RESUMO
Uveal melanoma (UM) is the most common primary ocular malignancy in adults and has high mortality. Recurrence, metastasis, and therapeutic resistance are frequently observed in UM, but no beneficial systemic therapy is available, presenting an urgent need for developing effective therapeutic drugs. Verteporfin (VP) is a photosensitizer and a Yes-Associated Protein (YAP) inhibitor that has been used in clinical practice. However, VP's lack of tumor targetability, poor biocompatibility, and relatively low treatment efficacy hamper its application in UM management. Herein, we developed a biocompatible CD44-targeting hyaluronic acid nanoparticle (HANP) carrying VP (HANP/VP) to improve UM treatment efficacy. We found that HANP/VP showed a stronger inhibitory effect on cell proliferation than that of free VP in UM cells. Systemic delivery of HANP/VP led to targeted accumulation in the UM-tumor-bearing mouse model. Notably, HANP/VP mediated photodynamic therapy (PDT) significantly inhibited UM tumor growth after laser irradiation compared with no treatment or free VP treatment. Consistently, in HANP/VP treated tumors after laser irradiation, the tumor proliferation and YAP expression level were decreased, while the apoptotic tumor cell and CD8+ immune cell levels were elevated, contributing to effective tumor growth inhibition. Overall, the results of this preclinical study showed that HANP/VP is an effective nanomedicine for tumor treatment through PDT and inhibition of YAP in the UM tumor mouse model. Combining phototherapy and molecular-targeted therapy offers a promising approach for aggressive UM management.
Assuntos
Proliferação de Células , Ácido Hialurônico , Melanoma , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes , Neoplasias Uveais , Verteporfina , Verteporfina/farmacologia , Verteporfina/uso terapêutico , Animais , Fotoquimioterapia/métodos , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/patologia , Camundongos , Melanoma/tratamento farmacológico , Melanoma/patologia , Humanos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fármacos Fotossensibilizantes/química , Linhagem Celular Tumoral , Nanopartículas/química , Proliferação de Células/efeitos dos fármacos , Ácido Hialurônico/química , Receptores de Hialuronatos/metabolismo , Apoptose/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAP , Camundongos Nus , Terapia de Alvo Molecular/métodos , Camundongos Endogâmicos BALB C , FemininoRESUMO
Background: Photodynamic therapy (PDT) has emerged as a promising strategy for oral cancer treatment. Verteporfin is a powerful photosensitizer and widely used in the treatment of macular degeneration. However, rare work has reported its potential in the treatment of oral cancer. Methods: In this study, we introduce an innovative approach of nano-photosensitizer based on Verteporfin, which was prepared by utilizing macrophage membrane to coat Verteporfin-loaded zeolitic imidazolate framework 8 (ZIF-8) for effective photodynamic therapy against oral cancer. Nanoparticle characteristics were assessed including size, zeta potential, and PDI. Cellular uptake studies were conducted using CAL-27 cells. Furthermore, inhibitory effects in both in vitro and in vivo settings were observed, ensuring biosafety. Assessment of anticancer efficacy involved tumor volume measurement, histological analyses, and immunohistochemical staining. Results: In vitro experiments indicated that the nano-photosensitizer showed efficient cellular uptake in the oral cancer cells. Upon the laser irradiation, the nano-photosensitizer induced the generation of reactive oxygen species (ROS), leading to cancer cell apoptosis. The in vivo experiments indicated that the coating with cell membranes enhanced the circulation time of nano-photosensitizer. Moreover, the specificity of the nano-photosensitizer to the cancer cells was also improved by the cell membrane-camouflaged structure in the tumor-bearing mouse model, which inhibited the tumor growth significantly by the photodynamic effect in the presence of laser irradiation. Conclusion: Overall, our findings demonstrate the potential of macrophage membrane-coated ZIF-8-based nanoparticles loaded with Verteporfin for effective photodynamic therapy in oral cancer treatment. This nano-system holds promise for synergistic cancer therapy by combining the cytotoxic effects of PDT with the activation of the immune system, providing a novel therapeutic strategy for combating cancer.
Assuntos
Neoplasias Bucais , Nanopartículas , Fotoquimioterapia , Camundongos , Animais , Fármacos Fotossensibilizantes/farmacologia , Verteporfina/uso terapêutico , Fototerapia , Neoplasias Bucais/tratamento farmacológico , Nanopartículas/química , Modelos Animais de Doenças , Linhagem Celular TumoralRESUMO
Corticosteroid-induced central serous chorioretinopathy (CSCR) has been reported to develop in many intraocular inflammatory diseases and usually resolves spontaneously after discontinuation of corticosteroids. Patients without any improvement may require alternative therapies. In this case report, we present the case of a 35-year-old man with Behçet's disease who had complaints of decreased vision due to CSCR in his left eye while using systemic corticosteroids along with cyclosporine and azathioprine. Half-fluence photodynamic therapy (PDT) was performed because the CSCR did not regress despite discontinuation of systemic corticosteroids. After treatment, his visual acuity increased with complete resolution of the subfoveal fluid. Half-fluence PDT seems to be an effective and safe treatment for patients who develop acute CSCR while under systemic or local corticosteroid therapy for intraocular inflammatory diseases such as Behçet's uveitis and do not improve despite steroid discontinuation.
Assuntos
Síndrome de Behçet , Coriorretinopatia Serosa Central , Fotoquimioterapia , Uveíte , Corticosteroides/uso terapêutico , Adulto , Síndrome de Behçet/complicações , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/tratamento farmacológico , Coriorretinopatia Serosa Central/induzido quimicamente , Coriorretinopatia Serosa Central/diagnóstico , Coriorretinopatia Serosa Central/tratamento farmacológico , Angiofluoresceinografia , Humanos , Masculino , Fotoquimioterapia/efeitos adversos , Fármacos Fotossensibilizantes/efeitos adversos , Tomografia de Coerência Óptica , Uveíte/tratamento farmacológico , Verteporfina/uso terapêuticoRESUMO
BACKGROUND: This study aimed to explore the effect of inhibiting the Hippo/Yes-associated protein (YAP) signaling pathway on the outcomes of transcatheter arterial chemoembolization (TACE) in treating transplanted hepatocellular carcinoma (HCC). METHODS: A transplanted HCC rat model was established. Then, rats were randomly divided into four groups: Sham, TACE, verteporfin (inhibitor of Hippo/YAP), and TACE+verteporfin. Lent-OE-YAP was transfected into rats to overexpress YAP in vivo. After treatments, morphological changes, tumor weight, and the overall survival of rats in different groups were analyzed. Real-time PCR, immunohistochemistry staining, and Western blotting were used to determine the expression of factors related to the Hippo/YAP signaling pathway. RESULTS: Tumor weight and tissue lesions in the TACE and verteporfin groups were significantly reduced compared with the Sham group. Verteporfin significantly decreased tumor weight after TACE treatment. In addition, verteporfin significantly improved the overall survival of rats with transplanted HCC after TACE treatment. Compared with the Sham group, both TACE and verteporfin groups exhibited significantly decreased expression of macrophage-stimulating (MST)1, MST2, long-acting thyroid stimulator 1, transcriptional co-activator with PDZ-binding motif (TAZ), Yes-associated protein (YAP), TEA domain transcription factor (TEAD)1, TEAD2, TEAD3, and TEAD4. TACE plus verteporfin significantly enhanced the downregulation of effectors in the Hippo/YAP signaling pathway and decreased tumor size, while the overexpression of YAP exerted opposite effects. CONCLUSION: The inhibition of the Hippo/YAP signaling pathway via verteporfin significantly improved the outcomes of TACE in treating transplanted HCC.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Via de Sinalização Hippo/efeitos dos fármacos , Neoplasias Hepáticas/terapia , Verteporfina/uso terapêutico , Animais , Western Blotting , Carcinoma 256 de Walker , Carcinoma Hepatocelular/mortalidade , Terapia Combinada , Neoplasias Hepáticas/mortalidade , Masculino , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Serina-Treonina Quinase 3/antagonistas & inibidores , Proteínas de Sinalização YAP/antagonistas & inibidoresRESUMO
PURPOSE: To analyze visual outcomes after treatment of choroidal hemangioma in the pre-photodynamic therapy (PDT) era versus PDT era. DESIGN: Retrospective, comparative case series. PARTICIPANTS: A total of 458 patients with circumscribed choroidal hemangioma. METHODS: Comparison of hemangioma managed in the pre-PDT (1967-2001) era versus PDT (2002-2018) era. MAIN OUTCOME MEASURE: Visual acuity outcome. RESULTS: A total of 458 tumors were treated over this 51-year period. A comparison (pre-PDT [n = 220 cases] vs. PDT [n = 238 cases]) revealed PDT era patients were of older mean age (48.9 vs. 53.8 years, P = 0.002) and were more likely to have systemic hypertension (17.7% vs. 33.8%, P < 0.001), tumor location in the macula (57.4% vs. 67.5%, P = 0.01), subretinal fluid on OCT (33.3% vs. 70.7%, P = 0.01), and greater extent of overlying lipofuscin (P = 0.001). Findings of tumor basal diameter and thickness and fluorescein and indocyanine green angiography were no different in the 2 eras. Treatment (pre-PDT vs. PDT) included argon laser photocoagulation (42.1% vs. 0.4%), PDT (0% vs. 43.8%), transpupillary thermotherapy (0% vs. 0.4%), plaque radiotherapy (7.0% vs. 5.2%), external beam radiotherapy (1.4% vs. 1.3%), enucleation (0.9% vs. 0.4%), and observation (48.6% vs. 47.6%). After treatment, patients in the PDT era demonstrated better mean logarithm of the minimum angle of resolution visual acuity (1.28 vs. 0.51, P < 0.001) (Snellen equivalent 20/400 vs. 20/63, P < 0.001). Final visual acuity was ≥20/40 for those with entering vision of ≥20/40 (59.6% vs. 74.7%, P = 0.001) and for those with entering vision of 20/50-20/200 (25.4% vs. 47.3%, P < 0.001). CONCLUSIONS: Management of choroidal hemangioma in the PDT era has allowed for significantly better visual outcome compared with the pre-PDT era, with mean final visual acuity of 20/400 (pre-PDT era) versus 20/63 (PDT era).
Assuntos
Neoplasias da Coroide/terapia , Corioide/patologia , Hemangioma/terapia , Fotocoagulação a Laser/métodos , Fotoquimioterapia/métodos , Verteporfina/uso terapêutico , Acuidade Visual , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Neoplasias da Coroide/diagnóstico , Feminino , Angiofluoresceinografia/métodos , Fundo de Olho , Hemangioma/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Fotossensibilizantes/uso terapêutico , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Gastric cancer stem cell (GCSC) is implicated in gastric cancer relapse, metastasis and drug resistance. However, the key molecule(s) involved in GCSC survival and the targeting drugs are poorly understood. We discovered increased secreted clusterin (S-Clu) protein expression during the sphere-forming growth of GCSC via mass spectrometry. Overexpression of clusterin was detected in 69/90 (77%) of primary GC tissues and significantly associated with T stage, lymph node metastasis and TNM stage. Depletion of clusterin (Clu, the full-length intracellular clusterin) led to the declustering of GCSC tumorspheres and apoptosis of GCSC. Subsequently, we found clusterin was in complex with heat shock protein 90 beta (HSP90) and involved in regulating the cellular level of HSP90 client proteins. Furthermore, by screening a collection of drugs/inhibitors, we found that verteporfin (VP), a phototherapy drug, blocked clusterin gene expression, decreased the HSP90 client proteins and caused cell death of GCSC. VP treatment is more effective in eradicating GCSCs than in killing GC cells. Both clusterin silencing or VP treatment deterred tumor growth in human GCSC xenografts. These findings collectively suggest that GC patients can promptly benefit from clusterin-targeted therapy as well as VP treatment in combination with or subsequent to conventional chemotherapy for reducing mortality of GC.
Assuntos
Clusterina/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Verteporfina/farmacologia , Verteporfina/uso terapêutico , Animais , Western Blotting , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos BALB C , Ligação Proteica/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Despite advances in cancer therapies, glioblastoma multiforme treatment remains inefficient due to the brain-blood barrier (BBB) inhibitory activity and to the low temozolomide (TMZ) chemotherapeutic selectivity. To improve therapeutic outcomes, in this work we propose two strategies, (i) photodynamic therapy (PDT) as adjuvant treatment and (ii) engineering of multifunctional theranostic/targeted nanoparticles ( m-NPs) that integrate biotin as a targeting moiety with rhodamine-B as a theranostic agent in pluronic P85/F127 copolymers. These smart m-NPs can surmount the BBB and coencapsulate multiple cargoes under optimized conditions. Overall, the present study conducts a rational m-NP design, characterization, and optimizes the formulation conditions. Confocal microscopy studies on T98-G, U87-MG, and U343 glioblastoma cells and on NIH-3T3 normal fibroblast cells show that the m-NPs and the encapsulated drugs are selectively taken up by tumor cells presenting a broad intracellular distribution. The formulations display no toxicity in the absence of light and are not toxic to healthy cells, but they exert a robust synergic action in cancer cells in the case of concomitant PDT/TMZ treatment, especially at low TMZ concentrations and higher light doses, as demonstrated by nonlinear dose-effect curves based on the Chou-Talalay method. The results evidenced different mechanisms of action related to the disjoint cell cycle phases at the optimal PDT/TMZ ratio. This effect favors synergism between the PDT and the chemotherapy with TMZ, enhances the antiproliferative effect, and overcomes cross-resistance mechanisms. These results point out that m-NP-based PDT adjuvant therapy is a promising strategy to improve TMZ-based glioblastoma multiforme treatments.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Quimioterapia Adjuvante/métodos , Composição de Medicamentos/métodos , Glioblastoma/tratamento farmacológico , Nanopartículas/química , Temozolomida/uso terapêutico , Verteporfina/uso terapêutico , Animais , Neoplasias Encefálicas/patologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Sinergismo Farmacológico , Glioblastoma/patologia , Humanos , Camundongos , Microscopia de Força Atômica , Microscopia Confocal , Células NIH 3T3 , Tamanho da Partícula , Poloxaleno/química , Rodaminas/químicaRESUMO
The purpose of this study is to describe the effects and complications of photodynamic therapy (PDT) on Chinese patients with circumscribed choroidal hemangioma (CCH). In this retrospective study, 22 CCH patients who underwent PDT performed 15 min after the injection of intravenous verteporfin (6 mg/m2)with multiple 83-second laser spots at 689 nm (50 J/cm2) were studied. Fluorescein angiography and/or indocyanine green angiography, B-scan ultrasonography and optical coherence tomography were performed in all patients. Follow-up was performed until 12 months post-treatment. All patients were treated with one session, except 1 case with prior transpupillary thermotherapy history. At the 12-month follow-up, the mean of the best corrected visual acuity (BCVA) increased from 0.40 ± 0.38 to 0.56 ± 0.42 (p < 0.05), tumors became thinner (1.96 ± 2.65 mm vs. 4.31 ± 2.04 mm) (p < 0.05), and exudative detachment were diminished. The mean fovea center thickness (FCT) decreased from 540.1 ± 470.6 to 171.6 ± 79.3 µm at the 3-month follow-up. The 12-month BCVA was correlated with prior laser treatment, symptom duration, baseline CCH diameter and thickness, baseline FCT and cystoid macular edema. One patient developed a branch retinal artery occlusion. In conclusion, PDT is an effective and safe treatment for CCH. Specific PDT protocols for CCH should be standardized. The retinal arteriole should be spared during the treatment.