RESUMEN
Sumoylation regulates many cellular processes, but its role in signaling via the T cell antigen receptor (TCR) remains unknown. We found that the kinase PKC-θ was sumoylated upon costimulation with antigen or via the TCR plus the coreceptor CD28, with Lys325 and Lys506 being the main sumoylation sites. We identified the SUMO E3 ligase PIASxß as a ligase for PKC-θ. Analysis of primary mouse and human T cells revealed that sumoylation of PKC-θ was essential for T cell activation. Desumoylation did not affect the catalytic activity of PKC-θ but inhibited the association of CD28 with PKC-θ and filamin A and impaired the assembly of a mature immunological synapse and central co-accumulation of PKC-θ and CD28. Our findings demonstrate that sumoylation controls TCR-proximal signaling and that sumoylation of PKC-θ is essential for the formation of a mature immunological synapse and T cell activation.
Asunto(s)
Isoenzimas/metabolismo , Proteína Quinasa C/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/enzimología , Linfocitos T/inmunología , Animales , Sitios de Unión , Antígenos CD28/metabolismo , Diferenciación Celular , Células Cultivadas , Filaminas/metabolismo , Células HEK293 , Humanos , Sinapsis Inmunológicas/metabolismo , Isoenzimas/química , Isoenzimas/deficiencia , Isoenzimas/genética , Células Jurkat , Activación de Linfocitos , Lisina/química , Ratones , Ratones Noqueados , Mutagénesis Sitio-Dirigida , Proteínas Inhibidoras de STAT Activados/metabolismo , Proteína Quinasa C/química , Proteína Quinasa C/deficiencia , Proteína Quinasa C/genética , Proteína Quinasa C-theta , Transducción de Señal , Sumoilación , Linfocitos T/citología , Células Th2/citología , Células Th2/enzimología , Células Th2/inmunologíaRESUMEN
To discover new photosensitizers with long wavelength UV-visible absorption, high efficiency, and low side effects for photodynamic therapy, here, a series of novel thieno[3,2-b]thiophene-fused BODIPY derivatives were designed, synthesized and characterized. These compounds had a distinct absorption band at 640-680 nm, fluorescence emission at 650-760 nm, and good solubility with anti-aggregation effects. These new compounds possessed obvious singlet oxygen generation ability and photodynamic anti-Eca-109 cancer cells activities in vitro. Among them, compound II4 could be well uptaked by Eca-109 cells, and result in the apoptosis after laser irradiation, and have outstanding photodynamic efficiency both in vitro and in vivo. Therefore, II4 could be considered as a potential photosensitizer drug candidate for PDT and photo-imaging.
Asunto(s)
Compuestos de Boro , Fotoquimioterapia , Fotoquimioterapia/métodos , Solubilidad , Tiofenos/farmacología , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
Photodynamic therapy (PDT) is a well-established treatment modality, typically conducted with single-wavelength irradiation, which may not always be optimal for varying tumor locations and sizes. To address this, photosensitizers with absorption wavelengths ranging from 550 to 760 nm are being explored. Herein, a series of 5,15-diaryltetrabenzoporphyrins (Ar2TBPs) were synthesized. All compounds displayed obvious absorption at 550-700 nm (especially at â¼668 nm), intense fluorescence, efficient generation of singlet oxygen and good photodynamic antitumor effects. Notably, compound I3 (5,15-bis[(4-carboxymethoxy)phenyl]tetrabenzoporphyrin) showed excellent cytotoxicity against Eca-109 cell line upon red light irradiation, with an IC50 value of 0.45 µM, and phototherapeutic index of 25.8. Flow cytometry revealed that I3 could induce distinct cell apoptosis. In vivo studies revealed that compound I3 selectively accumulated at tumor site and exhibited outstanding PDT effect with antitumor activity under single-time administration and light irradiation, and revealed more efficiency than the clinical photosensitizer Verteporfin. These findings underscore the considerable promise of I3 as a robust theranostic agent, offering capabilities in real-time fluorescence imaging and serving as a potent photosensitizer for personalized and precise photodynamic therapy of tumors.
RESUMEN
The synthesis of ideal photosensitizers (PSs) is considered to be the most significant bottleneck in photodynamic therapy (PDT). To discover novel PSs with excellent photodynamic anti-tumor activities, a series of novel photosensitizers 5,15-diaryl-10,20-dibromoporphyrins (I1-6) were synthesized by a facile method. Compared with hematoporphyrin monomethyl ether (HMME) as the representative porphyrin-based photosensitizers, it is found that not only the longest absorption wavelength of all compounds was red-shifted to therapeutic window (660 nm) of photodynamic therapy, but also the singlet oxygen quantum yields were significantly increased. Furthermore, all compounds exhibited lower dark toxicity (except I2) and stronger phototoxicity (except I4) against Eca-109 tumor cells than HMME. Among them, I3 possessed the highest singlet oxygen quantum yield (ΦΔ = 0.205), the lower dark toxicity and the strongest phototoxicity (IC50 = 3.5 µM) in vitro. The findings indicated the compounds I3 had the potential to become anti-tumor agents for PDT.
Asunto(s)
Neoplasias , Fotoquimioterapia , Porfirinas , Humanos , Fármacos Fotosensibilizantes/química , Oxígeno Singlete/química , Porfirinas/química , Neoplasias/tratamiento farmacológicoRESUMEN
Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T-cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the polyUb chain transfer and the higher binding affinity of TAK1 and p38IP for polyUb-bound TAB2 and TAK1, respectively. Moreover, p38IP scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Lipopolisacáridos , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Humanos , FN-kappa B/genética , FN-kappa B/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Transducción de Señal , Proteasas Ubiquitina-EspecíficasRESUMEN
The fast-rising CRISPR-derived gene editing technologies has been widely used in the fields of life science and biomedicine, as well as plant and animal breeding. However, the efficiency of homology-directed repair (HDR), an important strategy for gene knock-in and base editing, remains to be improved. In this study, we came up with the term Donor Adapting System (DAS) to summarize those CRISPR/Cas9 systems modified with adaptor for driving aptamer-fused donor DNA. A set of CRISPR/Cas9-Gal4BD DAS was designed in our study. In this system, Gal4 DNA binding domain (Gal4BD) is used as adaptor to fuse with Cas9 protein, and Gal4 binding sequence (Gal4BS) is used as aptamer to bind to the double-stranded DNA (dsDNA) donor, in order to improve the HDR efficiency. Preliminary results from the HEK293T-HDR.GFP reporter cell line show that the HDR editing efficiency could be improved up to 2-4 times when donor homologous arms under certain length (100-60 bp). Further optimization results showed that the choice of fusion port and fusion linker would affect the expression and activity of Cas9, while the Cas9-Gal4BD fusion with a GGS5 linker was the prior choice. In addition, the HDR efficiency was likely dependent on the aptamer-dsDNA donor design, and single Gal4BD binding sequence (BS) addition to the 5'-end of intent dsDNA template was suggested. Finally, we achieved enhanced HDR editing on the endogenous AAVS1 and EMX1 sites by using the CRISPR/Gal4BD-Cas9 DAS, which we believe can be applied to facilitate animal molecular design breeding in the future.
Asunto(s)
Sistemas CRISPR-Cas , Reparación del ADN por Recombinación , Animales , Humanos , ADN , Células HEK293RESUMEN
A photosensitizer with high phototoxicity, suitable amphipathy and low dark toxicity could play a pivotal role in photodynamic therapy (PDT). In this study, a facile and versatile approach was adopted to synthesize a series of novel fluorinated hematoporphyrin ether derivatives (I1-I5 and II1-II4), and the photodynamic activities of these compounds were studied. Compared to hematoporphyrin monomethyl ether (HMME), all PSs showed preferable photodynamic activity against A549 lung tumor cells. The longest visible absorption wavelength of these compounds was approximately 622 nm. Among them, II3 revealed the highest singlet oxygen yield (0.0957 min-1), the strongest phototoxicity (IC50 = 1.24 µM), the lowest dark toxicity in vitro, and exhibited excellent anti-tumor effects in vivo. So compound II3 could act as new drug candidate for photodynamic therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Éteres/uso terapéutico , Hematoporfirinas/uso terapéutico , Hidrocarburos Fluorados/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/uso terapéutico , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/efectos de la radiación , Teoría Funcional de la Densidad , Éteres/síntesis química , Éteres/efectos de la radiación , Femenino , Hematoporfirinas/síntesis química , Hematoporfirinas/efectos de la radiación , Humanos , Hidrocarburos Fluorados/síntesis química , Hidrocarburos Fluorados/efectos de la radiación , Luz , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Químicos , Neoplasias/patología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/efectos de la radiación , Oxígeno Singlete/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Antibiotic resistance is increasing day by day, thereby increase the chances of more infections by resistant bacteria. In this situation, antimicrobial photodynamic therapy (aPDT) is gaining more attraction. OBJECTIVE: To evaluate the antimicrobial effect of ALA derivatives using photodynamic therapy. MATERIALS AND METHODS: In this study, we evaluated the aPDT effect of different derivatives of 5-ALA. In vivo and in vitro studies were performed to measure the antimicrobial activity. Different light doses and different concentrations of drugs were used to test anti-bacterial effect of drugs as well as to detect any physiological changes in animal model after the treatment. RESULTS: In vivo studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are potent photosensitizers. In vitro studies involved wound healing rate, body weight, and dietary intake were evaluated, and results showed that ALA, ALA-methyl ester, ALA-hexyl ester, and ALA-13A had good anti-bacterial effects, fast healing rate, and no effect on other physical parameters. CONCLUSION: Photodynamic therapy is increasingly used to treat different types of skin infections caused by bacterial strains. Our studies revealed that ALA-methyl ester, ALA-hexyl ester, and ALA-13A are promising photosensitizers for photodynamic therapy to inhibit the growth of resistant bacterial strains.
Asunto(s)
Antiinfecciosos , Fotoquimioterapia , Ácido Aminolevulínico/farmacología , Animales , Antiinfecciosos/farmacología , Ésteres , Preparaciones Farmacéuticas , Fármacos Fotosensibilizantes/farmacologíaRESUMEN
A series of new fluoro-substituted benzimidazole derivatives were designed, synthesized and pharmacologically evaluated. All the target compounds were characterized by 1HNMR, 13CNMR, mass spectra and elemental analysis. The biological evaluation showed that most of the synthesized compounds displayed nanomolar affinity to the angiotensin II type 1 (AT1) receptor and could decrease blood pressure efficiently in spontaneously hypertensive rats. The maximal response of mean blood pressure (MBP) lowered 74.5 ± 3.5 mmHg (1g) and 69.2 ± 0.9 mmHg (2a) at 10 g/kg after oral administration, and the antihypertensive effect lasted beyond 24 h, which performed better than both losartan and telmisartan. So, compounds 1g and 2a may be considered as potential antihypertension drug candidates.
Asunto(s)
Antihipertensivos/uso terapéutico , Bencimidazoles/síntesis química , Bencimidazoles/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Animales , Antihipertensivos/farmacología , Diseño de Fármacos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A primitive adaptive immune system has recently been suggested to be present in a basal chordate amphioxus (Branchiostoma belcheri, Bb), making it an ideal model for studying the origin of adaptive immune. The novel protein kinase C isoform PKC-θ, but not its closest isoform PKC-δ, plays a critical role for mammalian T-cell activation via translocation to immunological synapse (IS) mediated by a unique PKC-θ V3 domain containing one PxxP motif. To understand the evolution of this unique PKC-θ V3 domain and the primitive adaptive immune system in amphioxus, we comparatively studied the orthologs of PKC-δ and -θ from amphioxus and other species. Phylogenetic analysis showed BbPKC-δ/θ to be the common ancestor of vertebrate PKC-δ and PKC-θ, with a V3 domain containing two PxxP motifs. One motif is conserved in both zebrafish and mammalian PKC-θ but is absent in PKC-δ V3 domain of these species, and has already emerged in drosophila PKC-δ. The other non-conserved motif emerged in BbPKC-δ/θ, and only retained in Danio rerio PKC-δ (DrPKC-δ) but lost in mammalian PKC-δ and -θ. Comparative analyses of the sequence and function of BbPKC-δ/θ, DrPKC-δ, DrPKC-θ and Homo sapiens PKC-θ (HsPKC-θ) in IS translocation and T-cell receptor (TCR)-induced NF-κB activation revealed that retention of the conserved PxxP motif and loss of the non-conserved PxxP motif in mammalian PKC-θ and loss of both PxxP motifs in mammalian PKC-δ accomplish the unique function of PKC-θ in T cells. Together, this study suggests an evolutionary mechanism for PKC-θ unique V3 and reveals BbPKC-δ/θ is the common ancestor of PKC-δ and -θ with a functional proto-V3 domain, supplying new evidence for the existence of primitive adaptive immune system in amphioxus.
Asunto(s)
Inmunidad Adaptativa/genética , Enfermedades de los Peces/inmunología , Regulación de la Expresión Génica/inmunología , Anfioxos/genética , Anfioxos/inmunología , Proteína Quinasa C-delta/genética , Proteína Quinasa C-delta/inmunología , Proteína Quinasa C-theta/genética , Proteína Quinasa C-theta/inmunología , Secuencia de Aminoácidos , Animales , Perfilación de la Expresión Génica/veterinaria , Anfioxos/enzimología , Filogenia , Proteína Quinasa C-delta/química , Proteína Quinasa C-theta/química , Alineación de Secuencia/veterinariaRESUMEN
A novel 131-pyridine substituted chlorin e6 derivative (Chlorin A) was synthesized. It has characteristic long wavelength absorption at 664â¯nm and the emission wavelength at 667â¯nm. The generation rate of singlet oxygen of this compound is higher than Temoporfin. In vitro, Chlorin A showed higher phototoxicity against the human esophageal cancer cells than Temoporfin while with lower dark-toxicity. Its accumulation effect in mitochondria, lysosomes and endoplasmic reticulum was traced in subcellular localization tests. In flow cytometry obvious apoptosis cells were observed after 2â¯h irradiation. Significant in vivo photodynamic anti-tumor efficacy was also exhibited on mice bearing esophageal cancer. So Chlorin A could be suggested as a promising anti-tumor drug candidate in photodynamic therapy.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Esofágicas/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Porfirinas/farmacología , Piridinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Neoplasias Esofágicas/patología , Humanos , Ratones , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Porfirinas/síntesis química , Porfirinas/química , Piridinas/síntesis química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Three novel 173-dicarboxylethyl-pyropheophorbide-a amide derivatives as photosensitizers for photodynamic therapy (PDT) were synthesized from pyropheophorbide-a (Ppa). Their photophysical and photochemical properties, intracellular localization, photocytotoxicity in vitro and in vivo were investigated. All target compounds exhibited low cytotoxicity in the dark and remarkable photocytotoxicity against human esophageal cancer cells. Among them, 1a showed highest singlet oxygen quantum yield. Upon light activation, 1a exhibited significant photocytotoxicity. After PDT treatment, the growth of Eca-109 tumor in nude mice was significantly inhibited. Therefore, 1a is a powerful and promising antitumor photosensitizer for PDT.
Asunto(s)
Antineoplásicos/farmacología , Clorofila/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Clorofila/análogos & derivados , Clorofila/síntesis química , Clorofila/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Conformación Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Oxígeno Singlete/química , Oxígeno Singlete/metabolismo , Relación Estructura-ActividadRESUMEN
Protoporphyrin IX (PpIX) is used as a photosensitizer in the photodynamic diagnosis (PDD) and photodynamic therapy (PDT) of cancer and is synthesized intracellularly from 5-aminolevulinic acid (5-ALA) precursors. Thirteen novel 5-ALA derivatives were designed and synthesized appropriately with tailored hydrophilicity and lipophilicity. The generation of PpIX was detected and their antitumor activity in vitro and in vivo was also investigated. It was shown that compounds 9b-c, 11b-c and 13a displayed a characteristic long wavelength absorption peak at 593 nm after 5 h incubation in mice fibrosarcoma S180 cells. After being exposed to 600 nm laser light irradiation, these compounds can inhibit cell proliferation in S180 cells in vitro. The growth of S180 cell tumors in Kunming mice was significantly inhibited by these compounds in vivo. Among these compounds, 13a has low dark toxicity and high phototoxicity, which makes it an effective and promising prodrug for PDT.
Asunto(s)
Ácido Aminolevulínico/farmacología , Antineoplásicos/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Profármacos/farmacología , Protoporfirinas/farmacología , Ácido Aminolevulínico/síntesis química , Ácido Aminolevulínico/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Masculino , Ratones , Ratones Endogámicos , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Profármacos/síntesis química , Profármacos/química , Protoporfirinas/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of 2-morpholinetetraphenylporphyrins functionalized with various substituents (Cl, Me, MeO group) at 4-phenyl position were prepared via nucleophilic substitution of 2-nitroporphyrin copper derivatives with morpholine by refluxing under a nitrogen atmosphere and then demetalization. Their basic photophysical properties, intracellular localization, cytotoxicities in vitro and in vivo were also investigated. All synthesized photosensitizers exhibited longer maxima absorption wavelengths than Hematoporphyrin monomethyl ether (HMME). They showed low dark cytotoxicity compared with that of HMME and were more phototoxic than HMME against Eca-109 cells in vitro. M3 also exhibited better photodynamic antitumor efficacy on BALB/c nude mice at a lower concentration. Therefore, M3 is a promising antitumor photosensitizer in photodynamic therapy application.
Asunto(s)
Morfolinas/química , Morfolinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Porfirinas/química , Porfirinas/uso terapéutico , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Hematoporfirinas/farmacología , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Morfolinas/síntesis química , Morfolinas/farmacología , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Porfirinas/síntesis química , Porfirinas/farmacologíaRESUMEN
This study aimed to investigate the effect of hematoporphyrin dimethylether (HDME)-mediated photodynamic therapy for laser-induced choroidal neovascularization (CNV) in adult Brown Norway rats. HDME was administered via tail vein at 14 d after the laser photocoagulation, and the rats received irradiance with a laser light at 570 nm at 15 min after injection. CNV was evaluated by fundus photography, fundus fluorescein angiography, optical coherence tomography, and hematoxylin and eosin staining. We found that CNV was occurred at 7 d after photocoagulation and reaching peak activity at 14 d after photocoagulation. There is a significant reduction in the total area of the fluorescein leakage and the number of strong fluorescein leakage spots on 7 d after HDME-mediated photodynamic therapy (PDT). The results suggest that HDME-mediated PDT inhibits laser-induced CNV in rats, representing a promising therapy for wet age-related macular degeneration.
Asunto(s)
Neovascularización Coroidal/tratamiento farmacológico , Hematoporfirinas/uso terapéutico , Éteres Metílicos/uso terapéutico , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes/uso terapéutico , Animales , Permeabilidad Capilar , Neovascularización Coroidal/diagnóstico por imagen , Neovascularización Coroidal/etiología , Modelos Animales de Enfermedad , Angiografía con Fluoresceína , Fondo de Ojo , Hematoporfirinas/química , Humanos , Rayos Láser/efectos adversos , Masculino , Éteres Metílicos/química , Fármacos Fotosensibilizantes/química , Ratas , Ratas Endogámicas BNRESUMEN
A novel porphyrin derivative, 5, 10, 15, 20-tetrakis (5-morpholinopentyl)-21H, 23H-Porphin (MPP, 4) and its photophysical characteristics, therapeutic efficacy of photodynamic therapy (PDT) in vitro and in vivo, tumor selectivity, and clearance from normal tissues were investigated here. MPP has strong absorption at relatively long wavelength (λmax = 648 nm, molar absorption coefficient ε â¼ 17,200 M(-1)cm(-1)) and can emit strong fluorescence at 653 and 718 nm. When administered to the animal tumor models by tail vein injection, MPP was capable of accumulating in the tumor site, as examined in vivo with the fluorescence signal of MPP. By the combination of MPP and a 650-nm laser irradiation, the viability of T24 cells could decrease by 4.37 %, and inhibition rate of T24 tumor could increase up to 91.21 % compared with control group, demonstrating the potential of MPP as an effective photosensitizer in PDT for tumor treatment.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Fotoquimioterapia , Porfirinas/síntesis química , Porfirinas/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Ratones , Análisis Espectral , Distribución Tisular , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of ß-alkylaminoporphyrins conjugated with different amines at ß position (D1-D3) or with electron-donating and electron-withdrawing substituents at phenyl position (D4-D6) were synthesized. Their photophysical and photochemical properties, intracellular localization, photocytotoxicities in vitro and vivo were also investigated. All target compounds exhibited no cytotoxicities in the dark and excellent photocytotoxicities against HeLa cells. Among them, D6 showed the highest phototoxicity and the lowest dark toxicity, which was more phototoxic than Hematoporphyrin monomethyl ether (HMME). In addition, D6 exhibited best photodynamic antitumor efficacy on BALB/c nude mice bearing HeLa tumor. Therefore, D6 is a powerful and promising antitumor photosensitizer for photodynamic therapy.
Asunto(s)
Antineoplásicos/farmacología , Fotoquimioterapia , Porfirinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/patología , Procesos Fotoquímicos , Porfirinas/síntesis química , Porfirinas/química , Relación Estructura-ActividadRESUMEN
In this paper, the antitumor activity of a novel porphyrin-based photosensitizer 5,10,15,20-tetrakis[(5-diethylamino)pentyl] porphyrin (TDPP) was reported in vitro and in vivo. The photophysical and cellular properties of TDPP were investigated. The singlet oxygen generation quantum yield of TDPP was detected; it showed a high singlet oxygen quantum yield of 0.52. The intracellular distribution of photosensitizer was detected with laser scanning confocal microscopy. The efficiency of TDPP-photodynamic therapy (PDT) in vitro was analyzed by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay and in situ trypan blue exclusion test. Treated with a 630-nm laser, TDPP can kill cultured human esophageal cancer cell line (Eca-109) cells and reduce the growth of Eca-109 xenograft tumors significantly in BABL/c nude mice. And histopathological study was also used to confirm the antitumor effect. It has the perspective to be developed as a new antitumor drug in photodynamic therapy and deserves further investigation.
Asunto(s)
Neoplasias Esofágicas/tratamiento farmacológico , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Neoplasias Esofágicas/patología , Humanos , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chlorin derivatives are promising photosensitive agents for photodynamic therapy (PDT) of tumors. The aim of the current study is to investigate the PDT therapeutic effects of a novel chlorin-based photosensitizer, meso-tetra[3-(N,N-diethyl)aminomethyl-4-methoxy]phenyl chlorin (TMPC) for gliomas in vitro and in vivo. Physicochemical characteristics of TMPC were recorded by ultraviolet visible spectrophotometer and fluorescence spectrometer. The rate of singlet oxygen generation of TMPC upon photo-excitation was detected by using 1,3-diphenylisobenzofuran (DPBF). The accumulation of TMPC in gliomas U87 MG cells was measured by fluorescence spectrometer. The efficiency of TMPC-PDT in vitro was analyzed by MTT assay and clonogenic assay. The biodistribution and clearance of TMPC were determined by fluorescence measuring. Human gliomas U87 MG tumor-bearing mice model was used to evaluate the antitumor effects of TMPC-PDT. TMPC shows a singlet oxygen generation rate of 0.05 and displays a characteristic long wavelength absorption peak at 653 nm (ε = 15,400). The accumulation of TMPC increased with the increase of incubation time. In vitro, PDT using TMPC and laser showed laser dose- and concentration-dependent cytotoxicity to U87 MG cells. In U87 MG tumor-bearing mice, TMPC-PDT significantly reduced the growth of the tumors. Both in vitro and in vivo, TMPC showed little dark toxicity. In vitro and in vivo studies, it found that TMPC has excellent antitumor activities. It suggests that TMPC is a potential photosensitizer of photodynamic therapy for cancer.
Asunto(s)
Glioma/terapia , Fotoquimioterapia , Fármacos Fotosensibilizantes/administración & dosificación , Porfirinas/administración & dosificación , Animales , Línea Celular Tumoral , Glioma/patología , Humanos , Ratones , Porfirinas/química , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new compound 2-(4-((2-butyl-5-nitro-1H-benzo[d]imidazol-1-yl)methyl)-1H-indol-1-yl) benzamide (1) was designed, synthesized and evaluated as a novel AT1 receptor antagonist. Compound 1 displayed high affinity to AT1 receptor with an IC50 value of 1.65 ± 0.2 nM in radio-ligand binding assays. It had an efficient and long-lasting effect in reducing blood pressure which could last for more than 12 h at the dose of 10 mg/kg in spontaneously hypertensive rats. Acute toxicity tests suggested that compound 1 was safe with the LD50 value of 2519.81 mg/kg. Besides, in vitro and in vivo tests suggested its anti-proliferative and anti-tumor activities, respectively. So compound 1 could be considered as a novel anti-hypertension, anti-tumor candidate and deserved further investigation.