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1.
Sci Rep ; 10(1): 1462, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996727

RESUMO

Gliomas are infiltrative brain tumors with a margin difficult to identify. 5-ALA induced PpIX fluorescence measurements are a clinical standard, but expert-based classification models still lack sensitivity and specificity. Here a fully automatic clustering method is proposed to discriminate glioma margin. This is obtained from spectroscopic fluorescent measurements acquired with a recently introduced intraoperative set up. We describe a data-driven selection of best spectral features and show how this improves results of margin prediction from healthy tissue by comparison with the standard biomarker-based prediction. This pilot study based on 10 patients and 50 samples shows promising results with a best performance of 77% of accuracy in healthy tissue prediction from margin tissue.


Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Aprendizado de Máquina , Ácido Aminolevulínico/metabolismo , Biomarcadores Tumorais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Análise por Conglomerados , Simulação por Computador , Glioma/patologia , Humanos , Margens de Excisão , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Protoporfirinas/química , Espectrometria de Fluorescência
2.
Adv Mater ; 31(52): e1904997, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31721331

RESUMO

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non-small-cell lung cancer because of its limited expression of PD-L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid-derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA-CuS/DTX@PEI-PpIX-CpG nanocomposites, denoted as FA-CD@PP-CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)-enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA-CD@PP-CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1-tumor-bearing mice modal. A low dosage of loaded DTX in FA-CD@PP-CpG can promote infiltration of CTLs to improve efficacy of anti-PD-L1 antibody (aPD-L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA-CD@PP-CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel-enhanced immunotherapy for clinical application of breast cancer.


Assuntos
Docetaxel/química , Oligonucleotídeos/química , Linfócitos T Citotóxicos/imunologia , Animais , Anticorpos Monoclonais Humanizados/química , Anticorpos Monoclonais Humanizados/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cobre/química , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Portadores de Fármacos/química , Ácido Fólico/química , Humanos , Imunoterapia , Lasers , Camundongos , Nanocompostos/química , Fototerapia , Polietilenoimina/química , Protoporfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
3.
J Photochem Photobiol B ; 201: 111640, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31734545

RESUMO

Fluorescence image guided surgical resection (FIGR) of high grade gliomas (HGGs) takes advantage of the accumulation of the tracer protoporphyrin IX (PpIX) in glioma cells following administration of 5-aminolevulinic acid (5-ALA). Occasionally, PpIX fluorescence intensity may be insufficient, thus compromising the efficacy and precision of the surgical intervention. The cause for the signal variation is unclear and strategies to improve the intensity of PpIX fluorescence are considered necessary. We have previously shown that differential expression of the epidermal growth factor receptor in glioblastoma cells affects PpIX fluorescence. Herein, we investigated other factors impairing PpIX accumulation and pharmacological treatments able to enhance PpIX fluorescence in glioblastoma cells displaying lower signal. In the present study we demonstrate that presence of serum in cell culture medium and differences in cellular confluence can negatively influence PpIX accumulation in U87 cell lines. We hypothesized that PpIX fluorescence intensity results from the interplay between the metabolic clearance of PpIX mediated by ferrochelatase and heme oxygenase-1 and the cellular efflux of PpIX through the ATP-binding cassette subfamily G member 2 (ABCG2). Based on the availability of compounds targeting these proteins and inhibiting them, in this study we used modulators such as genistein, an isoflavone able to inhibit ABCG2; deferoxamine, which chelate iron ions impairing FECH activity and tin protoporphyrin IX (SnPP), the specific HO-1 inhibitor. Finally, we showed the efficacy of a precisely tuned pharmacological treatment in increasing PpIX accumulation and consequently fluorescence in glioblastoma cells. This strategy may translate in more sensitive tracing of tumor cells in-vivo and improved FIGR of HGGs and possibly low grade gliomas (LGGs).


Assuntos
Corantes Fluorescentes/química , Microscopia Confocal , Protoporfirinas/química , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Ácido Aminolevulínico/farmacologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/metabolismo , Corantes Fluorescentes/metabolismo , Genisteína/metabolismo , Genisteína/farmacologia , Glioblastoma/patologia , Heme Oxigenase-1/antagonistas & inibidores , Heme Oxigenase-1/metabolismo , Humanos , Metaloporfirinas/química , Metaloporfirinas/metabolismo , Metaloporfirinas/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Protoporfirinas/metabolismo , Protoporfirinas/farmacologia
4.
Molecules ; 24(22)2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31752075

RESUMO

The fabrication of controlled supramolecular nanostructures via self-assembly of protoporphyrin IX (PPIX) was studied with enantiomerically pure l-arginine and d-arginine, and we have shown that stoichiometry controlled the morphology formed. The nanostructure morphology was mainly influenced by the delicate balance of π-π stacking interactions between PPIX cores, as well as H-bonding between the deprotonated acidic head group of PPIX with the guanidine head group of arginine. PPIX self-assembled with l-/d-arginine to create rose-like nanoflower structures for four equivalents of arginine that were 5-10 µm in length and 1-4 µm diameter. We employed UV-vis, fluorescence spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD), dynamic light scattering (DLS) and Fourier transform infrared spectroscopy (FT-IR) techniques to characterize the resulting self-assembled nanostructures. Furthermore, we investigated the catalytic activity of PPIX and arginine co-assembled materials. The fabricated PPIX-arginine nanostructure showed high enhancement of photocatalytic activity through degradation of rhodamine B (RhB) with a decrease in dye concentration of around 78-80% under simulated visible radiation.


Assuntos
Arginina/química , Nanopartículas/química , Protoporfirinas/química , Catálise , Luz , Água
5.
Australas Phys Eng Sci Med ; 42(4): 1039-1047, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617155

RESUMO

Sonodynamic therapy (SDT) is a new manner of killing cancer cells based on the cytotoxic interactions of ultrasound with sonosensitizing agents. It is shown that gold nanoparticles (GNPs) increase the efficiency of cavitation activity of ultrasound. In this study the influence of a single and/or two frequencies of ultrasound waves to generate hydroxyl radicals (·OH) was assessed in the presence of protoporphyrin IX (PpIX) and/or GNPs. Ultrasound cavitation activity was determined by recording fluorescence signals from chemical terephthalic acid (TA) dosimeters with or without PpIX and/or GNPs at the frequencies of 0.8 and 2.4 MHz individually and aggregately. To study hydroxyl radicals, experiments were performed with and without hydroxyl radical scavengers mannitol, histidine, and sodium azide. Cavitation activity was amplified by increasing ultrasound intensity and exposure time. The cavitation activity induced by dual ultrasound frequency was remarkably higher than the summation of effects produced by individual frequencies. All three scavengers reduced the fluorescence signal level. The effect of GNPs on intensifying cavitation activity at higher frequency was greater than that of lower frequency. PpIX showed a more effective sonosensitizing property at the lower frequency. Also, estimated synergism at dual frequency irradiation was improved in the presence of GNPs. We found that GNPs increased hydroxyl radical production at 2.4 MHz and that PpIX increased hydroxyl radical production at 0.8 MHz. Dual frequency exposure was more effective than single frequency exposure. PpIX at low frequency and gold nanoparticles at high frequency both enhance sonodynamic treatment efficacy.


Assuntos
Ouro/química , Radical Hidroxila/química , Nanopartículas Metálicas/química , Protoporfirinas/química , Ultrassom , Fluorescência , Ácidos Ftálicos/química , Radiometria , Processamento de Sinais Assistido por Computador
6.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614426

RESUMO

Head and neck squamous cell carcinomas (HNSCC) have a high mortality rate, although several potential therapeutic targets have already been identified. Gonadotropin-releasing hormone receptor (GnRH-R) expression is less studied in head and neck cancers, hence, we investigated the therapeutic relevance of GnRH-R targeting in HNSCC patients. Our results indicate that half of the patient-derived samples showed high GnRH-R expression, which was associated with worse prognosis, making this receptor a promising target for GnRH-based drug delivery. Photodynamic therapy is a clinically approved treatment for HNSCC, and the efficacy and selectivity may be enhanced by the covalent conjugation of the photosensitizer to a GnRH-R targeting peptide. Several native ligands, gonadotropin-releasing hormone (GnRH) isoforms, are known to target GnRH-R effectively. Therefore, different 4Lys(Bu) modified GnRH analogs were designed and conjugated to protoporphyrin IX. The receptor binding potency of the novel conjugates was measured on human pituitary and human prostate cancer cells, indicating only slightly lower GnRH-R affinity than the peptides. The in vitro cell viability inhibition was tested on Detroit-562 human pharyngeal carcinoma cells that express GnRH-R in high levels, and the results showed that all conjugates were more effective than the free protoporphyrin IX.


Assuntos
Neoplasias de Cabeça e Pescoço/metabolismo , Peptídeos/administração & dosagem , Protoporfirinas/química , Receptores LHRH/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Regulação para Cima , Adulto , Idoso , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/farmacologia , Fotoquimioterapia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Análise de Sobrevida , Análise Serial de Tecidos , Regulação para Cima/efeitos dos fármacos
7.
Mater Sci Eng C Mater Biol Appl ; 104: 109979, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500001

RESUMO

The efficacy of photodynamic therapy (PDT) is reduced in the context of hypoxic environments. This is problematic, considering that hypoxia is exhibited in the vast majority of malignant tumors. Thus, increasing the concentration of oxygen in malignant tumors improves PDT treatment outcomes. Studies show that MnO2 nanoparticles can produce oxygen when it reacts with endogenous H2O2. Herein, we encapsulated Protoporphyrin IX (PPIX) in the liposome bilayer (PPIX-Lipo), which was then coated with MnO2 nanoparticles to construct PPIX-Lipo-MnO2 (PPIX-Lipo-M) in order to enhance PDT efficacy under tumor hypoxia. The PDT results show that PPIX-Lipo-M was more cytotoxic to breast cancer cells than PPIX-Lipo while under hypoxic conditions, indicating that the production of oxygen gas in hypoxic conditions improved treatment outcomes. Upon encapsulating PPIX into the liposome, the aqueous solubility of PPIX significantly improved. Consequently, the cellular uptake of both PPIX-Lipo and PPIX-Lipo-M also increased significantly compared to that of bare PPIX. Overall, PPIX-Lipo-M has the capacity to act as a therapeutic agent that relieves hypoxia and hence improve PDT efficacy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Lipossomos/química , Compostos de Manganês/química , Óxidos/química , Protoporfirinas/química , Protoporfirinas/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Peróxido de Hidrogênio/farmacologia , Células MCF-7 , Nanopartículas/química , Oxigênio/química , Fotoquimioterapia/métodos
8.
J Fluoresc ; 29(5): 1089-1101, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31372800

RESUMO

In this paper, L-cysteine capped Ag doped ZnS nanoparticles (NPs) were synthesized and its usage in photodynamic therapy was examined. Also, the details of the conjugation method for prepared NPs with sensitizer of protoporphyrin IX (PpIX) were reported. FT-IR studies indicate the formation of ZnS:Ag nanoparticles capped with L-cysteine and an amide-bond formation between PpIX and L-cysteine-capped ZnS:Ag NPs. The formation of ZnS:Ag NPs conjugated to protoporphyrin IX was confirmed through the use of SEM, TEM, UV-Visible, FT-IR and DLS analysis. The efficient energy transfer from ZnS:Ag to PpIX sensitizer was estimated at about 90%. The production of reactive oxygen species, including singlet oxygen and free radicals, from ZnS:Ag NPs conjugated to protoporphyrin IX, was observed using a chemical method. The production of reactive oxygen species of this conjugate indicates its potential application in photodynamic therapy.


Assuntos
Corantes Fluorescentes/química , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/análise , Cisteína/química , Transferência de Energia , Corantes Fluorescentes/síntese química , Estrutura Molecular , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Protoporfirinas/química , Espécies Reativas de Oxigênio/metabolismo , Prata/química , Sulfetos/química , Compostos de Zinco/química
9.
J Photochem Photobiol B ; 199: 111585, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31450131

RESUMO

Thiosemicarbazone derivatives are known for their broad biological activity including their antitumor potency. The aim of the current study was to examine the effect of a novel series of non-toxic iron chelators on the accumulation of protoporphyrin IX after external 5-aminolevulonic acid administration. From this series we selected one the most promising derivative which causes a pronounced increase in the concentration of protoporphyrin IX. The increase of the photosensitizer concentration is necessary for the trigger the efficient therapeutic effect of the photodynamic reaction. For selected compound 2 we performed an examination of a panel of the genes that are involved in the heme biosynthesis and degradation. Results indicated the crucial roles of ferrochelatase and heme oxygenase in the described processes. Surprisingly, there was a strict dependence on the type of the tested cell line. A decrease in the expression of the two aforementioned enzymes after incubation with compound 2 and 5-aminolevulonic acid is a commonly known fact and we detected this trend for the MCF-7 and HCT 116 cell lines. However, we noticed the upregulation of the tested targets for the Hs683 cells. These unconventional results prompted us to do a more in-depth analysis of the described processes. In conclusion, we found that compound 2 is a novel, highly effective booster of photodynamic therapy that has prospective applications.


Assuntos
Antineoplásicos/síntese química , Ferro/química , Fármacos Fotossensibilizantes/síntese química , Protoporfirinas/química , Tiossemicarbazonas/metabolismo , Células A549 , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Desenho de Fármacos , Ferroquelatase/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Heme Oxigenase (Desciclizante)/metabolismo , Humanos , Células MCF-7 , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Protoporfirinas/farmacologia , Tiossemicarbazonas/síntese química
10.
Talanta ; 204: 812-816, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357368

RESUMO

The expression variations of uracil-DNA glycosylase (UDG) can be used as effective biomarkers for the evaluation of gene regulation and related diseases. Here, by using a new target-triggered activation of rolling circle amplification (RCA) signal enhancement strategy, we have established a sensitive and label-free fluorescent approach for UDG activity detection and inhibition. The target UDG specifically recognizes and excises the uracil bases in a three-strand containing DNA complex to liberate one of the strands. Subsequent ligation of the excised DNA complex converts it into a suitable primer/circular template structure for the initiation of RCA for the generation of long DNA sequences with many repeated G-quadruplexes. Protoporphyrin IX further binds these G-quadruplexes to show substantially enhanced fluorescence to achieve sensitive detecting the activity of UDG with the detection limit as low as 0.00014 U mL-1. Besides, this assay approach has a high specificity toward UDG and can also be utilized to evaluate its inhibition by the uracil glycosylase inhibitor, highlighting the promising applications for convenient and sensitive UDG activity detection and inhibition for disease diagnosis and drug screening.


Assuntos
Uracila-DNA Glicosidase/análise , Sequência de Bases , Sondas de DNA/química , Sondas de DNA/genética , Ensaios Enzimáticos/métodos , Quadruplex G , Humanos , Limite de Detecção , Técnicas de Amplificação de Ácido Nucleico/métodos , Hibridização de Ácido Nucleico , Protoporfirinas/química , Espectrometria de Fluorescência/métodos , Uracila-DNA Glicosidase/antagonistas & inibidores
11.
Biol Pharm Bull ; 42(7): 1199-1206, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257295

RESUMO

Metalloporphyrin derivatives have been investigated for their therapeutic potential for oxidative stress-related diseases because of their scavenging of reactive oxygen species (ROS). Here, we describe the synthesis, physicochemical properties, and ROS-scavenging activities of one such derivative-polyethylene glycol (PEG)-conjugated manganese protoporphyrin (PEG-MnPP). Carboxyl groups of the protoporphyrin ring at the C6 and C7 positions were first conjugated with ethylenediamine to introduce amino groups into the protoporphyrin structure. The amino groups were then reacted with succinimidyl PEG, with an average molecular weight of 2000, to obtain pegylated protoporphyrin (PEG-PP). Manganese was chelated to the protoporphyrin ring by incubating PEG-PP and manganese acetate in methanol. Dynamic light scattering and fluorescent spectrometry analyses revealed that PEG-MnPP self-assembled into nanoparticles in aqueous media with an apparent diameter of 70 nm. PEG-MnPP effectively eliminated hydrogen peroxide from cell culture media and protected cultured mammalian cells from toxic insults induced by hydrogen peroxide exposure or by 6-hydroxydopamine treatment. Intravenous administration of PEG-MnPP to mice significantly suppressed acute liver failure that had been induced by acetaminophen overdose. These data warrant additional investigation to study the therapeutic potential of PEG-MnPP as a water-soluble metalloporphyrin-based catalase mimic for oxidative stress-associated diseases.


Assuntos
Falência Hepática Aguda/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Protoporfirinas/administração & dosagem , Acetaminofen , Animais , Catalase , Linhagem Celular , Humanos , Peróxido de Hidrogênio/farmacologia , Falência Hepática Aguda/induzido quimicamente , Masculino , Camundongos Endogâmicos ICR , Polietilenoglicóis/química , Protoporfirinas/química
12.
PLoS One ; 14(7): e0220210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31344086

RESUMO

Photodynamic therapy (PDT) uses photosensitisers such as protoporphyrin IX (PpIX) to target tumours via the release of toxic singlet oxygen when irradiated. The effectivity of the treatment is limited by the innate properties of the photosensitizers; they typically exhibit inefficient accumulation in target tissue and high dark toxicity. Carbon dots (CDs) are biocompatible fluorescent nanoparticles which can improve PpIX cellular uptake and solubility. In this work, we present conjugates synthesised by host-guest encapsulation (PpIX@CD) and amide cross-linking (PpIX-CD). Characterization demonstrated conjugates have a loading efficiency of 34-48% and similar singlet oxygen production to PpIX. PpIX-containing CDs showed a 2.2 to 3.7-fold decrease in dark toxicity. PpIX-CD and PpIX@CD showed equivalent light-induced toxicity to PpIX in concentrations >1 µg/ml, leading to a 3.2 to 4.1-fold increase in photo-toxicity index (PI). The less soluble fraction of cross-linked conjugates (PpIX-CD)p did not show significant difference from PpIX. Confocal light scanning microscopy demonstrated rapid intracellular uptake and accumulation of conjugates. Our results demonstrate the variations between cross-linking strategies in CD-based conjugates, highlighting their potential as carriers in drug delivery and bioimaging applications.


Assuntos
Carbono/química , Diagnóstico por Imagem/métodos , Portadores de Fármacos/síntese química , Técnicas de Sonda Molecular , Fotoquimioterapia/métodos , Protoporfirinas/química , Portadores de Fármacos/química , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Humanos , Teste de Materiais , Nanoconjugados/química , Nanopartículas/química , Nanotubos de Carbono/química , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Oxigênio Singlete/química , Testes de Toxicidade , Células Tumorais Cultivadas
13.
J Photochem Photobiol B ; 197: 111544, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31295716

RESUMO

Photodynamic therapy (PDT) induced by protoporphyrin IX (PpIX) has been widely used in dermatological practices such as treatment of skin cancers. Clearance rate depends on different factors such as light irradiation, skin oxygenation and drug penetration. The poor penetration of 5-aminolevulinic acid (5-ALA) with topical application is limited and restrains the production of PpIX which could restrict PDT outcomes. This review will focus on techniques already used to enhance drug penetration in human skin, and will present their results, advantages, and drawbacks. Chemical and physical pretreatments will be discussed. Chemical pre-treatments comprise of drug formulation modification, use of agents that modify the heme cycle, enhance PpIX formation, and the combination of differentiation-promoting agent prior to PDT. On the other hand, physical pretreatments affect the skin barrier by creating holes in the skin or by removing stratum corneum. To promote drug penetration, iontophoresis and temperature modulation are interesting alternative methods. Cellular mechanisms enrolled during chemical or physical pretreatments have been investigated in order to understand how 5-ALA penetrates the skin, why it is preferentially metabolized in PpIX in tumour cells, and how it could be accumulated in deeper skin layers. The objective of this review is to compare clinical trials that use innovative technology to conventional PDT treatment. Most of these pretreatments present good or even better clinical outcomes than usual PDT.


Assuntos
Fármacos Fotossensibilizantes/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Ácido Aminolevulínico/química , Ácido Aminolevulínico/metabolismo , Ácido Aminolevulínico/uso terapêutico , Composição de Medicamentos , Humanos , Lipossomos/química , Micelas , Nanopartículas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/química , Protoporfirinas/metabolismo , Protoporfirinas/uso terapêutico , Neoplasias Cutâneas/patologia
14.
ACS Appl Mater Interfaces ; 11(29): 25750-25757, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31245990

RESUMO

At present, the intermittent photodynamic therapy (fractional PDT) for overcoming tumor hypoxia still have their own defects, such as irradiation-dependence and rapid metabolism of organic photosensitizers. Therefore, it is still a really formidable challenge to achieve efficient fractional PDT. Herein, a three-in-one functional silica nanocarrier (FSNC) with singlet oxygen (1O2) generating unit (protoporphyrin IX derivative), 1O2 storage/release unit (2-pyridone derivative), and 1O2 self-monitoring unit (cyanine derivative) was prepared by reverse microemulsion method. Also, it could be efficiently internalized in the HeLa cells because of an appropriate particle size (∼44.8 nm). In the presence of light, the endoperoxide is formed to achieve 1O2 storage together with 1O2 generated by 1O2 generating unit for traditional PDT. In the absence of light, the endoperoxide produces 1O2 through cycloreversion for continuous PDT. As a result, the fractional PDT process of the FSNC on the HeLa cells performed a higher phototoxicity than traditional photosensitizer protoporphyrin IX. Furthermore, this real-time release behavior of 1O2 can be visually captured by confocal laser scanning microscope via monitoring fluorescent bleaching of 1O2 self-monitoring unit. Therefore, this fluorescent imaging-guided fractional PDT process could effectively enhance the PDT effect compared with traditional PDT.


Assuntos
Portadores de Fármacos , Nanoestruturas , Neoplasias , Fotoquimioterapia , Protoporfirinas , Dióxido de Silício , Oxigênio Singlete/metabolismo , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Protoporfirinas/química , Protoporfirinas/farmacocinética , Protoporfirinas/farmacologia , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia
15.
J Colloid Interface Sci ; 553: 228-238, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31212225

RESUMO

An assembly of hybrid hydrogel derived from Carbon Dot (CD), Protoporphyrin IX (PpIX) and DNA is reported here. PpIX and CD were covalently conjugated to 5'-phosphate termini of Cytosine (C) rich single strand DNA (ssDNA) separately. The CD-DNA-PpIX hybrid hydrogel was assembled through the formation of intercalated motif (i-motif) DNA network structure from CD-DNA and PpIX-DNA conjugates where CD act as crosslinkers in the hydrogel as well as energy donor to excite the photosensitizer (PS), PpIX. While hydrogel derived from only PpIX-DNA conjugate showed an inadequate sol-gel transition, the same could be precisely achieved from the CD-DNA-PpIX hybrid hydrogel by controlled pH adjustment. Distinct photophysical properties of CD and PpIX including fluorescence emission potentially enable tracking of the PS loading and hydrogel dissolution that was visually detectable under UV illumination. Reactive Oxygen Species (ROS) generation and subsequent killing of gram-positive bacteria (Staphylococcus aureus (S. aureus)) were observed following excitation of PpIX (acceptor) in the hybrid hydrogel either through energy transfer from CD or by direct irradiation of PpIX with visible light. Complete dissolution of hydrogel and sustained release of PpIX and subsequent ROS generation was achieved over 10-11 days that could kill S. aureus systematically. This study provides a promising strategy to address self-quenching and solubility of PS for its sustained release in Antimicrobial Photodynamic Therapy (A-PDT) applications through smart hydrogel formulation.


Assuntos
Antibacterianos/farmacologia , Carbono/farmacologia , DNA/farmacologia , Protoporfirinas/farmacologia , Pontos Quânticos/química , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Carbono/química , DNA/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Processos Fotoquímicos , Fotoquimioterapia , Protoporfirinas/química , Propriedades de Superfície
16.
Int J Mol Sci ; 20(9)2019 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060340

RESUMO

Heme oxygenase 1 (HO-1) and carbon monoxide were shown to normalize oxidative stress and inflammatory reactions induced by neuropathic pain in the central nervous system, but their effects in the locus coeruleus (LC) of animals with peripheral inflammation and their interaction with nitric oxide are unknown. In wild-type (WT) and knockout mice for neuronal (NOS1-KO) or inducible (NOS2-KO) nitric oxide synthases with inflammatory pain induced by complete Freund's adjuvant (CFA), we assessed: 1) antinociceptive actions of cobalt protoporphyrin IX (CoPP), an HO-1 inducer; 2) effects of CoPP and tricarbonyldichlororuthenium(II)dimer (CORM-2), a carbon monoxide-liberating compound, on the expression of HO-1, NOS1, NOS2, CD11b/c, GFAP,and mitogen-activated protein kinases (MAPK)in the LC. CoPP reduced inflammatory pain in different time-dependent manners in WT and KO mice. Peripheral inflammation activated astroglia in the LC of all genotypes and increased the levels of NOS1 and phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK 1/2) in WT mice. CoPP and CORM-2 enhanced HO-1 and inhibited astroglial activationin all genotypes. Both treatments blocked NOS1 overexpression,and CoPP normalized ERK 1/2 activation. This study reveals an interaction between HO-1 and NOS1/NOS2 during peripheral inflammation andshows that CoPP and CORM-2 improved HO-1 expression and modulated the inflammatory and/or plasticity changes caused by peripheral inflammation in the LC.


Assuntos
Inflamação/etiologia , Inflamação/metabolismo , Óxido Nítrico/metabolismo , Compostos Organometálicos/farmacologia , Protoporfirinas/farmacologia , Animais , Biomarcadores , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo I/genética , Óxido Nítrico Sintase Tipo II/genética , Compostos Organometálicos/química , Protoporfirinas/química
17.
Chem Commun (Camb) ; 55(45): 6453-6456, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31099349

RESUMO

In this work, a novel fluorescent assay was proposed for the ultrasensitive detection of microRNA-21 (miRNA-21) based on the efficient immobilization of protoporphyrin IX (PPIX) as signal indicators in massive G-quadruplex structures obtained by target recycling, three-dimensional DNA walker and a rolling circle amplification (RCA) coupled cascade nucleic acid amplification strategy.


Assuntos
Quadruplex G , MicroRNAs/análise , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Espectrometria de Fluorescência/métodos , Sequência de Bases , Técnicas Biossensoriais , Humanos , Técnicas de Amplificação de Ácido Nucleico
18.
Int J Biol Macromol ; 134: 445-457, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078597

RESUMO

The evidence that Human Serum Albumin (HSA) binds metal ions and organometallic compounds has generated interest in its physiological role as a metalloprotein and as a vehicle for synthetic biology applications (e.g., synthetic blood and solar energy conversion). HSA has been shown to bind metallo-porphyrins, however, the structural details of such interactions are available only for the HSA:heme complex. A typical challenge for studying the interaction of proteins with metalloporphyrins is the poor solubility of the ligands that affect the characterization the complexes. The manuscript shows that a combination of dialysis and centrifugation yields aqueous solutions that contain >90% HSA:porphyrin complexes and virtually eliminate aggregated ligands. The removal of aggregates increases the quality of the optical spectroscopy data which, in turn, yield more accurate binding constants (~0.1 and 2.1 × 106 M-1) and reveal FRET between Trp214 and the porphyrins. The Trp-porphyrin distance was estimated to be within the 28-34 Šrange and was used to guide the search of binding sites through a novel feedback approach with docking simulations. Results suggest while some protoporphyrins (metal-free, Fe(III)PPIX and Mg(II)PPIX) bind HSA at the heme site, others (Zn(II)PPIX, Mn(III)PPIX and Sn(IV)PPIX) are more likely to bind the Cys34.


Assuntos
Metaloporfirinas/química , Modelos Moleculares , Protoporfirinas/química , Albumina Sérica Humana/química , Albumina Sérica Humana/metabolismo , Sítios de Ligação , Complexos de Coordenação/química , Complexos de Coordenação/isolamento & purificação , Humanos , Ligantes , Metaloporfirinas/metabolismo , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Protoporfirinas/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral , Relação Estrutura-Atividade
19.
J Colloid Interface Sci ; 549: 72-79, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31022525

RESUMO

Overuse and abuse of antibiotics greatly hasten the development of microbial drug resistance and substantially threat to global public health. Developing alternative methods for combating bacterial infections is urgently required. In this work, a simple hydrothermal approach was employed to prepare the protoporphyrin IX-polyethylenimine nanoparticles (PPIX-PEI NPs) containing abundant amine groups and PPIX moieties. The as-obtained PPIX-PEI NPs exhibit antibacterial properties against both Gram-positive and Gram-negative bacteria. The presence of PPIX in the PPIX-PEI NPs can generate reactive oxygen species (ROS) under 635 nm laser irradiation, which enhance the antibacterial properties of the PPIX-PEI NPs against Gram-positive bacteria. Thus, the PPIX-PEI NPs display a synergistic antibacterial activity against Gram-positive bacteria in the combination of antibacterial photodynamic therapy (PDT). In addition, emission of red fluorescence by the PPIX-PEI NPs can help to differentiate bacteria and observe the bacterial morphologies using a confocal laser scanning microscope (CLSM).


Assuntos
Antibacterianos/química , Nanopartículas/química , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Antibacterianos/farmacologia , Corantes Fluorescentes/química , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/metabolismo , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Positivas/metabolismo , Humanos , Iminas/química , Imagem Óptica/métodos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Polietilenos/química , Protoporfirinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo
20.
Nanoscale ; 11(18): 9008-9014, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31020984

RESUMO

An abnormal pH microenvironment results from the development of tumors, and also affects the therapeutic efficiency of anti-tumor drugs. In this work, a Förster resonance energy transfer (FRET)-based theranostic fluorescent nanoprobe was constructed for simultaneous ratiometric pH sensing and tumor-targeted photodynamic therapy. Based on the FRET process between rhodamine B and protoporphyrin IX (PpIX), the fabricated nanoprobe exhibited excellent pH responsiveness in both solutions and live cells with the ratiometric fluorescence changes. Moreover, this ratiometric pH fluorescent nanoprobe also possessed the capability for pH-responsive singlet oxygen (1O2) generation under light irradiation, guiding robust photodynamic therapy in a pH-dependent manner. Benefiting from the enhanced permeability and retention (EPR) effect, the nanoprobe could significantly inhibit tumor growth and metastasis via targeted photodynamic therapy in vivo. This work presents a novel paradigm for precise tumor theranostics by ratiometric pH fluorescence imaging-guided photodynamic therapy.


Assuntos
Nanoestruturas/química , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Linhagem Celular Tumoral , Transferência Ressonante de Energia de Fluorescência , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Microscopia Confocal , Neoplasias/diagnóstico por imagem , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Protoporfirinas/química , Rodaminas/química , Oxigênio Singlete/metabolismo , Transplante Heterólogo
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