Hyaluronic acid modified nanocarriers for aerosolized delivery of verteporfin in the treatment of acute lung injury.

Verteporfin (VER), a photosensitizer used in macular degeneration therapy, has shown promise in controlling macrophage polarization and alleviating inflammation in acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). However, its hydrophobicity, limited bioavailability, and side effects hinder its therapeutic potential. In this study, we aimed to enhance the therapeutic potential of VER through pulmonary nebulized drug delivery for ALI/ARDS treatment. We combined hydrophilic hyaluronic acid (HA) with an oil-in-water system containing a poly(lactic acid-co-glycolic acid) (PLGA) copolymer of VER to synthesize HA@PLGA-VER (PHV) nanoparticles with favorable surface characteristics to improve the bioavailability and targeting ability of VER. PHV possesses suitable electrical properties, a narrow size distribution (approximately 200 nm), and favorable stability. In vitro and in vivo studies demonstrated the excellent biocompatibility, safety, and anti-inflammatory responses of the PHV by suppressing M1 macrophage polarization while inducing M2 polarization. The in vivo experiments indicated that the treatment with aerosolized nano-VER (PHV) allowed more drugs to accumulate and penetrate into the lungs, improved the pulmonary function and attenuated lung injury, and mortality of ALI mice, achieving improved therapeutic outcomes. These findings highlight the potential of PHV as a promising delivery system via nebulization for enhancing the therapeutic effects of VER in ALI/ARDS.

YAP/TAZ Suppress Drug Penetration Into Hepatocellular Carcinoma Through Stromal Activation.

BACKGROUND AND AIMS: HCC is the most predominant type of liver cancer affecting 800,000 people globally each year. Various small-molecule compounds targeting diverse oncogenic signaling pathways have been tested for patients with HCC, and clinical outcomes were not satisfactory. In this study, we investigated molecular signaling that determines the efficiency of drug delivery into HCC. APPROACH AND RESULTS: Hydrodynamics-based transfection (HT) was performed to develop mouse models for HCC induced by various oncogenes. Mice bearing liver cancer were treated with verteporfin at 5 weeks after HT. Multicellular HCC organoid (MCHO) models were established that contained various types of stromal cells, such as hepatic stellate cells, fibroblasts, and endothelial cells together with HCC cells. Tumor organoids were treated with verteporfin, and distributions of the drug in the organoids were assessed using fluorescence microscopy. Murine HCC models developed by HT methods showed that a high Yes-associated protein/Transcriptional co-activator with PDZ-binding motif (YAP/TAZ) activity in HCC cells impaired verteporfin penetration into the cancer. Activation of tumor stroma was observed in HCC with a high YAP/TAZ activity. Consistent with the findings in the in vivo models of HCC, MCHOs with activated YAP/TAZ signaling showed stromal activation and impaired penetration of verteporfin into the tumor organoids. Inhibition of YAP/TAZ transcriptional activity in HCC cells significantly increased drug penetration into the MCHO. CONCLUSIONS: Drug delivery into liver cancer is impaired by YAP/TAZ signaling in tumor cells and subsequent activation of stroma by the signaling. Disrupting or targeting activated tumor stroma might improve drug delivery into HCC with an elevated YAP/TAZ activity.

Simultaneous Pharmacologic Inhibition of Yes-Associated Protein 1 and Glutaminase 1 via Inhaled Poly(Lactic-co-Glycolic) Acid-Encapsulated Microparticles Improves Pulmonary Hypertension.

Background Pulmonary hypertension (PH) is a deadly disease characterized by vascular stiffness and altered cellular metabolism. Current treatments focus on vasodilation and not other root causes of pathogenesis. Previously, it was demonstrated that glutamine metabolism, as catalyzed by GLS1 (glutaminase 1) activity, is mechanoactivated by matrix stiffening and the transcriptional coactivators YAP1 (yes-associated protein 1) and transcriptional coactivator with PDZ-binding motif (TAZ), resulting in pulmonary vascular proliferation and PH. Pharmacologic inhibition of YAP1 (by verteporfin) or glutaminase (by CB-839) improved PH in vivo. However, systemic delivery of these agents, particularly YAP1 inhibitors, may have adverse chronic effects. Furthermore, simultaneous use of pharmacologic blockers may offer additive or synergistic benefits. Therefore, a strategy that delivers these drugs in combination to local lung tissue, thus avoiding systemic toxicity and driving more robust improvement, was investigated. Methods and Results We used poly(lactic-co-glycolic) acid polymer-based microparticles for delivery of verteporfin and CB-839 simultaneously to the lungs of rats suffering from monocrotaline-induced PH. Microparticles released these drugs in a sustained fashion and delivered their payload in the lungs for 7 days. When given orotracheally to the rats weekly for 3 weeks, microparticles carrying this drug combination improved hemodynamic (right ventricular systolic pressure and right ventricle/left ventricle+septum mass ratio), histologic (vascular remodeling), and molecular markers (vascular proliferation and stiffening) of PH. Importantly, only the combination of drug delivery, but neither verteporfin nor CB-839 alone, displayed significant improvement across all indexes of PH. Conclusions Simultaneous, lung-specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease.

Choroidal neovascularization secondary to half-dose photodynamic therapy for chronic central serous chorioretinopathy: A case report.

RATIONALE: Half-dose or reduced-fluence photodynamic therapy (PDT) with verteporfin has been well acknowledged to be the most effective and permanent treatment with very low rates of complications. However, we report a case of chronic central serous chorioretinopathy (CSC) who developed choroidal neovascularization (CNV) secondary to half-dose PDT within only 3 weeks. Such an occurrence following this short a course of treatment has not been reported previously. PATIENT CONCERNS: A 46-year-old Chinese man who had been diagnosed as acute more than 1 year ago revisited our department recently and complained of blurred vision again in his left eye. DIAGNOSES: Fluorescein fundus angiography (FFA) and indocyanine green angiography (ICGA) revealed patchy hyperfluorescent dots and optical coherence tomography (OCT) indicated irregular flat pigment epithelium detachment (PED) in the central macula. The patient was diagnosed with chronic CSC. INTERVENTIONS: The patient was treated by half-dose PDT with verteporfin. Three weeks later, the patient complained of sudden blurred vision and fundus examination showed macular hemorrhages with a best-corrected visual acuity (BCVA) of 20/250. OCT angiography (OCTA) showed a distinct area of flower-like CNV located within the deep retinal slab. Secondary CNV had developed after a quite short course of half-dose PDT treatment. Subsequently, the patient was administered by 2 intravitreal injections of aflibercept (2 mg). OUTCOMES: Two months after the second intravitreal injection, macular hemorrhages and secondary CNV were completely resolved, and the BCVA improved to 20/25. LESSONS: Patients of chronic CSC with irregular PED who undergo PDT should be warned of secondary CNV within a short course after treatment. If happened, it should be treated by intravitreal injections of anti-vascular endothelial growth factor agents as soon as possible.

RESOLUTION OF A SUBFOVEAL CHOROIDAL CAVERN AFTER HALF-DOSE PHOTODYNAMIC THERAPY FOR CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To describe resolution of a subfoveal choroidal cavern after half-dose verteporfin photodynamic therapy for persistent central serous chorioretinopathy. METHODS: Case report. RESULTS: A 43-year-old man was referred for treatment of chorioretinopathy in his left eye. On presentation, swept-source optical coherence tomography demonstrated a serous retinal detachment and a 161-µm-thick subfoveal choroidal cavern showing a characteristic tail of hypertransmission extending posteriorly. Subfoveal choroidal thickness measured 456 µm in the affected eye. Complete resolution of subretinal fluid and the subfoveal choroidal cavern were observed 3 months after half-dose verteporfin photodynamic therapy. Twelve months after treatment, subfoveal choroidal thickness had decreased further to 276 µm, and visual acuity had improved to 20/15. CONCLUSION: After half-dose verteporfin photodynamic therapy for chorioretinopathy, resolution of subretinal fluid was accompanied by resolution of a subfoveal choroidal cavern at 3 months and a 39.5% reduction in subfoveal choroidal thickness at 1 year.

Quantitative Evaluation of Retinal Vessel Density in Central Serous Chorioretinopathy after Half-dose Photodynamic Therapy.

PURPOSE: To determine vessel changes in retinochoroid with optical coherence tomographic angiography (OCT angiography) and spectral-domain OCT (SD-OCT) of patients with central serous chorioretinopathy (CSC) after half-dose photodynamic therapy (hd-PDT). METHODS: A prospective observational study of 62 eyes of 58 patients undergoing hd-PDT was followed for 3 months. Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were performed at baseline; best-corrected visual acuity (BCVA), fundus photography, OCT angiography and SD-OCT were performed at baseline, 1-month, and 3-month follow-up visits. RESULTS: The mean vessel density of inner retina (VDIR) layer was 50.72 ± 3.17 at baseline, then decreased to 48.97 ± 4.34 at 1-month follow-up (p < .001), and partially recovered to 49.00 ± 4.28 at 3-month follow-up (p < .001); the mean area of foveal avascular zone (FAZ) was 0.303 ± 0.107 mm2 at baseline, and then increased to 0.339 ± 0.121 mm2 and 0.342 ± 0.125 mm2 at 1-month and 3-month follow-up after hd-PDT (p < .001, p < .001). The mean diameters of choroidal big vessels (DCV) were 309.66 ± 72.24 microns at baseline, then decreased to 300.13 ± 69.38 microns at 1-month and 293.39 ± 69.92 microns at 3-month after treatment (p < .001, p < .001). CONCLUSIONS: Currently common applied hd-PDT for patients with CSC has significantly impact on both retinal and choroidal vessels. The retinal capillary flow decreased, therefore optimizing PDT parameters for treating CSC may still be necessary in the future.

Theranostic verteporfin- loaded lipid-polymer liposome for photodynamic applications.

In this study we report a novel theranostic lipid-polymer liposome, obtained from DPPC and the triblock copolymer F127 covalently modified with 5(6)-carboxyfluorescein (CF) for photodynamic applications. Due to the presence of F127, small unilamellar vesicle (SUV) liposomes were synthesized by a simple and fast thin-film hydration method without the need for an extrusion process. The vesicles have around 100 nm, low polydispersity and superb solution stability. The clinically used photosensitizer verteporfin (VP) was entrapped into the vesicles, mostly in monomeric form, with 90% loading efficiency. Stern-Volmer and fluorescence lifetime assays showed heterogeneous distribution of the VP and CF into the vesicles, ensuring the integrity of their individual photophysical properties. The theranostic properties were entirely photoactivatable and can be trigged by a unique wavelength (470 nm). The feasibility of the system was tested against the Glioblastoma multiforme cell line T98G. Cellular uptake by time-resolved fluorescence microscopy showed monomerized VP (monoexponential decay, 6.0 ns) at nucleus level, while CF was detected at the membrane by fluorescence microscopy. The strategy's success was supported by the reduction of 98% in the viability of T98G cells by the photoactivated lipid-polymer liposome with [VP] = 1.0 µmol L-1. Therefore, the novel theranostic liposome is a potential system for use in cancer and ocular disease therapies.

Long-Term Effects of Half-Time Photodynamic Therapy on Retinal Sensitivity in Eyes with Chronic Central Serous Chorioretinopathy.

The purpose of this study was to evaluate the long-term effects of half-time photodynamic therapy (PDT) on the retinal sensitivity in eyes with chronic central serous chorioretinopathy (CSC). Twenty-two eyes of 22 patients with chronic CSC were studied. PDT was applied with full-dose verteporfin and half-time laser duration. The best-corrected visual acuity (BCVA) and retinal sensitivity in the central 2 and 10 degrees were evaluated at the baseline, and at 12 and 24 months after the half-time PDT. The retinal sensitivity was determined by Macular Integrity Assessment microperimetry (MAIA, Centervue, Padova, Italy). The results showed that the mean retinal sensitivities in the central 2 and 10 degrees were significantly improved at 12 months (25.6 ± 2.79 dB, median; 26.11 dB, 25.6 ± 2.25 dB, median; 25.65 dB, respectively; P < 0.001) and at 24 months (26.3 ± 2.62 dB, median; 27.38 dB, 26.6 ± 2.21 dB, median; 27.45 dB, respectively; P < 0.001) after the treatment compared to that at the baseline (19.2 ± 3.93 dB, median; 19.34 dB, 20.9 ± 2.92 dB, median; 20.9 dB, respectively). The BCVA was also significantly improved from 0.18 ± 0.19 median; 0.15 logarithm of the minimum angle of resolution (logMAR) units at the baseline to 0.07 ± 0.15 median; 0 logMAR units at 12 months (P < 0.001) and to 0.049 ± 0.16 median; -0.039 logMAR units at 24 months (P < 0.001). We conclude that half-time PDT results in a significant improvement of the mean central retinal sensitivity for at least 24 months in eyes with chronic CSC. Thus, half-time PDT is beneficial in resolving chronic CSC for a relatively long period.

Intractable Ocular Diseases and Treatment Progress.

In recent years, with the aging of the population and the frequent use of electronic devices, many eye diseases have shown a linear upward trend, such as dry eye disease, glaucoma, cataract, age-related macular degeneration, and diabetic retinopathy. These diseases are often chronic and difficult to cure. Based on the structure and barrier of the human eye, this review describes the pathogenesis and treatments of several intractable eye diseases and summarizes the advanced ocular drug delivery systems to provide new treatment ideas for these diseases. Finally, we also look forward to the prospect of RNAi therapy in the treatment of eye diseases.

Comparison of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: The EVEREST II Randomized Clinical Trial.

Importance: The 2-year efficacy and safety of combination therapy of ranibizumab administered together with verteporfin photodynamic therapy (vPDT) compared with ranibizumab monotherapy in participants with polypoidal choroidal vasculopathy (PCV) are unclear. Objective: To compare treatment outcomes of ranibizumab, 0.5 mg, plus prompt vPDT combination therapy with ranibizumab, 0.5 mg, monotherapy in participants with PCV for 24 months. Design, Setting, and Participants: This 24-month, phase IV, double-masked, multicenter, randomized clinical trial (EVEREST II) was conducted among Asian participants from August 7, 2013, to March 2, 2017, with symptomatic macular PCV confirmed using indocyanine green angiography. Interventions: Participants (N = 322) were randomized 1:1 to ranibizumab, 0.5 mg, plus vPDT (combination therapy group; n = 168) or ranibizumab, 0.5 mg, plus sham PDT (monotherapy group; n = 154). All participants received 3 consecutive monthly ranibizumab injections, followed by a pro re nata regimen. Participants also received vPDT (combination group) or sham PDT (monotherapy group) on day 1, followed by a pro re nata regimen based on the presence of active polypoidal lesions. Main Outcomes and Measures: Evaluation of combination therapy vs monotherapy at 24 months in key clinical outcomes, treatment exposure, and safety. Polypoidal lesion regression was defined as the absence of indocyanine green hyperfluorescence of polypoidal lesions. Results: Among 322 participants (mean [SD] age, 68.1 [8.8] years; 225 [69.9%] male), the adjusted mean best-corrected visual acuity (BCVA) gains at month 24 were 9.6 letters in the combination therapy group and 5.5 letters in the monotherapy group (mean difference, 4.1 letters; 95% CI, 1.0-7.2 letters; P = .005), demonstrating that combination therapy was superior to monotherapy by the BCVA change from baseline to month 24. Combination therapy was superior to monotherapy in terms of complete polypoidal lesion regression at month 24 (81 of 143 [56.6%] vs 23 of 86 [26.7%] participants; P < .001). Participants in the combination group received fewer ranibizumab injections (median, 6.0 [interquartile range (IQR), 4.0-11.0]) than the monotherapy group (median, 12.0 [IQR, 7.0-17.0]) up to month 24. The combination group required a median of 2.0 (IQR, 1.0-3.0) vPDT treatments for 24 months, with 75 of 168 participants (44.6%) requiring only 1 vPDT treatment. Conclusions and Relevance: The 24-month data findings confirm that ranibizumab therapy, given as monotherapy or in combination with vPDT, is efficacious and safe for treatment of PCV. Combination therapy with vPDT added to ranibizumab achieved superior BCVA gain, increased odds of complete polypoidal lesion regression, and fewer treatment episodes compared with ranibizumab monotherapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01846273.

Heat shock protein 90-targeted photodynamic therapy enables treatment of subcutaneous and visceral tumors.

Photodynamic therapy (PDT) ablates malignancies by applying focused near-infrared (nIR) light onto a lesion of interest after systemic administration of a photosensitizer (PS); however, the accumulation of existing PS is not tumor-exclusive. We developed a tumor-localizing strategy for PDT, exploiting the high expression of heat shock protein 90 (Hsp90) in cancer cells to retain high concentrations of PS by tethering a small molecule Hsp90 inhibitor to a PS (verteporfin, VP) to create an Hsp90-targeted PS (HS201). HS201 accumulates to a greater extent than VP in breast cancer cells both in vitro and in vivo, resulting in increased treatment efficacy of HS201-PDT in various human breast cancer xenografts regardless of molecular and clinical subtypes. The therapeutic index achieved with Hsp90-targeted PDT would permit treatment not only of localized tumors, but also more diffusely infiltrating processes such as inflammatory breast cancer.

Synergistic enhancement of efficacy of platinum drugs with verteporfin in ovarian cancer cells.

BACKGROUND: Epithelial ovarian cancers (EOCs) comprises the majority of malignant ovarian neoplasms. Combination treatment with chemotherapeutic agents seems to be a promising strategy in ovarian cancer (OVCA) patients in order to overcome drug resistance. In this in vitro study, we investigated the therapeutic efficacy of verteporfin (VP) alone and in combination with cisplatin (CDDP), carboplatin (CP) and paclitaxel (Taxol). The main objectives of this study are to determine the nature of interactions between VP and CDDP/CP/Taxol and to understand the mechanism of action of VP in OVCA cells. METHODS: The efficacy of VP on cell proliferation, cytotoxicity, invasion and clonogenic capacity was assayed in CDDP-sensitive (COV504, OV-90) and CDDP-resistant (A2780Cis) cell lines. The cytotoxic effects of drugs either alone or in combination were evaluated using MTT assay and Cell Viability Blue assay. The effects of drugs on the metabolic functions were studied using matrigel invasion assay and clonogenic assay. Immunoblot analysis was carried out to investigate changes in YAP and cell cycle genes. Changes in the cytokines due to drug treatments were analyzed using a cytokine array. RESULTS: Treatment with VP inhibited cell proliferation, invasion and increased cytotoxicity of OVCA cells. We observed that VP chemosensitized CDDP-resistant cells, even at lower doses. When added either in constant or non-constant ratios, VP produced synergistic effects in combination with CDDP/CP/Taxol. A cytokine array identified upregulation of cytokines in OVCA cells that were inhibited by VP treatment. CONCLUSIONS: Either in cisplatin-resistant cell lines or cisplatin-sensitive cell lines, VP proves to be more efficient in inhibiting cell proliferation and inducing cytotoxicity. Our results suggest that novel combinations of VP with CDDP or CP or Taxol might be an attractive therapeutic strategy to enhance OVCA chemosensitivity. The fact that lower doses of VP are effective in chemosensitizing the CDDP-resistant cells, might ultimately lead to the development of an innovative combination therapy for the treatment of OVCA patients.

YAP/TAZ are Activated by Mechanical and Hormonal Stimuli in Myometrium and Exhibit Increased Baseline Activation in Uterine Fibroids.

Uterine fibroids (UFs) are benign myometrial neoplasms. The mechanical environment activates signaling through the Hippo pathway effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) in other fibrotic disorders. Here, we assess the differences in YAP/TAZ responsiveness to signals in UF compared with myometrium (Myo). Matched samples of UF and Myo were collected. Atomic force microscopy (AFM) was used to determine in situ stiffness. Cells were plated sparsely on hydrogels or at confluence. Ten nanomolars of estradiol (E2) and 100 nM progesterone (P4) were used. Immunostaining for YAP/TAZ and extracellular matrix (ECM) proteins was performed. Cells were incubated with control or YAP1 (YAP)/WWTR1 (TAZ) small interfering RNA (siRNA). Real time qPCR was completed for connective tissue growth factor (CTGF). Cells were treated with verteporfin (a YAP inhibitor) or Y27632 (a ROCK inhibitor), and ECM gene expression was analyzed. Paired t test and Wilcoxon sign-rank test were used. AFM-measured tissue stiffness and YAP/TAZ nuclear localization in situ and in confluent cells were higher in UF compared with Myo (p < 0.05). Decreasing substrate stiffness reduced YAP/TAZ nuclear localization for both Myo and UF (p = 0.05). Stimulating cells with E2 or P4 increased YAP/TAZ nuclear localization, but only in Myo (p = 0.01). UFs had increased FN, COLI, and COLIII deposition. Following siRNA targeting, CTGF was found to be statistically decreased. Verteporfin treatment reduced cell survival and reduced FN deposition. Treatment with Y27632 demonstrated better cell tolerance and a reduction in ECM deposition. The mechanosensitive pathway may be linked to YAP/TAZ function and involved in transducing fibroid growth.

Cost-effectiveness of Intravitreal Ranibizumab With Verteporfin Photodynamic Therapy Compared With Ranibizumab Monotherapy for Patients With Polypoidal Choroidal Vasculopathy.

Importance: The EVEREST II trial showed that for patients with polypoidal choroidal vasculopathy (PCV), intravitreal ranibizumab in combination with verteporfin photodynamic therapy improves visual acuity relative to ranibizumab monotherapy. However, whether combination therapy is incrementally cost-effective relative to monotherapy during a lifetime is unclear. Objective: To assess the incremental cost-effectiveness of combination therapy compared with ranibizumab monotherapy in patients with PCV. Design, Setting, and Participants: This model-based, economic evaluation used 2018 unit cost data from a tertiary eye hospital in Singapore, first- and second-year outcomes and resource use data from a multicenter trial across various Asian countries (EVEREST II) to model a hypothetical cohort of patients with symptomatic PCV. Scenario analyses and deterministic and probabilistic sensitivity analyses were performed to examine uncertainty. Data were collected from October 2018 through April 2019 and analyzed from March through October 2019. Interventions: This model used data from the EVEREST II trial, in which all participants were given 0.5 mg of intravitreal ranibizumab once every 4 weeks for the first 3 months. Subsequent administration occurred as needed. For participants receiving combination therapy, standard fluence (50 J/cm3) photodynamic therapy with 6-mg/m2 verteporfin was administered once during the first 3 months and thereafter as needed. Main Outcomes and Measures: Incremental cost per quality-adjusted life-year (QALY) gained for combination therapy relative to monotherapy for patients with PCV. Results: In this model based on a cohort of 1000 patients aged 68 years, a patient with PCV incurred a total cost in Singapore dollars (SGD) of 92 327 (US $67 399) with combination therapy and SGD 92 371 (US $67 431) with monotherapy during a lifetime horizon, generating a modest cost savings of SGD 44 (US $32) per patient undergoing combination therapy. Lifetime QALYs were estimated to be 7.87 for combination therapy and 7.85 for monotherapy, for an incremental gain of 0.02 QALYs. Combination therapy remained cost-saving or cost-effective in all lifetime scenarios modeled, but during shorter time horizons and at lower monotherapy costs, it may not be cost-effective. Conclusions and Relevance: This study found combination therapy to be a dominant (more effective and less costly) strategy, being similar in costs and slightly more effective than ranibizumab monotherapy during a lifetime horizon. However, decreasing the time horizon to less than 10 years and/or reductions in the cost of monotherapy may result in combination therapy no longer being cost-effective.

Comparison of Half-Time and Half-Irradiance Photodynamic Therapy in Nonresolving Central Serous Chorioretinopathy.

Purpose: To compare the efficacy of half-time and half-irradiance photodynamic therapy (PDT) in patients with nonresolving central serous chorioretinopathy (CSC) Methods: This retrospective study included 32 patients with nonresolving CSC, of whom 14 were treated with half-time PDT and 18 with half-irradiance PDT. Therapeutic outcomes, including central retinal thickness (CRT), subretinal fluid (SRF) height, subfoveal choroidal thickness (SFCT), thickness of the Haller layer (HL), thickness of the choriocapillaris/Sattler layer (SL), and best-corrected visual acuity (BCVA), were measured at baseline, and at 1 and 3 months after treatment. Results: CRT, SRF, and SFCT decreased significantly at 1 and 3 months after treatment in both groups. Thickness of the HL decreased significantly at 1 and 3 months, whereas thickness of the choriocapillaris/SL did not. BCVA demonstrated a significant improvement at 3 months in both groups. Changes in outcome parameters were not significantly different between the 2 groups. Conclusion: Both half-time and half-irradiance PDT were effective in SRF resolution and visual improvement, reducing choroidal thickness mainly on HL.

Comparing effects of photodynamic therapy in central serous chorioretinopathy: full-dose versus half-dose versus half-dose-half-fluence.

PURPOSE: To compare the effects of full-dose, half-dose, and half-dose-half-fluence photodynamic therapy (PDT) in central serous chorioretinopathy (CSC). METHODS: This retrospective study enrolled patients with CSC who received full-dose (verteporfin 6 mg/m2), half-dose (verteporfin 3 mg/m2), and half-dose-half-fluence (verteporfin 3 mg/m2 and light energy reduced to 25 J/cm2) PDT. We measured visual acuity, subfoveal choroidal thickness (SFCT), subretinal fluid (SRF) thickness, and choroidal vascularity index (CVI) before and 3 months after PDT. RESULTS: Forty-three eyes (42 patients) were analyzed. Full-dose and half-dose groups showed improved vision (P = 0.023, 0.004, respectively), but half-dose-half-power group was not significantly improved (P = 0.254). SFCT in all three groups were significantly decreased (P = 0.005, 0.004, 0.002, respectively). SRF thicknesses in full-dose and half-dose groups showed significant decreases (P = 0.005, < 0.001, respectively). Half-dose-half-fluence group demonstrated the decrease but it was not statistically significant (P = 0.084). CVI were decreased in full-dose and half-dose groups (all P = 0.005). However, in the half-dose-half-fluence group, CVI was increased (P = 0.003). CONCLUSION: Full-dose and half-dose PDT were both effective in CSC treatment. Half-dose PDT can be considered to reduce complications. The effect of half-dose-half-fluence PDT was less clear than the other two protocols.

Prognostic factors for combined ranibizumab and prompt verteporfin photodynamic therapy for polypoidal choroidal vasculopathy.

PURPOSE: To investigate the prognostic factors for the combined therapy of ranibizumab and prompt verteporfin photodynamic therapy (vPDT) for eyes with polypoidal choroidal vasculopathy (PCV). METHODS: Sixty-two PCV eyes of 62 patients that received the initial treatment of intravitreal ranibizumab followed by vPDT within 1 week plus a 2nd intravitreal ranibizumab 1 month later in one single medical center were retrospectively enrolled. Best-corrected visual acuity (BCVA) and parameters obtained from optical coherence tomography at baseline, 3 months, 6 months and 1  year were measured and compared. Factors associated with polyp regression, recurrent hemorrhage and visual improvement were analyzed. RESULTS: After the loading treatment, complete and partial polyp regression was achieved in 53.6% and 39.3% of cases, respectively at Month 3. The mean logarithm of the minimum angle of resolution of BCVA improved from 0.64 ±â€¯0.38 to 0.55 ±â€¯0.46 (P =  0.008) at Month 12. Recurrent hemorrhage (P =  0.001) and previous anti-vascular endothelial growth factor (VEGF) treatment (P =  0.017) were associated with poorer visual improvement at Month 12. Incomplete polyp regression (P =  0.038) and previous anti-VEGF treatment (P =  0.005) were associated with a higher risk of recurrent hemorrhage. CONCLUSIONS: Recurrent hemorrhage was associated with poor visual improvement after combined ranibizumab and vPDT for PCV. Complete polyp eradication was associated with a lower risk of recurrent hemorrhage. Patients who had previously received anti-VEGF were associated with recurrent hemorrhage and poor visual improvement; more frequent follow-ups and more aggressive subsequent treatments may be needed for these cases.

Core-matched nanoassemblies for targeted co-delivery of chemotherapy and photosensitizer to treat drug-resistant cancer.

Emergence of drug resistance in tumors causes therapeutic failure or tumor relapse. Combination of chemotherapy and photodynamic therapy holds significant promise to treat drug-resistant tumors. However, stubborn hydrophobicity of photosensitizer (PS), low encapsulation efficiency and leaking problem of PS in organic carrier, and disparate physicochemical properties of PS and chemotherapeutics make the combination unachievable. Thus how to efficiently co-deliver the two functional agents to enable photo-chemotherapy seems to be one of the key challenges. Here, core-matched technology (CMT) was developed to realize efficient co-delivery of PS and chemotherapeutics, in which PS verteporfin (VP), tumor angiogenesis-targeting iNGR peptide and poly(lactic acid) (PLA) were respectively pre-modified with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), and the conjugates self-assembled into iNGR-modified and VP conjugated nanoassemblies (iNGR-VP-NA) with chemotherapeutic agent docetaxel (DTX) loaded in the hydrophobic core. The obtained iNGR-VP-NA-DTX was characterized by mean size of 166.0 ±â€¯9.2 nm and morphology of uniformly spherical shape. In vitro, with the assistance of laser, iNGR-VP-NA-DTX exhibited higher cellular uptake, stronger cytotoxicity in HUVEC cells, drug-resistant HCT-15 tumor cells and more effective inhibition of tube formation than iNGR-VP-NA-DTX without laser or VP-NA-DTX with laser. After intravenously injected into mice, through the near-infrared light emitted by VP, iNGR-VP-NA exhibited improved accumulation compared to VP-NA in drug-resistant HCT-15 tumor. Besides, iNGR-VP-NA-DTX with laser enhanced inhibition of angiogenesis and induced severe apoptosis and necrosis in tumor tissues along with minimal impact to normal areas. These evidences demonstrated that iNGR-VP-NA-DTX was of great potential to treat drug-resistant tumors via efficient angiogenesis-targeted photo-chemotherapy. STATEMENT OF SIGNIFICANCE: Combination of chemotherapy and photodynamic therapy is thought to be a potential approach to treat drug-resistant cancer. However, it is difficult to realize optimized photo-chemotherapy in one nano-system. Here, iNGR-modified nanoassemblies is created based on core-matched nanotechnology to realize targeted photo-chemotherapy. In this study, the improved co-loading of chemotherapy and photosensitizer in the nanoassemblies exerted a synergistic anti-tumor effect and the decoration with iNGR enhanced tumor-targeting efficiency. In the presence of laser irradiation, the nanoassemblies exhibited enhanced and targeted anti-tumor efficacy in drug-resistant HCT-15 tumor both in vitro and in vivo.

Effectiveness of photodynamic therapy with verteporfin combined with intrastromal bevacizumab for corneal neovascularization in Stevens-Johnson syndrome.

PURPOSE: To investigate the effectiveness of combined photodynamic therapy with verteporfin and intrastromal injection of bevacizumab for the treatment of corneal neovascularization in patients with Stevens-Johnson syndrome (SJS). METHODS: Eight eyes of eight patients with SJS having corneal neovascularization who were refractory to 1% prednisolone instillation received photodynamic therapy with verteporfin (6 mg/m2) combined with intrastromal bevacizumab injection (2.5 mg/0.1 mL). Best-corrected visual acuity and intraocular pressure were assessed, and slit-lamp biomicroscopic examination was performed before treatment and at 1 week and every month. A chronic ocular manifestation score was assigned based on the involvement area or the severity before treatment. The cumulative length of corneal blood vessels and area of corneal neovascularization were measured by anterior segment photographs before and after treatment. RESULTS: At 3 and 6 months after treatment, all eyes showed regression of corneal neovascularization. Complete regression was achieved in five eyes (62.5%) and partial regression in three eyes (37.5%). Among five patients who were followed up for more than 1 year, two eyes maintained complete regression and one eye maintained partial regression at 1 year. However, two eyes with severe chronic ocular manifestation showed revascularization. CONCLUSIONS: Combined photodynamic therapy with intrastromal bevacizumab injection can effectively inhibit corneal neovascularization in patients with SJS. However, patients with severe chronic ocular manifestation may exhibit revascularization.

Long-term results of photodynamic therapy or ranibizumab for polypoidal choroidal vasculopathy in LAPTOP study.

BACKGROUND/AIM: We previously reported that ranibizumab performed better on visual prognosis than photodynamic therapy (PDT) in a Ranibizumab (Lucentis) And Photodynamic Therapy On Polypoidal choroidal vasculopathy (LAPTOP) study. To determine if the first-choice treatment, either PDT or intravitreal ranibizumab, has a long-term effect in patients with polypoidal choroidal vasculopathy (PCV). METHODS: We reviewed medical records of patientsrandomised to either PDT (29 eyes) or ranibizumab (27 eyes) from July 2009 to June 2011 in LAPTOP study. Retreatment or switching to other treatments were at the investigator's discretion after release from the 2-year LAPTOP study up to 5years. We evaluated visual acuity (VA), continuity of initial treatment, percentage of dry macula achievement and macular atrophy at 5 years. RESULTS: The logarithm of minimal angle of resolution VA was 0.56 in the PDT and 0.44 in the ranibizumab groups at baseline (p=0.101) and was 0.55 and 0.28 at 5years, respectively (p<0.05). More than 70% of the patients converted to aflibercept in following years. Achievement percentages of dry macula were 74% (PDT) and 63% (ranibizumab) at 5years, and macular atrophy was detected in 78% (PDT) and 60% (ranibizumab) with a mean area of 7.7 and 3.5 mm2, respectively (p=0.155). CONCLUSIONS: The better VA in the initial ranibizumab group compared with the PDT group at 2 years was retained at the 5-year follow-up.