RESUMO
Photodynamic therapy (PDT) can eradicate not only cancer cells but also stimulate an antitumor immune response. Herein, we describe two efficient synthetic methodologies for the preparation of Chlorin e6 (Ce6) from Spirulina platensis and address the phototoxic effect of Ce6 in vitro along with antitumor activity in vivo. Melanoma B16F10 cells were seeded and phototoxicity was monitored by the MTT assay. The C57BL/6 mice were subcutaneously inoculated on the left and right flank with B16F10 cells. The mice were intravenously injected with Ce6 of 2.5 mg/kg and then exposed to red light (660 nm) on the left flank tumors 3 h after the injection. The immune response was studied by analyzing Interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and Interleukin-2 (IL-2) of the right flank tumors through qPCR. Our results revealed that the tumor was suppressed not only in the left flank but also in the right flank, where no PDT was given. The upregulated gene and protein expression of IFN-γ, TNF-α, and IL-2 revealed antitumor immunity due to Ce6-PDT. The findings of this study suggest an efficient methodology of Ce6 preparation and the efficacy of Ce6-PDT as a promising antitumor immune response.
Assuntos
Clorofilídeos , Melanoma Experimental , Fotoquimioterapia , Fármacos Fotossensibilizantes , Animais , Camundongos , Linhagem Celular Tumoral , Clorofilídeos/síntese química , Clorofilídeos/uso terapêutico , Imunoterapia/métodos , Interleucina-2 , Camundongos Endogâmicos C57BL , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Fator de Necrose Tumoral alfa , Melanoma Experimental/tratamento farmacológicoRESUMO
Currently, activatable photodynamic therapy (PDT) that is precisely regulated by endogenous or exogenous stimuli to selectively produce cytotoxic reactive oxygen species at the tumor site is urgently in demand. Herein, we fabricated a dual-activatable PDT nanosystem regulated by the redox tumor microenvironment and near-infrared (NIR) light-induced photothermal therapy (PTT). In this study, photosensitizer chlorin e6 (Ce6) was conjugated to hyaluronic acid (HA) via a diselenide bond to form an amphiphilic polymer (HSeC) for loading PTT agent IR780 to produce HSeC/IR nanoparticles (NPs). The photoactivity of Ce6 for PDT was "double-locked" by the aggregation-caused quenching (ACQ) effect and the fluorescence resonance energy transfer (FRET) from Ce6 to IR780 during blood circulation. After selective accumulation into tumors, HSeC/IR NPs were subsequently dissociated due to the "double-key", which included diselenide bond dissociation under high redox conditions and IR780 degradation upon NIR laser irradiation, resulting in recovering Ce6. In vitro studies indicated that Ce6 photoactivity in HSeC/IR NPs was significantly suppressed when compared with free Ce6 or in HSeC NPs. Moreover, BALB/c mice treated with HSeC/IR NPs displayed distinctly alleviated skin damage during PDT. Synergetic cascaded PTT-PDT with superior tumor suppression was observed in SCC7 tumor-bearing mice. Therefore, the study findings could provide a promising treatment strategy for PTT-facilitated PDT with high antitumor efficacies and reduced skin phototoxicity levels.
Assuntos
Clorofilídeos , Nanopartículas , Neoplasias , Fotoquimioterapia , Porfirinas , Animais , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias/tratamento farmacológico , Oxirredução , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Porfirinas/química , Microambiente TumoralRESUMO
Using bacteria for tumor-targeted therapy has attracted much attention in recent years. However, how to improve the targeted delivery and cancer therapy efficacy is an important but challenging scientific issue. Herein, a drug delivery system using a probiotic as a carrier was developed for tumor-targeted photodynamic and sonodynamic synergistic therapy. In this system, chlorin e6 (Ce6) nanoparticles (NPs) were prepared and incorporated into B. bifidum, followed by the conjugation of anti-death receptor 5 antibody (anti-DR5 Ab). Interestingly, B. bifidum under 671 nm laser or ultrasound (US) irradiation could generate reactive oxygen species (ROS), and Ce6-B. bifidum-anti-DR5 Ab obtained could target hypoxic regions in tumor with high efficiency after intravenous injection. The ROS level generated by Ce6-B. bifidum-anti-DR5 Ab under both laser and US irradiation was much higher than the combined ROS generated separately using a laser and US for the same probiotics. The cytotoxicity and laryngeal tumor growth-inhibiting efficiency of Ce6-B. bifidum-anti-DR5 Ab under both laser and US irradiation were significant higher than the values obtained using laser or US irradiation alone, which demonstrated the synergistic effect on tumor growth. B. bifidum could be eliminated from the body without exerting harmful effects on mouse health. This strategy is a platform that can be extended to treat other solid tumors. STATEMENT OF SIGNIFICANCE: Using bacteria as drug delivery carriers will show unique advantages. However, how to improve the targeted delivery efficiency and tumor inhibiting capacity is a challenging scientific issue. Herein, a delivery system using a probiotic as carrier was developed for tumor-targeted therapy. In this delivery system, chlorin e6 nanoparticles were prepared and then incorporated into living Bifidobacterium bifidum (B.bifidum), followed by the conjugation of anti-death receptor 5 antibody. This delivery system could efficiently target to mouse tumors, accumulate the hypoxic areas and inhibit the tumor growth through the photodynamic and sonodynamic synergistic effect. Our results will provide a platform for B.bifidum-mediated tumor targeted therapy.
Assuntos
Bifidobacterium bifidum , Clorofilídeos , Nanopartículas , Neoplasias , Fotoquimioterapia , Porfirinas , Animais , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Portadores de Fármacos/uso terapêutico , Camundongos , Nanopartículas/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Espécies Reativas de OxigênioRESUMO
Herein, novel laser-responsive multi-functional nanoparticles (NPs-Lip@PTX/CyA/Ce6) were fabricated with bovine serum albumins (BSA) based nanoparticles, which simultaneously carried chemotherapeutic drug paclitaxel (PTX) and P-gp inhibitor cyclosporin A (CyA), as core and photosensitizer agent Chlorin e6 (Ce6) loaded Tf-modified liposomal bilayer as shell. NPs-Lip@PTX/CyA/Ce6 exhibited apparent core-shell structure morphology with particle size of 160.9 ± 1.7 nm and zeta potential of - 26.7 ± 0.6 mV, indicating their excellent stability in aqueous solution. Besides, NPs-Lip@PTX/CyA/Ce6 possessed laser-responsive release profiles upon laser irradiation at specific wavelength, which was favor to exert efficient combinatorial chemo-photodynamic therapy and effectively reverse the multiple drug resistance (MDR). Under laser irradiation, as expected, NPs-Lip@PTX/CyA/Ce6 demonstrated superb intracellular ROS productivity and fantastic in vitro and in vivo anti-cancer therapy effect but absent of systemic toxicity. In conclusion, the nano-drug delivery system would be prospectively applied in clinic as resultful therapeutic tactic for investing compositional chemo-photodynamic therapy synergistically.
Assuntos
Neoplasias da Mama , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Feminino , Humanos , Lasers , Paclitaxel , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologiaRESUMO
Photodynamic therapy (PDT) damages cancer cells via photosensitization using harmless laser irradiation. We synthesized a new photosensitizer, mannose-conjugated-chlorin e6 (M-chlorin e6), which targets mannose receptors that are highly expressed on M2-like tumor-associated macrophages (M2-TAMs) and cancer cells. In our previous study, we demonstrated that M-chlorin e6 PDT reduces tumor volume and decreases the proportion of M2-TAMs. Whether M-chlorin e6 PDT-treated cancer cells activate tumor immunity remains unclear, although the decrease in M2-TAMs is thought to be a direct injurious effect of M-chlorin e6 PDT. Calreticulin (CRT) is exposed at the surface of the membrane of cancer cells in response to treatment with chemotherapeutic agents such as anthracycline and oxaliplatin. Surface-exposed CRT induces phagocytosis of CRT receptor-positive cells, including macrophages, inducing anticancer immune responses. In the present study, we found that M-chlorin e6 PDT increases CRT on the surface of cancer cells, leading to macrophage phagocytosis of cancer cells. Furthermore, M-chlorin e6 PDT increases CD80+CD86+ macrophages. These results suggest that M-chlorin e6 PDT exerts anti-tumor effects by both enhancing the phagocytosis of cancer cells and strengthening the anti-tumor phenotype of macrophages.
Assuntos
Clorofilídeos , Neoplasias , Fotoquimioterapia , Calreticulina , Clorofilídeos/uso terapêutico , Humanos , Macrófagos , Manose/farmacologia , Manose/uso terapêutico , Neoplasias/tratamento farmacológico , Fagocitose , Fotoquimioterapia/métodosRESUMO
We combined phosphoinositol-3-kinin inhibitor IPI-549 and photodynamic Chlorin e6 (Ce6) on carboxymethyl chitosan to develop a novel drug delivery nanoparticle (NP) system (Ce6/CMCS-DSP-IPI549) and evaluate its glutathione (GSH) sensitivity and targeting ability for breast cancer treatment. The NPs were spherical with a uniform size of 218.8 nm, a stable structure over 7 days. The maximum encapsulation efficiency was 64.42%, and NPs drug loading was 8.05%. The NPs released drugs within tumor cells due to their high GSH concentration, while they maintained structural integrity in normal cells, which have low GSH concentration. The cumulative release rates of IPI-549 and Ce6 at 108 h were 70.67% and 40.35% (at GSH 10 mM) and 8.11% and 2.71% (at GSH 2µM), respectively. The NPs showed a strong inhibitory effect on 4T1 cells yet did not affect human umbilical vein endothelial cells (HUVECs). After irradiation by a 660 nm infrared laser for 72 h, the survival rate of 4T1 cells was 15.51%. Cellular uptake studies indicated that the NPs could accurately release drugs into tumor cells. In addition, the NPs had a good photodynamic effect and promoted the release of reactive oxygen species to damage tumor cells. Overall, the combination therapy of IPI-549 and Ce6 is safe and effective, and may provide a new avenue for the treatment of breast cancer.
Assuntos
Neoplasias da Mama , Clorofilídeos , Nanopartículas , Fotoquimioterapia , Porfirinas , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Células Endoteliais/patologia , Feminino , Glutationa , Humanos , Isoquinolinas , Nanopartículas/química , Fármacos Fotossensibilizantes , Porfirinas/química , Pirazóis , PirimidinasRESUMO
Accurate diagnosis of cancer cells directly affects the clinical treatment of cancer and can significantly improve the therapeutic effect of cancer patients. Cancer cells have a unique microenvironment with a large amount of peroxide inside, effectively differentiated from relevant microenvironment normal cells. Therefore, designing the high-sensitive probes to recognize and distinguish the special physiological microenvironment of cancer cells can shed light on the early diagnosis of cancers. In this article, we design and construct a fluorescence (FL) contrast agent for cancer cell recognition and imaging analysis. Firstly, luminol-gold NPs (Lum-AuNPs) have been initially built, and then successfully loaded with the fluorescent receptor Chlorin e6 (Ce6) to prepare the luminescent nanoprobes (Ce6@Lum-AuNPs) with green synthesis, i.e., with biocompatible agents and mild temperature. The as-prepared fluorescent Ce6@Lum-AuNPs can efficiently and sensitively realize FL bioimaging of cancer cells. The relevant bio-sensing mechanism pertains to the presence of hypochlorite (ClO-); hydrogen peroxide (H2O2) in cancer cells could readily interact with luminol to produce chemiluminescence, which can activate the Ce6 component to emit near-infrared (NIR) FL. Therefore, this raises the possibility of utilizing the Ce6@Lum-AuNPs as efficient fluorescent nanoprobes for promising cancer early diagnosis and other relevant disease bioanalysis.
Assuntos
Clorofilídeos/farmacologia , Nanopartículas Metálicas , Neoplasias , Fotoquimioterapia , Animais , Linhagem Celular Tumoral , Clorofilídeos/química , Clorofilídeos/uso terapêutico , Ouro , Humanos , Peróxido de Hidrogênio/química , Ácido Hipocloroso/química , Luminol/química , Camundongos , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodosRESUMO
BACKGROUND: Non-small-cell lung cancer (NSCLC) is the most common malignant lung tumor and is difficult to be eradicated due to its immunosuppressive microenvironment. Chlorin e6 (Ce6)-mediated photodynamic therapy (PDT) could improve immunogenicity while destroying malignant tumor cells. However, the clinic application of Ce6-mediated PDT is limited by Ce6's poor water solubility and insufficient accumulation in lung cancer. To address this issue, Ce6 was loaded onto functionalized iron oxide nanoparticles linked with glucose to improve the distribution of Ce6 in lung cancer. MATERIALS AND RESULTS: The results of transmission electron microscopy (TEM), UV-Vis spectrophotometry, dynamic light scattering and near-infrared (NIR) spectroscopy confirmed the successful preparation of the composites. Confocal and flow cytometry showed IO-PG-GLU-Ce6 significantly enhanced the uptake of Ce6 by lung cancer cells and produced more reactive oxygen species (ROS) under NIR light irradiation. In addition, the detection of cell viability, proliferation and apoptosis indicated IO-PG-GLU-Ce6 achieved stronger photo-toxicity to lung cancer cells. Moreover, IO-PG-GLU-Ce6 treatment effectively damaged the DNA of lung cancer cells and thereby activated STING, up-regulated the expression of IFN-ß, HMGB1 and HSP90, indicating augmented immunogenicity of lung cancer cells. Further results of in vivo, organ imaging and tissue fluorescence sections demonstrated IO-PG-GLU-Ce6 significantly improved the distribution of Ce6 in tumor tissues of lung cancer-bearing mice as well. Finally, the findings of in vivo study and immunohistochemistry confirmed the better efficacy of IO-PG-GLU-Ce6. HE staining results of vital organs suggested that the composites were less toxic. CONCLUSION: In conclusion, Ce6 loaded by functionalized iron oxide nanoparticles linked with glucose exhibited both target photodynamic efficacy and the ability to enhance its immunogenicity in lung cancer. This study provides a promising strategy for augment of the targeting delivery of Ce6 and its mediated photodynamic and immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Clorofilídeos , Neoplasias Pulmonares , Nanopartículas , Fotoquimioterapia , Porfirinas , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Clorofilídeos/uso terapêutico , Glucose , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas Magnéticas de Óxido de Ferro , Camundongos , Nanopartículas/química , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/química , Porfirinas/farmacologia , Microambiente TumoralRESUMO
In situ oxygen generation is the most common strategy to boost reactive oxygen species (ROS) for enhancing the efficacy of phototherapy in cancer, including photodynamic therapy (PDT) and photothermal therapy (PTT). However, hyperoxidation or hyperthermia often triggers stress-defense pathways and promotes tumor cell survival, thus severely limiting the therapeutic efficacy. To overcome the tumor hypoxia and thermal resistance existing in phototherapy, we constructed a self-synergistic nanoplatform for tumors by incorporating brusatol, a nuclear factor erythroid 2-related factor (Nrf2) inhibitor, into the silica nanonetwork. It was then sequentially decorated with MnO2 and the photosensitizer chlorin e6 (Ce6) and then coated with poly(ethylene glycol)-folate (PEG-FA)-functionalized polydopamine (PDA) (designated as brusatol/silica@MnO2/Ce6@PDA-PEG-FA). As an oxygen generator, MnO2 can promote ROS production, which not only directly enhances Ce6-mediated PDT but also strengthens PDA-mediated PTT by attacking heat shock proteins (HSPs). Particularly, brusatol could efficiently inhibit the activation of Nrf2 defense pathway under hyperoxidation and hyperthermia and cause glutathione peroxidase 4 (GPX4) and ferritin heavy chain (FTH) inactivation, thereby inducing ferroptosis and ultimately enhancing the phototherapeutic effects. By exploiting these features, brusatol/silica@MnO2/Ce6@PDA-PEG-FA exhibited excellent antitumor efficacy with enhanced PDT and PTT both in in vitro and in vivo studies. Overall, our work highlights a promising strategy against hypoxia- and hyperthermia-associated resistance in phototherapy via suppressing stress-defense system and inducing ferroptosis.
Assuntos
Ferroptose , Fator 2 Relacionado a NF-E2/metabolismo , Nanoestruturas/química , Fototerapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Animais , Linhagem Celular Tumoral , Clorofilídeos/química , Clorofilídeos/farmacologia , Clorofilídeos/uso terapêutico , Ferroptose/efeitos dos fármacos , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Humanos , Hipertermia Induzida , Indóis/química , Raios Infravermelhos , Compostos de Manganês/química , Camundongos , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Nanoestruturas/uso terapêutico , Nanoestruturas/toxicidade , Óxidos/química , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Polietilenoglicóis/química , Polímeros/química , Quassinas/química , Dióxido de Silício/químicaRESUMO
Integrating chemodynamic therapy (CDT) and photodynamic therapy (PDT) into one nanoplatform can produce much more reactive oxygen species (ROS) for tumor therapy. Nevertheless, it is still a great challenge to selectively generate sufficient ROS in tumor regions. Meanwhile, CDT and PDT are restricted by insufficient H2O2 content in the tumor as well as by the limited tumor tissue penetration of the light source. In this study, a smart pH/ROS-responsive nanoplatform, Fe2+@UCM-BBD, is rationally designed for tumor combination therapy. The acidic microenvironment can induce the pH-responsive release of doxorubicin (DOX), which can induce tumor apoptosis through DNA damage. Beyond that, DOX can promote the production of H2O2, providing sufficient materials for CDT. Of note, upconversion nanoparticles at the core can convert the 980 nm light to red and green light, which are used to activate Ce6 to produce singlet oxygen (1O2) and achieve upconversion luminescence imaging, respectively. Then, the ROS-responsive linker bis-(alkylthio)alkene is cleaved by 1O2, resulting in the release of Fenton reagent (Fe2+) to realize CDT. Taken together, Fe2+@UCM-BBD exhibits on-demand therapeutic reagent release capability, excellent biocompatibility, and remarkable tumor inhibition ability via synergistic chemo/photodynamic/chemodynamic combination therapy.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos/química , Linhagem Celular Tumoral , Clorofilídeos/química , Clorofilídeos/efeitos da radiação , Clorofilídeos/uso terapêutico , Terapia Combinada , Doxorrubicina/química , Portadores de Fármacos/química , Portadores de Fármacos/efeitos da radiação , Liberação Controlada de Fármacos , Tratamento Farmacológico , Érbio/química , Érbio/efeitos da radiação , Érbio/uso terapêutico , Feminino , Fluoretos/química , Fluoretos/efeitos da radiação , Fluoretos/uso terapêutico , Humanos , Ferro/química , Ferro/efeitos da radiação , Ferro/uso terapêutico , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Camundongos Endogâmicos BALB C , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/diagnóstico por imagem , Itérbio/química , Itérbio/efeitos da radiação , Itérbio/uso terapêutico , Ítrio/química , Ítrio/efeitos da radiação , Ítrio/uso terapêuticoRESUMO
Gold nanoparticles (AuNPs) were surface-engineered with a cationic corona to enhance the incorporation of photosensitizers for photodynamic therapy (PDT). The cationic corona composed of poly(2-(dimethylamino)ethyl methacrylate) was atom transfer radical-polymerized on the surface of the AuNPs. The cationic corona of the engineered surface was characterized by dynamic light scattering, electron microscopy, Raman spectroscopy, and mass spectroscopy. Chlorin-e6 (Ce6) incorporated onto the surface-engineered AuNPs exhibited higher cell incorporation efficiency than bare AuNPs. Ce6-incorporated AuNPs were confirmed to release singlet oxygen upon NIR irradiation. Compared to Ce6, Ce6-incorporated AuNPs exhibited higher cellular uptake and cytotoxicity against cancer cells in an irradiation time-dependent manner. Near-infrared-irradiated animals administered Ce6-incorporated AuNPs exhibited higher levels of tumor suppression without noticeable body weight loss. This result was attributed to the higher localization of Ce6 at the tumor sites to induce cancer cell apoptosis. Thus, we envision that engineered AuNPs with cationic corona can be tailored to effectively deliver photosensitizers to tumor sites for photodynamic therapy.
Assuntos
Antineoplásicos/uso terapêutico , Nanopartículas Metálicas/uso terapêutico , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/efeitos da radiação , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Clorofilídeos/síntese química , Clorofilídeos/efeitos da radiação , Clorofilídeos/uso terapêutico , Feminino , Ouro/química , Ouro/efeitos da radiação , Humanos , Raios Infravermelhos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/efeitos da radiação , Metacrilatos/síntese química , Metacrilatos/química , Metacrilatos/efeitos da radiação , Camundongos Endogâmicos BALB C , Camundongos Nus , Nylons/síntese química , Nylons/química , Nylons/efeitos da radiação , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/efeitos da radiação , Polimerização , Oxigênio Singlete/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The efficacy of a new photosensitizer of chlorin E6 conjugated with a prostate-specific membrane antigen (PSMA) in photodynamic therapy of murine melanoma B16 was studied in in vivo experiments. The dynamics of photosensitizer accumulation in the tumor and surrounding tissues was evaluated and antitumor efficacy of photodynamic therapy was assessed by parameters of regression and morphological characteristics of experimental transplanted melanoma B16. The inhibitory effect of photodynamic therapy on melanoma was evaluated by complete regression of the tumor, absolute tumor growth coefficient in animals with continuation of tumor growth, and the increase in life span in comparison with the control; the criterion of cure was the absence of signs of tumor recurrence in mice within 90 days after therapy. The therapeutic potential of photodynamic therapy was determined by devitalization of tumor cells (histological examination of the zones of laser exposure on day 21 after treatment). The photosensitizer with PSMA-ligand exhibited high antitumor activity in photodynamic therapy for melanoma B16. Photodynamic therapy carried out at the optimum time after photosensitizer injection with experimentally determined parameters of laser exposure allows achieving the maximum inhibitory effect on melanoma. Pathomorphological study in the zones of exposure detected no survived tumor cells.
Assuntos
Clorofilídeos/uso terapêutico , Melanoma Experimental/tratamento farmacológico , Fotoquimioterapia/métodos , Neoplasias Cutâneas/tratamento farmacológico , Ureia/análogos & derivados , Animais , Linhagem Celular Tumoral , Clorofilídeos/química , Clorofilídeos/farmacocinética , Feminino , Ligantes , Melanoma Experimental/diagnóstico por imagem , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Ureia/química , Ureia/farmacocinética , Ureia/uso terapêuticoRESUMO
Nanotechnology has emerged as a promising solution to permanent elimination of cancer. However, nanoparticles themselves lack specificity to tumors. Due to enhanced migration to tumors, mesenchymal stem cells (MSCs) were suggested as cell-mediated delivery vehicles of nanoparticles. In this study, we have constructed a complex composed of photoluminescent quantum dots (QDs) and a photosensitizer chlorin e6 (Ce6) to obtain multifunctional nanoparticles, combining cancer diagnostic and therapeutic properties. QDs serve as energy donors-excited QDs transfer energy to the attached Ce6 via Förster resonance energy transfer, which in turn generates reactive oxygen species. Here, the physicochemical properties of the QD-Ce6 complex and singlet oxygen generation were measured, and the stability in protein-rich media was evaluated, showing that the complex remains the most stable in protein-free medium. In vitro studies on MSC and cancer cell response to the QD-Ce6 complex revealed the complex-loaded MSCs' potential to transport theranostic nanoparticles and induce cancer cell death. In vivo studies proved the therapeutic efficacy, as the survival of tumor-bearing mice was statistically significantly increased, while tumor progression and metastases were slowed down.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Lewis/diagnóstico por imagem , Carcinoma Pulmonar de Lewis/tratamento farmacológico , Células-Tronco Mesenquimais/metabolismo , Nanopartículas Multifuncionais/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/efeitos da radiação , Compostos de Cádmio/química , Compostos de Cádmio/metabolismo , Compostos de Cádmio/efeitos da radiação , Compostos de Cádmio/uso terapêutico , Carcinoma Pulmonar de Lewis/metabolismo , Linhagem Celular Tumoral , Clorofilídeos/química , Clorofilídeos/metabolismo , Clorofilídeos/efeitos da radiação , Clorofilídeos/uso terapêutico , Feminino , Humanos , Luz , Camundongos Endogâmicos C57BL , Nanopartículas Multifuncionais/química , Nanopartículas Multifuncionais/metabolismo , Nanopartículas Multifuncionais/efeitos da radiação , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/metabolismo , Fármacos Fotossensibilizantes/efeitos da radiação , Fármacos Fotossensibilizantes/uso terapêutico , Medicina de Precisão/métodos , Pontos Quânticos/química , Pontos Quânticos/metabolismo , Pontos Quânticos/efeitos da radiação , Pontos Quânticos/uso terapêutico , Compostos de Selênio/química , Compostos de Selênio/metabolismo , Compostos de Selênio/efeitos da radiação , Compostos de Selênio/uso terapêutico , Oxigênio Singlete/metabolismo , Sulfetos/química , Sulfetos/metabolismo , Sulfetos/efeitos da radiação , Sulfetos/uso terapêutico , Compostos de Zinco/química , Compostos de Zinco/metabolismo , Compostos de Zinco/efeitos da radiação , Compostos de Zinco/uso terapêuticoRESUMO
Sasa veitchii and other Sasa species are traditional medicinal herbs belonging to a group of Japanese bamboos collectively called Kumazasa, and these species possess the potential for a wide variety of uses. The present study aimed to elucidate the anticancer mechanisms exerted by S. veitchii extract (SE) against a human breast cancer cell line, MCF-7 cells. Freeze-dried Sunchlon® was used as the SE, and cell proliferation activity was measured using the [3H]-thymidine incorporation assay. Induction of apoptosis was assessed via Annexin V and caspase-3 fluorescent staining, the induction of necrosis was measured via propidium iodide staining, and cell cycle-related protein expression was determined using western blotting. The IC50 value of the SE was 7.7 µg/mL in MCF-7 cells. Although the primary active ingredient in Sunchlon® is sodium copper chlorophyllin (0.25%), the present results indicated that ingredients other than SCC exert anti-cancer activities (the IC50 value of SCC was 715 µg/mL), and late apoptosis or necrosis was induced in an SE dose-dependent manner. The expression levels of cyclin D1 and Cdk6 were decreased after SE treatment, and there was no change in the Cdk1/2 expression levels. Additionally, the expression of the necrosis-related cell death indicators RIP1 and RIP3 was increased in response to high-dose SE treatments, and this was indicative of cells preparing for programmed cell death. SE induces cell death in MCF-7 cells via the inhibition of cyclin D1 expression at low concentrations, and this extract induces programmed necrosis (necroptosis) by potentiating RIP1/RIP3 expression.
Assuntos
Ciclina D1/metabolismo , Extratos Vegetais/uso terapêutico , Sasa/química , Neoplasias da Mama/metabolismo , Proliferação de Células/efeitos dos fármacos , Clorofilídeos/uso terapêutico , Quinase 6 Dependente de Ciclina/metabolismo , Feminino , Humanos , Células MCF-7 , Extratos Vegetais/químicaRESUMO
The present study was designed to evaluate the effect of sodium copper chlorophyllin (SCC) in adenine-induced chronic kidney disease (CKD). CKD was induced in male Wistar rats by feeding 0.3% w/w adenine diet for 28 days. After induction, animals were treated with sodium copper chlorophyllin at dose 2.7, 5.4, and 10.8 mg/kg for the next 28 days. The biochemical and urines parameters like creatinine, blood urea nitrogen (BUN), albumin, total protein creatinine clearance, urea clearance, and glomerular filtration rate were assessed on days 0, 14, and 28. Plasma TGF-ß1, COX-2, and IL-6 levels were assessed. Various oxidative stress parameters and TGF-ß1 expression were determined in the kidney. Histopathology of the kidney was studied with different stains. Sodium copper chlorophyllin-treated animals showed a significant reduction in urine output and relative kidney weight. The treatment with sodium copper chlorophyllin significantly improved kidney function by normalizing biochemical and urine parameters. Treatment with SCC significantly reduced circulatory inflammatory mediators-TGF-ß1, COX-2, and IL-6. Additionally, the treatment also significantly reduced oxidative stress and TGF-ß1 expression in kidney tissues. Histopathology studies showed inhibition in the kidney damage due to the treatment of SCC. The sodium copper chlorophyllin treatment attenuated adenine-induced chronic kidney disease in rats.
Assuntos
Adenina/toxicidade , Clorofilídeos/uso terapêutico , Citocinas/antagonistas & inibidores , Mediadores da Inflamação/antagonistas & inibidores , Insuficiência Renal Crônica/tratamento farmacológico , Fator de Crescimento Transformador beta/antagonistas & inibidores , Animais , Antimutagênicos/farmacologia , Antimutagênicos/uso terapêutico , Clorofilídeos/farmacologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Mediadores da Inflamação/metabolismo , Masculino , Ratos , Ratos Wistar , Insuficiência Renal Crônica/induzido quimicamente , Insuficiência Renal Crônica/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
In study, we aimed to determine the mechanisms underlying the gastroprotective effects of sodium copper chlorophyllin (SCC) against ethanol-induced gastric ulcer injury in mice. First, the gastroprotective effects of SCC against gastric ulcer induced by ethanol were assessed. Then, biochemical, histopathological, immunohistochemistry assays, and western blot analysis were conducted to determine the possible mechanisms of action underlying the effects of SCC. Compared to the effects of omeprazole (OME) in a confirmed mouse model of ethanol-induced gastric ulcer injury, treatment with various doses of SCC resulted in up-regulation of Bcl-2 and down-regulation of the pro-apoptotic protein Bax. Significant decreases in the levels of the malondialdehyde (MDA), myeloperoxidase (MPO), and NO in the gastric tissues were observed. Furthermore, inflammatory cytokine analysis revealed that SCC treatment inhibited the expressions of TNF-α and IL-6, greatly reduced the phosphorylation level of IκB, and repressed the nuclear translocation of NF-κB p65, which demonstrated that SCC inhibited the activation of the NF-κB pathway. The present findings suggest that the protective effects of SCC may be beneficial as a potential preventive and therapeutic agent for gastric ulcer through the NF-κB pathway. Taken together, SCC administration significantly decreased the levels of MPO, NO, and MDA in gastric tissue and exerted a powerful anti-inflammatory activity as demonstrated by reduction in the secretions of proinflammatory mediators such as IL-6 and TNF-α in the serum of mice exposed to ethanol.
Assuntos
Clorofilídeos/uso terapêutico , Etanol/efeitos adversos , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/prevenção & controle , Animais , Feminino , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND & OBJECTIVE: Thylakoids and chloroplasts harbor several vital metabolic processes, but are most importantly associated with photosynthesis. The undisturbed functioning of this process necessitates the ceaseless synthesis of photosynthetic pigments, including closed tetrapyrroles such as chlorophylls (Chls). Chls probably represent the most abundant natural pigment molecules which are via photosynthesis not only crucial for the autotrophic production of food sources for heterotrophic organisms but have also contributed to oxygen production essential for aerobic metabolism. This review first briefly discusses the physico-chemical properties, biosynthesis, occurrence, in vivo localization and roles of the different Chl pigments. Then we provide a detailed overview of their potential applications in the food industry and medicine. These include the use of Chls and their derivatives (different chlorophyllins) as food colorants (identified as E140 and E141 in the European Union). METHOD: Different sources used for industrial extraction as well as different factors influencing pigment stability during processing are also critically reviewed. The problems surrounding the nomenclature, the production and the composition of different chlorophyllin mixtures are also discussed. RESULTS & CONCLUSION: Finally, a comprehensive overview of the health benefits and potential medicinal applications of these pigments and the future directions of research in these fields are provided.
Assuntos
Clorofila/biossíntese , Corantes de Alimentos/química , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Antioxidantes/química , Antioxidantes/metabolismo , Antioxidantes/uso terapêutico , Clorofila/química , Clorofila/uso terapêutico , Clorofilídeos/biossíntese , Clorofilídeos/química , Clorofilídeos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , FotoquimioterapiaRESUMO
Water-soluble chlorophyll (chlorophyllin) was used in a phototoxic reaction against a number of fish ectoparasites such as Ichtyobodo, Dactylogyrus, Trichodina, and Argulus. Chlorophyllin is applied to the water at concentrations of several micrograms per milliliter for a predefined incubation time, and afterwards, the parasites are exposed to simulated solar radiation. Application in the dark caused only little damage to the parasites; likewise, light exposure without the addition of the photosensitizer was ineffective. In Ichthyobodo, 2 µg/mL proved sufficient with subsequent simulated solar radiation to almost quantitatively kill the parasites, while in Dactylogyrus, a concentration of about 6 µg/mL was necessary. The LD50 value for this parasite was 1.02 µg/mL. Trichodina could be almost completely eliminated at 2 µg/mL. Only in the parasitic crustacean Argulus, no killing could be achieved by a photodynamic reaction using chlorophyllin. Chlorophyllin is non-toxic, biodegradable, and can be produced at low cost. Therefore, we propose that chlorophyllin (or other photodynamic substances) are a possible effective countermeasure against several ectoparasites in ponds and aquaculture since chemical remedies are either forbidden and/or ineffective.
Assuntos
Antiparasitários/uso terapêutico , Clorofilídeos/uso terapêutico , Doenças dos Peixes/parasitologia , Doenças dos Peixes/terapia , Parasitos/efeitos dos fármacos , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Aquicultura , Arguloida/efeitos dos fármacos , Clorofila , Cilióforos/efeitos dos fármacos , Peixes/parasitologia , Platelmintos/efeitos dos fármacos , Spiroplasma/efeitos dos fármacos , ÁguaRESUMO
Water-soluble chlorophyll (chlorophyllin) exerts pronounced photodynamic activity on fish parasites. In order to determine its potential as a remedy against ectoparasites in fish carps were incubated in water with defined concentrations of chlorophyllin. The main focus of the experiments was on the ciliate Ichthyophthirius multifiliis (Fouquet) which is responsible for considerable losses in livestock in aquaculture. As malachite green, which in the past efficiently cured infected fishes, is banned because of its possible carcinogenicity; no effective remedy is presently available in aquaculture to treat ichthyophthiriasis. Using chlorophyllin, the number of trophonts was significantly reduced (more than 50 %) after 3 h incubation of infested fish at 2 and 4 mg/L and subsequent irradiation with simulated solar radiation. The lack of reinfection after light treatment indicates that also the remaining parasites have lost their multiplication capacity. In the controls (no chlorophyllin and no light, light but no chlorophyllin, or chlorophyllin but no light), no reduction of the I. multifiliis infection was observed. We propose that chlorophyllin (or other photodynamic substances) is a possible effective countermeasure against I. multifiliis and other ectoparasites in aquaculture.
Assuntos
Anti-Infecciosos Locais/uso terapêutico , Carpas , Clorofilídeos/uso terapêutico , Infecções por Cilióforos/veterinária , Cilióforos/classificação , Animais , Aquicultura , Cilióforos/efeitos dos fármacos , Infecções por Cilióforos/tratamento farmacológico , Infecções por Cilióforos/parasitologia , Doenças dos Peixes/parasitologiaRESUMO
Physicians are often presented with patients complaining of facial redness and difficult to control rosacea. The water soluble sodium copper chlorophyllin complex has been shown to have anti-oxidant, anti-inflammatory, and anti-bacterial activities in vitro and anti-redness, pore reduction, and anti-acne activities in pilot clinical studies. In these case studies, the safety and efficacy of a topical gel containing a liposomal suspension of sodium copper chlorophyllin complex was assessed in subjects with facial redness and erythematotelangiectatic rosacea.