RESUMO
AIM: To construct a novel nano-carrier with dual ligands to achieve superior anti-tumour efficacy and lower toxic side effects. METHODS: Liposomes were prepared by thin film hydration method. Ultraviolet, high performance liquid chromatography, nano-size analyser, ultrafiltration centrifugation, dialysis, transmission electron microscope, flow cytometry, Cell Counting Kit-8, confocal laser scanning microscopy, transwell, and tumorsphere assay were used to study the characterisations, cytotoxicity, and in vitro targeting of dg-Bcan targeting peptide (BTP-7)/pHA-temozolomide (TMZ)/tetra(4-carboxyphenyl)porphyrin (TCPP)-Lip. RESULTS: BTP-7/pHA-TMZ/TCPP-Lip was a spheroid with a mean diameters of 143 ± 3.214 nm, a polydispersity index of 0.203 ± 0.025 and a surface charge of -22.8 ± 0.425 mV. The drug loadings (TMZ and TCPP) are 7.40 ± 0.23% and 2.05 ± 0.03% (mg/mg); and the encapsulation efficiencies are 81.43 ± 0.51% and 84.28 ± 1.64% (mg/mg). The results showed that BTP-7/pHA-TMZ/TCPP-Lip presented enhanced targeting and cytotoxicity. CONCLUSION: BTP-7/pHA-TMZ/TCPP-Lip can specifically target the tumour cells to achieve efficient drug delivery, and improve the anti-tumour efficacy and reduces the systemic toxicity.
Assuntos
Glioblastoma , Lipossomos , Temozolomida , Glioblastoma/tratamento farmacológico , Humanos , Linhagem Celular Tumoral , Temozolomida/farmacologia , Temozolomida/administração & dosagem , Temozolomida/farmacocinética , Temozolomida/química , Porfirinas/química , Porfirinas/administração & dosagem , Porfirinas/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias Encefálicas/tratamento farmacológico , Peptídeos/química , Peptídeos/farmacologiaRESUMO
Photodynamic therapy (PDT) utilizes photochemical reactions induced by a photosensitizer and light in the target tissue and is used to treat various cancers. There is a high degree of anticipation of success regarding the application of PDT with talaporfin (photosensitizer) for gastric cancer. Olaparib is an oral inhibitor of Poly (ADP-Ribose) polymerase (PARP) and has demonstrated optimal efficacy and clinical activity in trials. Therefore, the aim of the present study was to investigate the efficacy of talaporfin PDT combined with olaparib for gastric cancer. MKN45, a gastric cancer cell line, was incubated with talaporfin, followed by irradiation, in the presence/absence of olaparib. Talaporfin PDT and olaparib exhibited excellent synergistic action in a concentration-dependent manner. PARP-DNA complexes were characterized based on bound chromatin using Western blot analyses. The combination of talaporfin PDT and olaparib enhanced PARP1 accumulation (the entrapment of PARP1-DNA complexes) in bound chromatin. The combination of talaporfin PDT and olaparib induced DNA double-strand breaks, which was confirmed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established, and antitumor effects were analyzed. In vivo, tumor growth was significantly suppressed following PDT with talaporfin and olaparib. Our results demonstrated that olaparib enhances the efficacy of talaporfin PDT by inducing the formation of PARP-DNA complexes. Therefore, our results suggest that the combination of talaporfin PDT and olaparib is a potential antitumor therapy for gastric cancer.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Fotoquimioterapia/métodos , Ftalazinas/farmacologia , Piperazinas/farmacologia , Porfirinas/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Terapia Combinada , Sinergismo Farmacológico , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/farmacologia , Ftalazinas/administração & dosagem , Piperazinas/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Porfirinas/administração & dosagem , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
An emerging class of targeted therapy relies on light as a spatially and temporally precise stimulus. Photodynamic therapy (PDT) is a clinical example in which optical illumination selectively activates light-sensitive drugs, termed photosensitizers, destroying malignant cells without the side effects associated with systemic treatments such as chemotherapy. Effective clinical application of PDT and other light-based therapies, however, is hindered by challenges in light delivery across biological tissue, which is optically opaque. To target deep regions, current clinical PDT uses optical fibers, but their incompatibility with chronic implantation allows only a single dose of light to be delivered per surgery. Here we report a wireless photonic approach to PDT using a miniaturized (30 mg, 15 mm3) implantable device and wireless powering system for light delivery. We demonstrate the therapeutic efficacy of this approach by activating photosensitizers (chlorin e6) through thick (>3 cm) tissues inaccessible by direct illumination, and by delivering multiple controlled doses of light to suppress tumor growth in vivo in animal cancer models. This versatility in light delivery overcomes key clinical limitations in PDT, and may afford further opportunities for light-based therapies.
Assuntos
Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/farmacocinética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Tecnologia sem Fio/instrumentação , Animais , Clorofilídeos , Relação Dose-Resposta a Droga , Fontes de Energia Elétrica , Desenho de Equipamento , Implantes Experimentais , Camundongos Endogâmicos C57BL , Miniaturização , Neovascularização Patológica , Fotoquimioterapia/instrumentação , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Porfirinas/farmacocinética , Neoplasias da Bexiga Urinária/irrigação sanguínea , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
AIMS: To construct a self-assembly supramolecular drug delivery system (DDS) to co-deliver chlorin e6 (Ce6) and tripeptide tyroseroleutide (YSL) and evaluate the anti-tumour effects. METHODS: A supramolecular DDS was constructed via self-assembly of Ce6 and YSL based on π-π stacking and hydrogen-bond interaction. The size, morphology, stability, in vitro drug release, cellular uptake, cytotoxicity, pharmacokinetics analysis and pharmacodynamics analysis were respectively studied. RESULTS: Ce6-YSL nanoparticles with a uniform size of 75 ± 3.5 nm (PDI = 0.128) and monodispersed spherical morphology were constructed. The nanoparticles exhibited good stability with zeta potential -21.2 ± 1.73 mV. Under the weak acidic conditions, the accumulative drug release was 82.8% (w/w) (pH = 6.0) and 91.5% (w/w) (pH = 5.0), respectively, indicating that nanoparticles performed smart responsive properties and achieved controlled release characteristics in acidic tumour microenvironment. In addition, nanoparticles could easily enter the tumour cells and induce ROS production and inhibit cell proliferation in SMMCC-7721 cells with IC50 value 3.4 ± 0.023 µg/mL under laser irradiation. Furthermore, the nanoparticles could retain a much higher blood concentration in vivo and displayed excellent antitumor effect in tumour-bearing mice, showing no influence on body weight. CONCLUSIONS: This self-assembly supramolecular DDS can be used for combination of photodynamic therapy and chemotherapy in future research.
Assuntos
Antineoplásicos/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Oligopeptídeos/administração & dosagem , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Clorofilídeos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/análise , Nanopartículas/uso terapêutico , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacocinética , Porfirinas/uso terapêutico , Ratos Sprague-DawleyRESUMO
Recent cancer immunotherapy has attracted much attention due to high specificity and recurrence prevention of tumor. Nevertheless, its therapeutic effects are still challenging in solid cancer. To establish superior antitumor immunity, chlorin e6 (Ce6)-loaded pH sensitive carbon dots were investigated (Ce6@IDCDs). At tumoral pH 6.5, Ce6 was released four times compared with the release at physiological pH 7.4 due to an imbalance between hydrophilic and hydrophobic forces via protonation of imidazole groups in Ce6@IDCDs. This result led to the superior singlet oxygen generating activity of Ce6@IDCDs without Ce6 quenching. The maturation effects of dendritic cells after co-incubation with supernatant media obtained from Ce6@IDCDs with laser-treated cells at pH 6.5 were much higher than at physiological pH. Furthermore, Ce6@IDCDs following a laser at pH 6.5 significantly promoted calreticulin exposure and high-mobility group box 1 release, as major immunogenic cell death markers. In bilateral CT-26-bearing mice model, the Ce6@IDCDs elicited significant antitumoral effects at laser treated-primary tumor regions via therapeutic reactive oxygen species. Furthermore, Ce6@IDCDs upon laser irradiation induced a large amount of activated CD8+ T cells, natural killer cells, and mature dendritic cells recruitment into tumoral tissue and hampered tumor growth even at untreated sites approximately four-fold compared with those of others. Overall, this pH-sensitive immunoinducer can accomplish primary and distant tumor ablation via photomediated cancer immunotherapy.
Assuntos
Carbono/química , Células Dendríticas/efeitos dos fármacos , Imunoterapia/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Fotoquimioterapia/métodos , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Calreticulina/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/imunologia , Morte Celular/efeitos da radiação , Linhagem Celular Tumoral , Clorofilídeos , Células Dendríticas/imunologia , Células Dendríticas/efeitos da radiação , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Imidazóis/química , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Transmissão , Nanopartículas/efeitos da radiação , Nanopartículas/ultraestrutura , Neoplasias/imunologia , Neoplasias/radioterapia , Tamanho da Partícula , Porfirinas/química , Porfirinas/farmacocinética , Radiossensibilizantes/química , Radiossensibilizantes/efeitos da radiação , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/uso terapêutico , Espectroscopia de Infravermelho com Transformada de Fourier , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The prognosis for patients with HER-2 negative breast cancer is currently poor, largely due to the lack of efficacious targeted therapeutics. Photodynamic nanomaterial technologies have rapidly developed in recent years, but their anti-tumor effects are often limited by poor targeting, low transformation efficiency, toxicity, and other factors. Thus, we prepared a new type of nanoparticles (Ce6/Dox@NPs-cRGD, CDNR) with cyclo(Arg-Gly-Asp-d-Phe-Cys) (c(RGDfC)) that target the ανß3 receptor. We loaded those nanoparticles (NPs) with a combination of the doxorubicin (Dox) and photosensitizer chlorin E6 (Ce6) to test synergy between chemotherapy and photodynamic therapy (PDT) for the treatment of ανß3 receptor positive and HER-2 negative breast cancer. Through analysis of the Fourier transform infrared and UV-vis spectra of these NPs, we found that Ce6 and Dox were successfully loaded into the CDNR. According to dynamic light scattering (DLS) analyses, CDNR particles had a diameter of 112.6 nm (polydispersity index 0.11), which was also confirmed via TEM characterization. The zeta potential was about -21.5 mV. Stability studies showed that CDNR particle size was stable in ddH2O, PBS, and DMEM + 5 % FBS for 16 days. The drug loading content of Dox and Ce6 were 5.3 and 6.8 %, respectively. Release studies of CDNR showed that the slow release of Dox was accelerated with increasing GSH concentration, and there was no burst release effect. From studying the absorbance of 9,10-dimethylanthrancene (ABDA), we found that CDNR produces high levels of ROS after excitation with a 670 nm laser, and ROS production increased with increasing radiation time. CDNR was significantly taken up by MCF-7 cells at 6 h because of cRGD targeting. In a CCK8 test, the relative growth rate (RGR) of CDNR +670 nm laser for MCF-7 cells was less than 75 % at 20 µg/mL after 24 h treatment and 15 µg/mL after 48 h treatment. We found that CDNR's effects on RGR were concentration dependent. Live-cell staining with a DCFH-DA kit and flow cytometry assay further supported that a CDNR +670 nm laser provided the maximum chemotherapy-PDT toxicity and production of intracellular ROS, and that cell death was mainly caused by necrosis and apoptosis. In vivo experiments showed that using the cRGD-targeting strategy, CDNR had a stronger affinity and increased half-life relative to Ce6/Dox@NPs in mice with MCF-7 xenograft tumors. Further, the Cmax of CDNR in the transplanted tumor occurred 8 h post-injection (HPI) and there was still detectable signal at 24 HPI. In addition, MCF-7 bearing mice that were treated with CDNR +670 nm PDT at 8 HPI had a significantly decreased tumor volume (P < 0.05) and prolonged survival time compared to other groups. Thus, CDNR plus 670 nm PDT was associated with favorable anti-tumor activity with no appreciable impact on body weight or the major organs in mice, as determined by immunohistochemistry/immunofluorescence and hematoxylin-eosin staining. In conclusion, CDNR with 670 nm laser irradiation represents a promising new potential treatment paradigm for the management of breast cancers that are ανß3-receptor positive and HER-2 negative.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Neoplasias da Mama/terapia , Doxorrubicina/uso terapêutico , Integrina alfaVbeta3/genética , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/administração & dosagem , Porfirinas/uso terapêutico , Receptor ErbB-2/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Clorofilídeos , Terapia Combinada , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas , Tamanho da Partícula , Espécies Reativas de Oxigênio , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cancer treatment has always been a big problem for people. With the application of photodynamic therapy, the problem has been alleviated. However, the problem of tumor hypoxia affecting photodynamic therapy has been waiting to be resolved. Therefore, we report here that a redox nanocarrier (called RN) is prepared by hollow mesoporous silica sphere (HMSNs) and a redox-responsive polymer ligand. The nanocarrier is loaded with metformin and catalase, and the polymer is linked to the photosensitizer chlorin e6 (Ce6). Metformin inhibits the mitochondrial respiration of cancer cells, reducing the activity of cancer cells and increasing the oxygen concentration required for photodynamic therapy. Not only the effect of photodynamic therapy is enhanced, but also the effect of chemotherapy is increased to achieve super additive treatment. These RNs exhibit not only low cytotoxicity but also high biocompatibility in vitro experiments. In vitro Ce6 release studies have shown a higher release in the presence of glutathione (GSH). Confocal microscopy can further indicate that the nanoparticles are carried to the area around the nucleus of the cancer cells. In addition, treatment with a mouse tumor model demonstrated that RN has an effective therapeutic effect on tumors.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Catalase/química , Metformina/administração & dosagem , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Dióxido de Silício/química , Animais , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Clorofilídeos , Terapia Combinada , Feminino , Glutationa/metabolismo , Humanos , Metformina/química , Metformina/farmacologia , Camundongos , Nanopartículas , Oxigênio/metabolismo , Fotoquimioterapia , Porosidade , Porfirinas/química , Porfirinas/farmacologia , Radiossensibilizantes/química , Radiossensibilizantes/farmacologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
The independence of photodynamic or photothermal modality create difficulties in the success of tumor therapy. In this current study, a multifunctional nanotheranostic agent of PDE-Ce6-HA was developed for tumor targeted and MRI-guided photodynamic/photothermal combined therapy (PDT/PTT). For this purpose, the near-infrared-absorbing nanoparticles of prussian blue were coated with polydopamine and successively conjugated with chlorin e6 (Ce6) for reactive oxygen species (ROS) generation. The resultant nanoparticles, denoted as PDE-Ce6, were then modified with hyaluronic acid (HA) through electrostatic interaction to yield the final therapeutic agent of PDE-Ce6-HA NPs. PDE-Ce6-HA NPs not only exhibited high colloid stability, good biocompatibility and suitable transverse relaxation rate (0.54 mM-1 s-1), but also high photothermal conversion efficiency (40.4%) and excellent ROS generation efficiency under NIR light irradiation. The confocal microscopy images demonstrated a selective uptake of PDE-Ce6-HA by CD44 overexpressed HeLa cells via HA-mediated endocytosis. Meanwhile, in vitro anti-cancer evaluation verified the significant photodynamic and photothermal combined effects of PDE-Ce6-HA on cancer cells. Moreover, PDE-Ce6-HA led to an increase of T1-MRI contrast in tumor site. Furthermore, in vivo anti-tumor evaluation proved that the PDE-Ce6-HA under both 808 and 670 nm laser showed significantly high tumor growth inhibition effects compared with individual PTT or PDT. Hence, PDE-Ce6-HA is applicable in tumor targeted and MRI-guided photodynamic/photothermal combined treatment.
Assuntos
Ferrocianetos/química , Ácido Hialurônico/administração & dosagem , Indóis/química , Fármacos Fotossensibilizantes/administração & dosagem , Polímeros/química , Porfirinas/administração & dosagem , Neoplasias do Colo do Útero/terapia , Animais , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorofilídeos , Endocitose/efeitos dos fármacos , Feminino , Células HeLa , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Imageamento por Ressonância Magnética , Camundongos , Células NIH 3T3 , Nanopartículas , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Porfirinas/química , Nanomedicina Teranóstica , Neoplasias do Colo do Útero/diagnóstico por imagem , Neoplasias do Colo do Útero/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Tumor cells adapt to reactive oxygen species (ROS) attacking by launching DNA damage repairing mechanisms such as nucleotide pool sanitizing enzyme mutt homologue 1 (MTH1) to mitigate the oxidatively induced DNA lesions, which could greatly limit the therapeutic efficiency of current oxidation therapy. Here, an amplified oxidative damage strategy for tumor therapy was proposed that was focused not only on the enhancement of ROS generation but also the inhibition of subsequent MTH1 enzyme activity simultaneously. In our formulation, mesoporous silica-coated Prussian blue nanoplatforms (PB@MSN) with excellent catalase-like activity and drug loading capability were employed to encapsulate MTH1 inhibitor TH287, followed by the modification of tetraphenylporphrin zinc (Zn-Por) via metallo-supramolecular coordination (PMPT), where Zn-Por behaved as photodynamic and fluorescence imaging agents, as well as acid-responsive gatekeepers. The intelligent PMPT nanosystems could induce the decomposition of H2O2 to relieve the hypoxic tumor environment, thus elevating the generation of singlet oxygen for improved oxidative damage. In the meantime, controllable-released TH287 from pores could hinder MTH1-mediated damage repairing process and aggravate oxidative damage, thereby resulting in cellular toxicity as well as tumor growth inhibition.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Enzimas Reparadoras do DNA/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Neoplasias da Mama/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Células MCF-7 , Camundongos Nus , Imagem Óptica , Monoéster Fosfórico Hidrolases/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Pirimidinas/administração & dosagem , Espécies Reativas de Oxigênio/metabolismoRESUMO
Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide-thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior in vivo antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.
Assuntos
Preparações de Ação Retardada/química , Ferroptose/efeitos dos fármacos , Neoplasias Mamárias Animais/tratamento farmacológico , Estruturas Metalorgânicas/química , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Clorofilídeos , Feminino , Glutationa/metabolismo , Neoplasias Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Oxirredução , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêuticoRESUMO
Nanomedicines have been demonstrated as promising strategies for cancer therapy due to the advantages in pharmacokinetics and drug targeting delivery to tumor tissues. However, creation of delivery platforms able to intrinsically and spatially optimize drug cellular uptake during the entire delivering process remain challenging. To address this challenge, here we report on tumor microenvironment-adaptable self-assembly (TMAS) of pentapeptides regulated by the pH-sensitive cis/trans isomerization of 4-amino-proline (Amp) amide bonds for enhanced drug delivery and photodynamic therapeutic (PDT) efficacy. We found that decreasing solution pH led to the cis â trans isomerization of Amp amide bonds, thus promoting reversible self-assembly of pentapeptide FF-Amp-FF (AmpF) into superhelices and nanoparticles upon alternating exposure to neutral and mild acidic conditions. Co-assembly of peptide AmpF with its derivative containing a photosensitizer Chlorin e6 (AmpF-C) allows for creation of TMAS systems undergoing a morphological transition adaptable to the pH gradient present in cellular uptake pathway. Ex vivo studies revealed that TMAS nanomedicines prolonged circulation in the animal body and improved accumulation at tumor sites compared to morphology-persistent nanomedicines. In addition to the optimized cellular uptake, the morphological transition of TMAS into nanofibers in cytoplasm caused an enhanced intracellular ROS level compared to nanoparticle counterparts, thus leading to a lowered half lethal dose value for cancer cells. The combined advantages of TMAS eventually allowed in vivo PDT therapy for significant inhibition of tumor growth, thus demonstrating the improved drug delivery efficiency and therapeutic efficacy of TMAS systems toward new-generation nanomedicines.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Preparações de Ação Retardada/química , Oligopeptídeos/química , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Prolina/química , Animais , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Clorofilídeos , Feminino , Isomerismo , Camundongos , Nanoestruturas/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/uso terapêutico , Microambiente Tumoral/efeitos dos fármacosRESUMO
Colon cancer is the third major cancer contributor to mortality worldwide. Nanosized particles have attracted attention due to their possible contribution towards cancer treatment and diagnosis. Photodynamic therapy (PDT) is a cancer therapeutic modality that involves a light source, a photosensitizer and reactive oxygen species. Carbon nanotubes are fascinating nanocarriers for drug delivery, cancer diagnosis and numerous potential applications due to their unique physicochemical properties. In this study, single walled carbon nanotubes (SWCNTs) were coupled with hyaluronic acid (HA) and chlorin e6 (Ce6) coated on the walls of SWCNTs. The newly synthesized nanobiocomposite was characterized using ultraviolet-visible spectroscopy, Fourier transform electron microscopy (FTIR), X-ray diffraction analysis (XRD), particle size analysis and zeta potential. The loading efficiency of the SWCNTs-HA for Ce6 was calculated. The toxicity of the nanobiocomposite was tested on colon cancer cells using PDT at a fluence of 5 J/cm2 and 10 J/cm2. After 24 h, cellular changes were observed via microscopy, LDH cytotoxicity assay and cell death induction using annexin propidium iodide. The results showed that the newly synthesized nanobiocomposite enhanced the ability of PDT to be a photosensitizer carrier and induced cell death in colon cancer cells.
Assuntos
Neoplasias do Colo/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Apoptose/efeitos dos fármacos , Células CACO-2 , Clorofilídeos , Neoplasias do Colo/patologia , Humanos , Ácido Hialurônico/química , Nanocompostos/química , Nanocompostos/ultraestrutura , Nanotubos de Carbono/química , Nanotubos de Carbono/ultraestrutura , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Porfirinas/química , Espectrofotometria , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
Macrophage-derived foam cells play critical roles in the initiation and progression of atherosclerosis. Activated macrophages and foam cells are important biomarkers for targeted imaging and inflammatory disease therapy. Macrophages also express the dectin-1 receptor, which specifically recognizes ß-glucan (Glu). Here, we prepared photoactivatable nanoagents (termed Glu/Ce6 nanocomplexes) by encapsulating hydrophobic chlorin e6 (Ce6) within the triple-helix structure of Glu in aqueous condition. Glu/Ce6 nanocomplexes generate singlet oxygen upon laser irradiation. The Glu/Ce6 nanocomplexes were internalized into foam cells and delivered Ce6 molecules into the cytoplasm of foam cells. Upon laser irradiation, they induced significant membrane damage and apoptosis of foam cells. These results suggest that Glu/Ce6 nanocomplexes can be a photoactivatable material for treating atherogenic foam cells.
Assuntos
Aterosclerose/tratamento farmacológico , Células Espumosas/efeitos dos fármacos , Glucanos/farmacologia , Lasers , Nanopartículas/administração & dosagem , Porfirinas/farmacologia , Radiossensibilizantes/farmacologia , Animais , Apoptose , Aterosclerose/metabolismo , Aterosclerose/patologia , Clorofilídeos , Células Espumosas/metabolismo , Células Espumosas/patologia , Glucanos/administração & dosagem , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Nanopartículas/química , Fotoquimioterapia , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Oxigênio Singlete/química , Oxigênio Singlete/metabolismoRESUMO
In sonodynamic therapy (SDT), when Chlorin e6 (Ce6) accumulates in tumor tissues, its anti-tumor effect can be achieved by ultrasound activation. To increase the local drug concentration of Ce6 in tumor cells, we had established a novel drug delivery system, Ce6-loaded sonosensitive magnetic nanoliposome (Ce6/SML), which realized the targeting delivery by the external magnetic field. It was worth mentioning that the targeting release of Ce6/SML and the activation on Ce6 could be achieved simultaneously by ultrasound of SDT. In our study, after Ce6 was loaded into the sonosensitive magnetic nanoliposome (SML), the values of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in vitro and in vivo were determined, indicating the activation on Ce6 of ultrasound. The delivery system also displayed the tumor-targeting ability and anti-tumor activity, which associated with the determined tumor growth and expression levels of angiogenin (ANG), vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α). In conclusion, the Ce6/SML-SDT-Targeted delivery system could effectively enhance the anti-tumor activity of SDT and had a great potential application for the treatment of malignant tumors located in deep tissues.
Assuntos
Fenômenos Magnéticos , Nanopartículas , Porfirinas/farmacologia , Terapia por Ultrassom/métodos , Células A549 , Animais , Clorofilídeos , Sistemas de Liberação de Medicamentos , Humanos , Lipossomos , Neoplasias Pulmonares/terapia , Campos Magnéticos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Although nanocarriers containing perfluorocarbon (PFC) have been widely investigated as an ultrasound (US) imaging agent and a high intensity focused ultrasound (HIFU) agent, these carriers have suffered from low stability and biocompatibility limiting their further biomedical applications. Here, we developed surface cross-linked polymer nanodroplets as a HIFU therapeutic agent guided by bimodal photoacoustic (PA) and US imaging. Pluronic F127 was reacted with 4-nitrophenyl chloroformate (NPC) and mixed with naphthalocyanine (Nc) in dichloromethane, which was added into the aqueous solution of amine-functionalized six-arm-branched poly(ethylene glycol) (PEG) to form an oil-in-water emulsion for the cross-linking reaction between the terminal NPC of Pluronic F127 and the primary amine of six-arm PEG. The resulting solution was sonicated with liquid perfluorohexane (PFH) to prepare PEG cross-linked Pluronic F127 nanoparticles encapsulating Nc and PFH (Nc/PFH@PCPN). Nc/PFH@PCPN appeared to be stable without any coalescence or vaporization in the physiological condition. Upon the application of HIFU, Nc/PFH@PCPN was vaporized and showed increased US intensity for 180 min. The Nc dye in the nanodroplets enabled the stable encapsulation of PFH and the bimodal US/PA imaging. In vivo PA/US image-guided HIFU ablation therapy confirmed that the nanodroplets increased the cavitation effect, induced necrosis and apoptosis of tumor cells, and reduced tumor growth significantly for 12 days. Taken together, the multifunctional Nc/PFH@PCPN was successfully developed as a new platform for PA/US image-guided HIFU therapy.
Assuntos
Meios de Contraste/química , Tratamento por Ondas de Choque Extracorpóreas/métodos , Fluorocarbonos/química , Nanocápsulas/química , Porfirinas/química , Ultrassonografia/métodos , Animais , Bovinos , Clorobenzoatos/química , Meios de Contraste/administração & dosagem , Fluorocarbonos/administração & dosagem , Humanos , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Técnicas Fotoacústicas/métodos , Poloxâmero/química , Polietilenoglicóis/química , Porfirinas/administração & dosagem , VolatilizaçãoRESUMO
Taking advantage of the mesoporous structure of bismuth sulfide nanostars (Bi2S3 NSs), a chemotherapeutic drug of doxorubicin (DOX) and a photosensitizer of chlorin e6 (Ce6) were concurrently loaded in the PEGylated Bi2S3 NSs to formulate a multifunctional nanocomplex (BPDC NSs) for tumor theranostics. BPDC NSs have excellent photothermal conversion efficiency and a capacity of yielding reactive oxygen species (ROS) upon laser irradiation, and can realize on-demand drug release by either pH-activation or thermal induction. Accumulation of the nanodrug could be monitored in real-time by infrared thermal imaging, fluorescence imaging and computed tomography (CT). More importantly, the combination effects of photothermal therapy (PTT), photodynamic therapy (PDT) and chemotherapy were demonstrated to dramatically suppress solid tumors without recurrence in vivo. Featuring low systemic toxicity and high biocompatibility, this nanoplatform could be a promising derivative of Bi2S3 NSs for imaging-guided theranostics of cancer.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Fármacos Fotossensibilizantes/administração & dosagem , Porfirinas/administração & dosagem , Animais , Antibióticos Antineoplásicos/uso terapêutico , Bismuto/uso terapêutico , Linhagem Celular Tumoral , Clorofilídeos , Preparações de Ação Retardada/uso terapêutico , Doxorrubicina/uso terapêutico , Hipertermia Induzida , Camundongos , Nanopartículas/uso terapêutico , Nanopartículas/ultraestrutura , Imagem Óptica , Fotoquimioterapia , Fármacos Fotossensibilizantes/uso terapêutico , Polietilenoglicóis/uso terapêutico , Porosidade , Porfirinas/uso terapêutico , Sulfetos/uso terapêutico , Nanomedicina Teranóstica , Tomografia Computadorizada por Raios XRESUMO
Ciliopathies are a group of genetic multi-systemic disorders related to dysfunction of the primary cilium, a sensory organelle present at the cell surface that regulates key signaling pathways during development and tissue homeostasis. In order to identify novel genes whose mutations would cause severe developmental ciliopathies, >500 patients/fetuses were analyzed by a targeted high throughput sequencing approach allowing exome sequencing of >1200 ciliary genes. NEK8/NPHP9 mutations were identified in five cases with severe overlapping phenotypes including renal cystic dysplasia/hypodysplasia, situs inversus, cardiopathy with hypertrophic septum and bile duct paucity. These cases highlight a genotype-phenotype correlation, with missense and nonsense mutations associated with hypodysplasia and enlarged cystic organs, respectively. Functional analyses of NEK8 mutations in patient fibroblasts and mIMCD3 cells showed that these mutations differentially affect ciliogenesis, proliferation/apoptosis/DNA damage response, as well as epithelial morphogenesis. Notably, missense mutations exacerbated some of the defects due to NEK8 loss of function, highlighting their likely gain-of-function effect. We also showed that NEK8 missense and loss-of-function mutations differentially affect the regulation of the main Hippo signaling effector, YAP, as well as the expression of its target genes in patient fibroblasts and renal cells. YAP imbalance was also observed in enlarged spheroids of Nek8-invalidated renal epithelial cells grown in 3D culture, as well as in cystic kidneys of Jck mice. Moreover, co-injection of nek8 MO with WT or mutated NEK8-GFP RNA in zebrafish embryos led to shortened dorsally curved body axis, similar to embryos injected with human YAP RNA. Finally, treatment with Verteporfin, an inhibitor of YAP transcriptional activity, partially rescued the 3D spheroid defects of Nek8-invalidated cells and the abnormalities of NEK8-overexpressing zebrafish embryos. Altogether, our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Cílios/genética , Fosfoproteínas/genética , Doenças Renais Policísticas/genética , Proteínas Quinases/genética , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Animais , Diferenciação Celular/genética , Cílios/patologia , Feminino , Estudos de Associação Genética , Humanos , Rim/metabolismo , Rim/patologia , Camundongos , Morfogênese/genética , Mutação , Quinases Relacionadas a NIMA , Fosfoproteínas/antagonistas & inibidores , Fosfoproteínas/biossíntese , Doenças Renais Policísticas/patologia , Porfirinas/administração & dosagem , Transdução de Sinais , Fatores de Transcrição , Verteporfina , Proteínas de Sinalização YAP , Peixe-ZebraRESUMO
We fabricated poly (ethylene glycol)-block-polycaprolactone (PEG-b-PCL) nanoemulsion for drug delivery and photodynamic therapy. PEG-b-PCL effectively stabilized the interface between water and soybean oil, and the resulting nanoemulsion was about 220.3 nm in diameter with spherical shape. For photodynamic therapy (PDT), chlorin e6 (Ce6) was loaded into the nanoemulsion as a photosensitizer (PS). These chlorin e6-loaded PEG-PCL nanoemulsions (Ce6-PCL-NEs) showed efficient cellular uptake and, upon laser irradiation, generated singlet oxygen to kill tumor cells. Particularly, Ce6-PCL-NEs showed prolonged blood circulation and about 60% increased tumor accumulation compared to free Ce6 after intravenous injection to 4T1 tumor-bearing mice. These results demonstrate the promising potential of Ce6-PCL-NEs for efficient PDT and in vivo drug delivery to tumor tissue.
Assuntos
Portadores de Fármacos/química , Emulsões , Lactonas/química , Nanopartículas , Polietilenoglicóis/química , Porfirinas/administração & dosagem , Radiossensibilizantes/administração & dosagem , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Clorofilídeos , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Emulsões/química , Camundongos , Modelos Animais , Nanopartículas/química , Nanopartículas/ultraestrutura , Fotoquimioterapia , Porfirinas/química , Porfirinas/farmacocinética , Radiossensibilizantes/química , Distribuição TecidualRESUMO
DNAzymes have been recognized as potent therapeutic agents for gene therapy, while their inefficient intracellular delivery and insufficient cofactor supply precludes their practical biological applications. Metal-organic frameworks (MOFs) have emerged as promising drug carriers without in-depth consideration of their disassembled ingredients. Herein, we report a self-sufficient MOF-based chlorin e6-modified DNAzyme (Ce6-DNAzyme) therapeutic nanosystem for combined gene therapy and photodynamic therapy (PDT). The ZIF-8 nanoparticles (NPs) could efficiently deliver the therapeutic DNAzyme without degradation into cancer cells. The pH-responsive ZIF-8 NPs disassemble with the concomitant release of the guest DNAzyme payloads and the host Zn2+ ions that serve, respectively, as messenger RNA-targeting agent and required DNAzyme cofactors for activating gene therapy. The auxiliary photosensitizer Ce6 could produce reactive oxygen species (ROS) and provide a fluorescence signal for the imaging-guided gene therapy/PDT.
Assuntos
Neoplasias da Mama/terapia , DNA Catalítico/química , Proteína 1 de Resposta de Crescimento Precoce/genética , Terapia Genética , Estruturas Metalorgânicas/química , Fotoquimioterapia , Porfirinas/administração & dosagem , Animais , Apoptose , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células , Clorofilídeos , Portadores de Fármacos , Proteína 1 de Resposta de Crescimento Precoce/administração & dosagem , Proteína 1 de Resposta de Crescimento Precoce/antagonistas & inibidores , Feminino , Inativação Gênica , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/administração & dosagem , Nanopartículas/química , Porfirinas/química , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioma is the most frequent primary brain tumour of the central nervous system. Its high aggressiveness and deep-seated brain lesion make it a great challenge to develop a non-invasive, precise and effective treatment approach. Here, we report a multifunctional theranostic agent that can integrate imaging and therapy into a single nano-platform for imaging-guided sonodynamic therapy (SDT). The SDT agents were fabricated by encapsulation of sinoporphyrin sodium (DVDMS) chelating with manganese ions into nanoliposomes (DVDMS-Mn-LPs). DVDMS-Mn-LPs are physiologically stable and biologically compatible, and they can produce singlet oxygen upon ultrasound irradiation to kill cancer cells. Both cell and animal studies demonstrated that SDT with DVDMS-Mn-LPs can significantly improve the antitumour growth efficiency even in the presence of skull. In addition, DVDMS-Mn-LPs are good for MR and fluorescence imaging. Thus, DVDMS-Mn-LPs reported here may provide a promising strategy for imaging-guided modality for glioma treatment.