RESUMO
The current photodynamic therapy (PDT) is majorly hindered by the shallow penetration depth and oxygen dependency, limiting its application to deep-seated solid hypoxic tumors. Thus, it is meaningful to develop efficient X-ray mediated PDT system capable of generating reactive oxygen species (ROS) under both the normoxic and hypoxic conditions. Herein, we report the synthesis and characterization of nanocomposite, YAG:Pr@ZnO@PpIX with an amalgamation of UV-emitting Y2.99Pr0.01Al5O12 (YAG:Pr) nanoscintillator, and zinc oxide (ZnO) and protoporphyrin IX (PpIX) as photosensitizers. YAG:Pr surface was coated with a ZnO layer (â¼10â¯nm) by atomic layer deposition, and then PpIX was covalently conjugated via a linker to give YAG:Pr@ZnO@PpIX. The photo- and cathodoluminescence analyses gave the evidences of efficient energy transfer from YAG:Pr to ZnO at â¼320â¯nm, and YAG:Pr@ZnO to PpIX at Soret region (350-450â¯nm). The nanohybrid was able to produce both, Type I and Type II ROS upon direct and indirect photoactivation with UV365nm and UV290nm, respectively. In vitro cytotoxicity of non-activated YAG:Pr@ZnO@PpIX in mouse melanoma cells revealed low toxicity, which significantly enhanced upon photoactivation with UV365nm indicating the photokilling property of the nanohybrid. Overall, our preliminary studies successfully demonstrate the potential of YAG:Pr@ZnO@PpIX to overcome the limited penetration and oxygen-dependency of traditional PDT.
Assuntos
Nanocompostos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Alumínio/química , Alumínio/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Estrutura Molecular , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Praseodímio/química , Praseodímio/farmacologia , Protoporfirinas/química , Protoporfirinas/farmacologia , Propriedades de Superfície , Células Tumorais Cultivadas , Ítrio/química , Ítrio/farmacologia , Óxido de Zinco/química , Óxido de Zinco/farmacologiaRESUMO
The aim of this study was to evaluate the antitumor efficiency of chemotherapy with cisplatin alone and incorporated into europium(III)-doped yttrium vanadate nanoparticles functionalized with 3chloropropyltrimethoxysilane with folic acid and without folic acid in a syngeneic mouse melanoma model. Histopathological, biochemical and genotoxic analyses of treated animals were performed to assess the toxicity of treatments. The treatment of the animals with cisplatin alone and the nanoparticles functionalized with cisplatin at a dose of 5â¯mg/kg b.w. for 5â¯days reduced tumor weight about 86% and 65%, respectively. Histopathological analysis showed lower mean frequency of mitoses in tumor tissue of the groups receiving cisplatin alone (90% reduction) and the nanoparticles functionalized with cisplatin (70% reduction) compared to the tumor control group. A reduction in body and liver weight and an increase in serum creatinine and urea levels were observed in animals treated with CDDP, but not in those receiving the nanoparticles functionalized with cisplatin. Genotoxicity assessment by the comet assay revealed lower frequencies of DNA damage in animals treated with the nanoparticles functionalized with cisplatin (mean scoreâ¯=â¯140.80) compared to those treated with cisplatin alone (mean scoreâ¯=â¯231.80). Marked toxic effects were observed in animals treated with cisplatin alone, while treatment with the nanoparticles functionalized with cisplatin showed no toxicity. Moreover, folic acid in the inorganic nanoparticles reduced the genotoxicity of cisplatin in the bone marrow micronucleus test (10⯱â¯1.4 and 40⯱â¯0.0 micronucleus, respectively). These results demonstrate the antitumor efficiency and significantly reduced systemic toxicity of the nanoparticles compared to CDDP.
Assuntos
Cisplatino/toxicidade , Európio/farmacologia , Nanopartículas/química , Ítrio/farmacologia , Animais , Linhagem Celular Tumoral , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Európio/química , Ácido Fólico/química , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes para Micronúcleos , Baço/efeitos dos fármacos , Ítrio/químicaRESUMO
BACKGROUND: Photodynamic therapy is a promising cancer therapy modality but its application for deep-seated tumor is mainly hindered by the shallow penetration of visible light. X-ray-mediated photodynamic therapy (PDT) has gained a major attention owing to the limitless penetration of X-rays. However, substantial outcomes have still not been achieved due to the low luminescence efficiency of scintillating nanoparticles and weak energy transfer to the photosensitizer. The present work describes the development of Y2.99Pr0.01Al5O12-based (YP) mesoporous silica coated nanoparticles, multifunctionalized with protoporphyrin IX (PpIX) and folic acid (YPMS@PpIX@FA) for potential application in targeted deep PDT. RESULTS: A YP nanophosphor core was synthesized using the sol-gel method to be used as X-ray energy transducer and was then covered with a mesoporous silica layer. The luminescence analysis indicated a good spectral overlap between the PpIX and nanoscintillator at the Soret as well as Q-band region. The comparison of the emission spectra with or without PpIX showed signs of energy transfer, a prerequisite for deep PDT. In vitro studies showed the preferential uptake of the nanocomposite in cancer cells expressing the folate receptorFolr1, validating the targeting efficiency. Direct activation of conjugated PpIX with UVA in vitro induced ROS production causing breast and prostate cancer cell death indicating that the PpIX retained its activity after conjugation to the nanocomposite. The in vivo toxicity analysis showed the good biocompatibility and non-immunogenic response of YPMS@PpIX@FA. CONCLUSION: Our results indicate that YPMS@PpIX@FA nanocomposites are promising candidates for X-ray-mediated PDT of deep-seated tumors. The design of these nanoparticles allows the functionalization with exchangeable targeting ligands thus offering versatility, in order to target various cancer cells, expressing different molecular targets on their surface.
Assuntos
Substâncias Luminescentes/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/uso terapêutico , Ítrio/uso terapêutico , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Feminino , Ácido Fólico/farmacologia , Ácido Fólico/uso terapêutico , Substâncias Luminescentes/farmacologia , Masculino , Camundongos , Nanocompostos/uso terapêutico , Nanopartículas/uso terapêutico , Neoplasias/metabolismo , Fármacos Fotossensibilizantes/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/farmacologia , Dióxido de Silício/uso terapêutico , Ítrio/farmacologiaRESUMO
This study investigated changes in the roughness parameters (Sa in µm(2) and Ra in µm) of yttrium-stabilized tetragonal zirconia polycrystal (Y-TZP) and large-grit sandblasted acid-etched (SLA) titanium (TI) materials after decontamination by erbium chromium-doped:yttrium, scandium, gallium, and garnet (Er,Cr:YSGG) laser irradiation. Twenty disks were analyzed in this study: 10 disks of Y-TZP (5 mm in diameter and 3 mm in height), standardized with CAD-CAM procedures, and 10 disks of SLA TI (5 mm in diameter and 4 mm in thickness). Disks were randomized into four groups (n = 5), according to whether laser irradiation was performed: Y-TZP_G1 and TI_G1 were not treated by laser (control groups), whereas Y-TZP_G2 and TI_G2 were irradiated with Er,Cr:YSGG laser (1.5 W/20 Hz, air-water cooling proportion of 80%/25%). The surface topography of the disks was analyzed by confocal light microscopy. The mean Sa and Ra values were calculated from five profiles from each group. The results were statistically analyzed by t-test at the 95% confidence level (α = 0.05). For Y-TZP, the Sa results (in mean ± SD) for Y-TZP_G1 and Y-TZP_G2 were 2.60 ± 1.1 and 0.80 ± 0.17 µm(2), respectively, and the Ra results were 2.01 ± 0.71 and 0.18 ± 0.15 µm, respectively (both p < .05). For SLA TI, the Sa results for TI_G1 and TI_G2 were 1.99 ± 0.5 and 3.37 ± 0.75 µm(2), respectively, and the Ra results were 1.78 ± 0.53 and 3.84 ± 0.63 µm, respectively (both p < .05). Er,Cr:YSGG laser irradiation alters the surface roughness of zirconia and SLA TI.