosan against peri-implantitis have been published. The aim of this study was to evaluate the possible synergistic antimicrobial effect of PDT and chitosan on the titanium-adherent biofilms of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa. A total of 60 titanium discs were included in this study. The discs were randomized into three bacterial contaminations (n=20 discs per bacterium). After being cultured (incubated for 48hours) they were randomized again into four different disinfection modalities (n=5 discs per treatment): control (without treatment), PDT, chitosan 3mg/mL, and PDT + chitosan 3mg/mL. After the treatments, the colony forming units (CFU) were measured to determine antimicrobial effects, and field emission scanning electron microscopy (FESEM) was used to study cell morphology and titanium adherence. For all the evaluated bacteria and all the variables studied the order from highest to lowest antimicrobial effectiveness was: PDT + chitosan 3mg/mL>chitosan 3mg/mL>PDT>control. Although, all disinfection methods were significantly effective when compared to control, the combined treatment of PDT + chitosan 3mg/mL had the greatest antimicrobial effect against the three studied bacteria. The combination of PDT and chitosan has a synergistic antimicrobial effect against the bacteria S. aureus, E. coli, and P. aeruginosa, all closely related to peri-implantitis. However, further in vivo studies are needed because this study provides data based on an in vitro scenario that might not be extrapolated to patients with peri-implantitis.

H2O2/O2 self-supplementing and GSH-depleting Ca2+ nanogenerator with hyperthermia-triggered, TME-responsive capacities for combination cancer therapy

The tumor microenvironment (TME) is complex in composition and unique in nature, and is closely related to the growth, invasion and metastasis of tumor cells. Improving and remodeling the TME to return it to a normalized state can fundamentally disrupt the environment and/or nutrient supply on which tumor cells depend. To achieve this goal, based on the unique physicochemical properties and biological effects of CaO2, we designed and constructed a Ca2+ nanogenerator (named as CaO2-Cu/ICG@PCM) that enables H2O2/O2 self-supplementation and GSH depletion. The 808 nm laser induces the heat generation of photosensitizer indocyanine green (ICG) to initiate a series of reactions, followed by the production of copper ions, H2O2, O2 and large amounts of Ca2+, which can eventually lead to the combined treatment of photodynamic therapy (PDT), chemodynamic therapy (CDT) and calcium overload. Additionally, the reaction process is accompanied by the generation of Ca(OH)2, which greatly improves the acidic environment of TME and effectively promotes the oxidation process of GSH by H2O2, achieving the purpose of remodeling TME. It is worth mentioning that a large amount of free Ca2+ accumulating in tumor cells can rapidly initiate the process of calcium overload and calcification, which can not only play a role in tumor suppression, but also assist CT imaging to detect the effect of treatment. Thus, CaO2-Cu/ICG@PCM could be a promising candidate for bioimaging and tumor therapy.

The cover photo shows different neovascularization types from the paper by Smid et al.

The cover photo shows different neovascularization types from the paper by Smid et al.

Near-Infrared Light-Initiated Upconversion Nanoplatform with Tumor Microenvironment Responsiveness for Improved Photodynamic Therapy.

Photodynamic therapy (PDT) is inflowing the mainstream of the cancer treatments, yet the shallow light penetration, thermal damage to normal cells, poor tumor targeting, and skin phototoxicity compromised the PDT efficacy. This paper designed and prepared an upconversion nanoplatform that could effectively convert 808 nm NIR light to red and green light emission, both of which could excite photosensitizers and exert the PDT curative effects. A thin layer of mesoporous silica covering core-shell nanostructure NaGdF4:Yb,Er@NaGdF4:Yb,Nd upconversion nanoparticles was prepared as the carrier to load the photosensitizer pyropheophorbide-a (PPa), which could be excited by green and red light simultaneously and produce high singlet oxygen (1O2) quantum yield (79.1%). Meanwhile, the chemotherapy drug doxorubicin (DOX) was absorbed in the pores of the SiO2 layer to improve the therapeutic effect, and the folic acid-coupled chitosan (Cs-FA) was modified on the surface of the SiO2 layer to obtain the targeting and biocompatible UCNP@SiO2/PPa&DOX@Cs-FA nanoplatform. The physically adsorbed DOX in the pore channel could be released slowly under faintly acidic or GSH stimuli (84% release of DOX after 16 h), suggesting that the nanoplatform was responsive to the tumor microenvironment. In vitro experiments showed that the combined treatment of PDT and DOX was superior to that of PDT alone or DOX chemotherapy alone, implying a synergistic therapeutic effect. The morphological changes and dye staining research of HeLa cells were consistent with the MTT assay. Therefore, this research provided a strategy for the development of an efficient and safe multifunctional cancer treatment nanoplatform integrating low-intensity light excitation, slow release, targeting, photodynamic therapy, and chemotherapy.

Clinical characters and treatments of retinal vasoproliferative tumors

Retinal vasoproliferative tumors (VPT) are uncommon benign vascular tumors. They mostly occur in healthy patients, but may be associated with other chorioretinal diseases. Here we report four patients with VPT at a referral center from 2006 to 2015. Three patients denied any past history and one had a history of retinal detachment surgery. VPT-related complications included epiretinal membrane (ERM) (n=2), cystoids macular edema (n=1), and lamellar hole combined with dense cataract, rigid anterior capsule and vitreous opacity (n=1). Treatments for VPT and comorbidities included vitrectomy (VT) and membrane peeling with tumor resection (n=2), a combined treatment of photodynamic therapy (PDT) and intravitreal injection (IVI) of anti-vascular endothelial growth factor (anti-VEGF) (n=2). Tumor shrinkage was achieved in both patients treated with PDT and IVI of anti-VEGF injection. The other two patients with ERM were successfully treated with VT and tumor resection. Visual acuity improved at least two lines in three patients, and one patient had decreased vision due to cataract formation after VT. Pathology of the resected tumor in one case revealed massive gliosis with positive stain of vascular endothelial cells and glial fibrillary acidic protein stain. Yet the peeled membrane was acellular. Possible beneficial treatments for VPT and comorbidities include PDT combined with IVI of anti-VEGF, or VT and membrane peeling with tumor resection.

Primary Combined Photodynamic Therapy and Intravitreal Bevacizumab Injection for Neovascular Age-related Macular Degeneration

Purpose: To investigate the efficacy of the combined treatment of photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab in patients with neovascular age-related macular degeneration. Methods: Forty-five eyes received a single session of PDT following three intravitreal bevacizumab (1.25 mg) injections at six-week intervals (IVB+PDT group). Twenty-seven eyes received three intravitreal bevacizuamb (1.25 mg) injections only at six-week intervals (IVB group). Results: After the six months of follow up, the mean BCVA (LogMAR) changed significantly from 0.620.34 to 0.560.33 in the IVB group (p=0.03) and from 0.610.33 to 0.480.21 in the IVB+PDT group (p=0.001). The mean BCVA was more improved in the IVB+PDT group (p=0.049). The mean CMT changes were significant in both groups immediately after treatment, but there was no significant difference at six months between the two groups. Ten eyes (37.0%) in the IVB group and 12 eyes (26.7%) in the IVB+PDT group required retreatments during the six months of follow-up (p=0.02). Conclusions: Significant improvement in visual acuity and reduction in central macular thickness over a six-months period were observed in both groups. The mean visual acuity was significantly better and the rate of reinjections after the initial treatment schedule was lower in the IVB+PDT group.

Pattern electroretinographic results after photodynamic therapy alone and photodynamic therapy in combination with intravitreal bevacizumab for choroidal neovascularization in age-related macular degeneration

To evaluate the changes in pattern electroretinography (PERG) 1 month after photodynamic therapy alone and photodynamic therapy in combination with intravitreal bevacizumab for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). This is a prospective series of 45 eyes with subfoveal CNV secondary to AMD. Twenty eyes were treated with photodynamic therapy (PDT) with verteporfin and 1.25 mg of intravitreal bevacizumab, and 25 patients were treated with PDT alone. Visual acuities and serial PERG recordings were performed both before and 1 month after therapy. Following the 1-month therapy period, visual acuity improved in 56% of patients in the PDT group and 76% of patients in the combination group. No significant ocular or systemic adverse effects were observed in either group. According to the PERG results, the mean P50 amplitude was 1.5 +/- 0.9 microV before PDT and improved to 2.1 +/- 1.1 microV at 1 month after PDT. The mean P50 amplitudes in the combination therapy group before and after therapy were 1.6 +/- 0.8 microV and 2.7 +/- 1.2 microV, respectively, and the difference was statistically significant between the groups. In this small series of eyes with limited follow-up, the combined treatment of PDT with verteporfin and intravitreal bevacizumab seems to be associated with improvement in VA and pattern electroretinographic results when compared to those in the PDT group.

Simultaneous but Not Prior Inhibition of VEGF165 Enhances the Efficacy of Photodynamic Therapy in Multiple Models of Ocular Neovascularization

To investigate the effect of the combined treatment of photodynamic therapy and specific VEGF165 inhibition with pegaptanib sodium (Macugen; Eyetech Pharmaceuticals, Lexington, MA) on ocular neovascularization. Photodynamic therapy's (PDT's) effects on the integrity of pegaptanib sodium were analyzed by HPLC, a VEGF165-binding assay, and a VEGF165-induced tissue factor gene expression assay. The effects of mono- or combined treatment on vessel growth and regression were determined in a murine corneal neovascularization model. The effects of combined treatment on vessel growth were also determined in a murine choroidal neovascularization model. PDT did not affect the chemical composition of pegaptanib sodium nor the efficacy of pegaptanib sodium in the inhibition of VEGF165 binding to Flt-1 and VEGF165-induced gene expression. In an animal model of effects on existing ocular neovascular lesions (corneal neovascularization), PDT monotherapy yielded an initial regression of these vessels, but there followed a rapid regrowth. In contrast, pegaptanib sodium monotherapy yielded little regression but potently abrogated further vessel growth. The combination of pegaptanib sodium and PDT resulted in the regression of the neovascular lesions, as observed with PDT alone, but also prevented significant vessel regrowth, leading to a significantly greater reduction in lesion size than did each monotherapy. In addition, there was a significantly greater effect of the combination of pegaptanib sodium and PDT on lesion size in choroidal neovascularization than with each monotherapy. Pretreatment with pegaptanib sodium appeared to decrease the efficacy of PDT-induced vessel regression in corneal neovascularization, and as such the enhanced efficacy over monotherapy when the agents were delivered simultaneously was not observed. Although the combined simultaneous treatment of ocular neovascularization with PDT and pegaptanib sodium may provide a more effective approach for the regression and overall treatment of CNV associated with AMD, the order of addition of these treatments may play a role in achieving optimal efficacy.

COMBINED PHOTODYNAMIC THERAPY WITH VERTEPORFIN AND INTRAVITREAL BEVACIZUMAB FOR CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION

To examine the 7-month results for patients treated with combined photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab for choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). This is a retrospective series of 24 eyes with juxtafoveal or subfoveal CNV secondary to AMD. Patients were treated with PDT with verteporfin and 1.25 mg of intravitreal bevacizumab. All patients were naive to treatment and had either treatment within a 14-day interval. Main outcome measures were visual acuity stabilization (defined as no change or a gain in visual acuity) and retreatment rate. At the 7-month follow-up, 20 (83%) of 24 patients had stabilization of visual acuity. Sixteen eyes (67%) had improvement in visual acuity. Mean improvement in visual acuity (n = 24) was 2.04 Snellen lines. Fifteen eyes (63%) required only a single combined treatment for CNV resolution. There were no complications, including endophthalmitis, uveitis, and ocular hypertension. The results of this study suggest that combined treatment of PDT with verteporfin and intravitreal bevacizumab may be useful in treating neovascular AMD by reducing retreatment rates and improving visual acuity. Further investigation with large, controlled trials is warranted to outline the appropriate treatment paradigm for combination therapy.

Combining vascular and cellular targeting regimens enhances the efficacy of photodynamic therapy

Photodynamic therapy (PDT) can be designed to target either tumor vasculature or tumor cells by varying the drug-light interval. Photodynamic therapy treatments with different drug-light intervals can be combined to increase tumor response by targeting both tumor vasculature and tumor cells. The sequence of photosensitizer and light delivery can influence the effect of combined treatments. The R3327-MatLyLu rat prostate tumor model was used in this study. Photosensitizer verteporfin distribution was quantified by fluorescence microscopy. Tumor blood flow changes were monitored by laser-Doppler system and tumor hypoxia was quantified by the immunohistochemical staining for the hypoxic marker EF5. The therapeutic effects of PDT treatments were evaluated by the histologic examination and tumor regrowth assay. Fluorescence microscopic studies indicated that tumor localization of verteporfin changed from predominantly within the tumor vasculature at 15 min after injection, to being throughout the tumor parenchyma at 3 h after injection. Light treatment (50 J/cm(2)) at 15 min after verteporfin injection (0.25 mg/kg, i.v.) induced significant tumor vascular damage, as manifested by tumor blood flow reduction and increase in the tumor hypoxic fraction. In contrast, the vascular effect observed after the same light dose (50 J/cm(2)) delivered 3 h after administration of verteporfin (1 mg/kg, i.v.) was an initial acute decrease in blood flow, followed by recovery to the level of control. The EF5 staining revealed no significant increase in hypoxic fraction at 1 h after PDT using 3 h drug-light interval. The combination of 3-h interval PDT and 15-min interval PDT was more effective in inhibiting tumor growth than each individual PDT treatment. However, it was found that the combined treatment with the sequence of 3-h interval PDT before 15-min interval PDT led to a superior antitumor effect than the other combinative PDT treatments. Histologic studies confirmed that this combined treatment led to damage to both tumor vasculature and tumor cells. Importantly, the combined PDT treatment did not increase normal tissue damage and tissue recovered well at 60 days after treatment. Our results suggest that targeting both tumor vascular and cellular compartments by combining a long-interval PDT with a short-interval PDT can be an effective and safe way to enhance PDT damage to tumor tissue.

Photodynamic therapy and intravitreal triamcinolone for a subretinal neovascularization in bilateral idiopathic juxtafoveal telangiectasis

To report combined treatment of photodynamic therapy (PDT) with verteporfin and intravitreal triamcinolone acetonide injection for subfoveal neovascularization secondary to bilateral idiopathic juxtafoveal telangiectasis. Interventional case report. A patient with a subfoveal neovascularization secondary to bilateral idiopathic juxtafoveal telangiectasis was treated with PDT plus an intravitreal injection of 4 mg of triamcinolone acetonide. Leakage in the late-phase of fluorescein angiography resolved with attenuation of telangiectatic vessels and improvement in visual acuity from 20/200 to 20/50. At 9 months post-treatment, recurrent leakage was treated with repeat PDT and intravitreal triamcinolone. One year after initial presentation, visual acuity was 20/60 with no leakage on fluorescein. Combined treatment with PDT and intravitreal triamcinolone acetonide resulted in regression of a subfoveal neovascular membrane and improvement in visual acuity during the course of follow-up.

Effect of combined photodynamic and chemotherapeutic treatment on lymphoma cells in vitro

We investigated the cytotoxic and apoptotic effects of a combination of photodynamic therapy (PDT) and cisplatin (CDDP) on L5178Y (LY) cells. Treatment with PDT by photofrin ® (5 μg/ml) alone or with CDDP (20 μg/ml) alone killed 41.5±8.5% or 42.9±6.5% of LY cells, respectively, while a combination of these two treatments killed 99.7±0.6%. Apoptotic cell death after combination treatment was also revealed to be 49.6±7.8% compared to 12.4±3.4% after PDT alone, and 18.8±2.6% after CDDP. This study demonstrated that combined treatment of PDT and CDDP results in enhanced apoptotic cell death as well as a cytotoxic effect on LY cells.