RESUMO
Negative therapeutic feedback of inflammation would extensively attenuate the antitumor effect of photodynamic therapy (PDT). In this work, tumor homing chimeric peptide rhomboids (designated as NP-Mel) are fabricated to improve photodynamic performance by inhibiting PDT-upregulated cyclooxygenase-2 (COX-2). The hydrophobic photosensitizer of protoporphyrin IX (PpIX) and palmitic acid are conjugated onto the neuropilin receptors (NRPs) targeting peptide motif (CGNKRTR) to obtain tumor homing chimeric peptide (Palmitic-K(PpIX)CGNKRTR), which can encapsulate the COX-2 inhibitor of meloxicam. The well dispersed NP-Mel not only improves the drug stability and reactive oxygen species (ROS) production ability, but also increase the breast cancer targeted drug delivery to intensify the PDT effect. In vitro and in vivo studies verify that NP-Mel will decrease the secretion of prostaglandin E2 (PGE2) after PDT treatment, inducing the downregulation of IL-6 and TNF-α expressions to suppress PDT induced inflammation. Ultimately, an improved PDT performance of NP-Mel is achieved without inducing obvious systemic toxicity, which might inspire the development of sophisticated nanomedicine in consideration of the feedback induced therapeutic resistance.
Assuntos
Ciclo-Oxigenase 2 , Peptídeos , Fotoquimioterapia , Fotoquimioterapia/métodos , Ciclo-Oxigenase 2/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Animais , Humanos , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Feminino , Meloxicam/farmacologia , Meloxicam/uso terapêutico , Camundongos , Protoporfirinas/química , Protoporfirinas/farmacologia , Dinoprostona/metabolismoRESUMO
INTRODUCTION: Eleutherococcus senticosus fruit (ESF) is a natural health supplement resource that has been extensively applied as a tonic for the nervous system. The structures and neural bioactivities of triterpenoid saponins (TS), which are the major constituents of ESF, have not been comprehensively analyzed thus far. OBJECTIVE: We conducted a complete in-depth MS/MS molecular networking (MN)-based targeted analysis of TS from the crude extract of ESF and investigated its neuroprotective value. METHODS: An MS/MS MN-guided strategy was used to rapidly present a series of precursor ions (PIs) of TS in a compound cluster as TS-targeted information used in the discovery and characterization of TS. In addition, a prepared TS-rich fraction of ESF was assayed for its restraining effects on ß-amyloid-induced inhibition of neurite outgrowth. RESULTS: A total of 87 TS were discovered using a PI tracking strategy, 28 of which were characterized as potentially undescribed structures according to their high-resolution MS values. Furthermore, the TS-rich fraction can significantly reduce ß-amyloid-induced damage to neural networks by promoting the outgrowth of neurites and axons. CONCLUSION: Our findings reveal the richness of TS in ESF and will accelerate their application in the treatment of neurodegenerative diseases.
Assuntos
Eleutherococcus , Saponinas , Triterpenos , Espectrometria de Massas em Tandem , Extratos Vegetais/química , Eleutherococcus/química , Saponinas/química , Frutas/química , Triterpenos/análiseRESUMO
Tumor cells adapt to excessive oxidative stress by actuating reactive oxygen species (ROS)-defensing system, leading to a resistance to oxidation therapy. In this work, self-delivery photodynamic synergists (designated as PhotoSyn) are developed for oxidative damage amplified tumor therapy. Specifically, PhotoSyn are fabricated by the self-assembly of chlorine e6 (Ce6) and TH588 through π-π stacking and hydrophobic interactions. Without additional carriers, nanoscale PhotoSyn possess an extremely high drug loading rate (up to 100%) and they are found to be fairly stable in aqueous phase with a uniform size distribution. Intravenously injected PhotoSyn prefer to accumulate at tumor sites for effective cellular uptake. More importantly, TH588-mediated MTH1 inhibition could destroy the ROS-defensing system of tumor cells by preventing the elimination of 8-oxo-2'-deoxyguanosine triphosphate (8-oxo-dG), thereby exacerbating the oxidative DNA damage induced by the photodynamic therapy (PDT) of Ce6 under light irradiation. As a consequence, PhotoSyn exhibit enhanced photo toxicity and a significant antitumor effect. This amplified oxidative damage strategy improves the PDT efficiency with a reduced side effect by increasing the lethality of ROS without generating superabundant ROS, which would provide a new insight for developing self-delivery nanoplatforms in photodynamic tumor therapy in clinic.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Estresse Oxidativo , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de OxigênioRESUMO
Immunotherapeutic effect is restricted by the nonimmunogenic tumor phenotype and immunosuppression behaviors of tumor-associated macrophages (TAMs). In this work, a drug self-assembly (designated as CeBLZ) is fabricated based on chlorin e6 (Ce6) and BLZ945 to activate photodynamic immunotherapy through tumor immunogenic induction and tumor-associated macrophage depletion. It is found that Ce6 tends to assemble with BLZ945 without any drug excipients, which can enhance the cellular uptake, tumor penetration, and blood circulation behaviors. The robust photodynamic therapy effect of CeBLZ efficiently suppresses the primary tumor growth and also triggers immunogenic cell death to reverse the nonimmunogenic tumor phenotype. Moreover, CeBLZ can deplete TAMs in tumor tissues to reverse the immunosuppression microenvironment, activating abscopal effect for distant tumor inhibition. In vitro and in vivo results confirm the superior antitumor effect of CeBLZ with negligible side effect, which might promote the development of sophisticated drug combinations for systematic tumor management.
Assuntos
Clorofilídeos , Imunoterapia , Fotoquimioterapia , Porfirinas , Macrófagos Associados a Tumor , Porfirinas/química , Porfirinas/farmacologia , Animais , Fotoquimioterapia/métodos , Macrófagos Associados a Tumor/efeitos dos fármacos , Macrófagos Associados a Tumor/imunologia , Camundongos , Imunoterapia/métodos , Linhagem Celular Tumoral , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Humanos , Feminino , Células RAW 264.7 , Microambiente Tumoral/efeitos dos fármacos , Camundongos Endogâmicos BALB CRESUMO
Tumor cells resist oxidative damage and apoptosis by activating defense mechanisms. Herein, a self-delivery biomedicine (designated as BSC) is developed by the self-assembly of Bortezomib (BTZ), Sabutoclax (Sab) and Chlorin e6 (Ce6). Interestingly, BTZ can be coordinated with Sab to promote the assembly of uniform ternary biomedicine through non-covalent intermolecular interactions. Moreover, BTZ as a proteasome inhibitor can prevent tumor cells from scavenging damaged proteins to reduce their oxidative resistance. Sab can downregulate B-cell lymphoma 2 (Bcl-2) to decrease the antiapoptotic protein. Both the proteasome and Bcl-2 inhibitions contribute to increasing cell apoptosis and amplifying photodynamic therapy (PDT) efficacy of Ce6. Encouragingly, carrier-free BSC receives all biological activities of these assembly elements, including photodynamic performance as well as inhibitory capabilities of proteasome and Bcl-2. Besides, BSC has a preferable cellular uptake ability and tumor retention property, which increase the drug delivery efficiency and bioavailability. In vitro and in vivo research demonstrate the superior PDT efficiency of BSC by proteasome and Bcl-2 inhibitions. Of special note, the coordination-driven self-assembly of BSC is pH-responsive, which can be disassembled for controlled drug release upon tumor acidic microenvironment. This study will expand the applicability of self-delivery nanomedicine with sophisticated mechanisms for tumor treatment.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Fármacos Fotossensibilizantes/farmacologia , Complexo de Endopeptidases do Proteassoma , Linhagem Celular Tumoral , Porfirinas/farmacologiaRESUMO
Abnormal metabolism of cancer cells results in complex tumor microenvironments (TME), which play a dominant role in tumor metastasis. Herein, self-delivery ternary bioregulators (designated as TerBio) are constructed for photodynamic amplified immunotherapy against colorectal cancer by TME reprogramming. Specifically, carrier-free TerBio are prepared by the self-assembly of chlorine e6, SB505124 (SB), and lonidamine (Lon), which exhibit improved tumor accumulation, tumor penetration, and cellular uptake behaviors. Interestingly, TerBio-mediated photodynamic therapy (PDT) could not only inhibit the primary tumor growth but also induce immunogenic cell death of tumors to activate the cascade immune response. Furthermore, TerBio are capable of TME reprograming by SB-triggered transforming growth factor (TGF)-ß blockage and Lon-induced lactic acid efflux inhibition. As a consequence, TerBio significantly suppresses distant and metastatic tumor growth by PDT-amplified immunotherapy. This study might advance the development of self-delivery nanomedicine against malignant tumor growth and metastasis.
Assuntos
Nanopartículas , Fotoquimioterapia , Microambiente Tumoral , Linhagem Celular Tumoral , Imunoterapia/métodos , Fotoquimioterapia/métodos , Fatores Imunológicos/farmacologia , Fármacos Fotossensibilizantes/farmacologiaRESUMO
Cinnamon oil is obtained by steam distillation from cinnamon leaves and is usually considered highly cost-effective compared to bark oil, however, which results in tons of waste cinnamon leaves (WCL) discarded annually. By using MS/MS molecular networking (MN) assisted profiling, six main chemical diversities including flavonols and flavones, phenolic acids, lactones, terpenoids, phenylpropanoids and flavanols were rapid revealed from WCL aqueous extract. 101 compounds were tentatively identified by assigning their MS/MS fragments within typical pathways under ESI-MS/MS dissociation. The featured phenolic acids, terpenoids and their glycosides in cinnamon species were recognized as the main constituents of WCL. The hydrophilic lactones, lignans and flavanols were reported for the first time in cinnamon leaves. Furthermore, ABTS and FRAP assays integrated with MN analysis were conducted to uncover an antioxidant fraction, from which 40 potential antioxidant compounds were rapidly annotated. This fundamental information will help expand the utilization of WCL from cinnamon oil industry.
Assuntos
Antioxidantes , Cinnamomum zeylanicum , Cromatografia Líquida , Extratos Vegetais , Espectrometria de Massas em TandemRESUMO
Glutamine metabolism of tumor cells plays a crucial role in maintaining cell homeostasis and reducing oxidative damage. Herein, a valid strategy of inhibiting glutamine metabolism is proposed to amplify the oxidative damage of photodynamic therapy (PDT) to tumor cells. Specifically, the authors develop a drug co-delivery system (designated as CeV) based on chlorine e6 (Ce6) and V9302 via the self-assembly technology. In spite of the strong hydrophobicity of therapeutic agents, the assembled CeV holds a favorable dispersibility in water and an improved cellular uptake capability. Under light irradiation, the internalized CeV is capable of generating abundant reactive oxygen species (ROS) for PDT. More importantly, CeV can reduce the uptake of glutamine through V9302-mediated alanine-serine-cysteine transporter of type-2 (ASCT2) inhibition, leading to a reduced glutathione (GSH) production and an amplified oxidative stress. As a result, CeV has a robust PDT efficacy on tumor inhibition by the blockade of glutamine transport. Notably, CeV exhibits a superiority on tumor suppression over the single treatment as well as the combined administration of Ce6 and V9302, which indicates the advantage of CeV for synergistic treatment. It may serve as a novel nanoplatform for developing a drug co-delivery system to improve PDT efficiency by inhibiting cell metabolism.
Assuntos
Nanopartículas , Fotoquimioterapia , Porfirinas , Linhagem Celular Tumoral , Glutamina , Nanomedicina , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Porfirinas/farmacologiaRESUMO
Abnormal tumor microenvironments play important roles in cancer progression. In general, tumor cells are capable of upregulating glutathione (GSH) levels to maintain aberrant redox homeostasis and cause resistance to oxidative damage. Herein, we develop a photodynamic oxidizer to disrupt the redox homeostasis of tumor cells for enhanced photodynamic tumor therapy. Based on pyropheophorbide-a (Pyro) and naphthazarin (Nap), a carrier free photodynamic oxidizer (named PyroNap) is prepared by the self-assembly technique through hydrophobic interactions. It is confirmed that nanosized PyroNap has high drug contents as well as favorable dispersity and stability. Besides, the photodynamic property of Pyro has obviously improved after self-assembly into the nanomedicine of PyroNap, which facilitates the production of reactive oxygen species (ROS) for robust photodynamic therapy (PDT). More importantly, the Nap induced GSH decrease could disrupt the redox homeostasis of tumor cells to further improve the PDT efficacy on tumor suppression. Consequently, after intravenous administration, PyroNap was able to significantly inhibit tumor growth and cause minimal side effects. This study might shed light on developing translational nanomedicine for tumor precision therapy.
Assuntos
Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Homeostase , Nanopartículas/química , Oxirredução , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Espécies Reativas de OxigênioRESUMO
Cysestermerol A (1), a rare and new stilbene sestermer, was isolated from the whole herb of Cynodon dactylon. The planar and relative structures of 1 were elucidated based on HRESIMS, one- and two-dimensional NMR analyses, and its absolute configuration was further established by electronic circular dichroism calculations. Compound 1 obviously increased the glucose consumption in HepG2 cells equivalent to the positive control rosiglitazone and markedly inhibited the activity of α-glucosidase in vitro.
Assuntos
Cynodon , Hipoglicemiantes/farmacologia , Estilbenos , Cynodon/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Hipoglicemiantes/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Compostos Fitoquímicos/isolamento & purificação , Compostos Fitoquímicos/farmacologia , Extratos Vegetais , Estilbenos/isolamento & purificação , Estilbenos/farmacologia , alfa-GlucosidasesRESUMO
Oxygen-dependent photodynamic therapy (PDT) could exacerbate tumor hypoxia to induce the upregulation of hypoxia-inducible factor-1α (HIF-1α), which would promote tumor growth and metastasis. In this paper, a self-remedied nanomedicine is developed based on a photosensitizer and a HIF-1α inhibitor to surmount the Achilles' heel of PDT for enhanced antitumor efficacy. Specifically, the nanomedicine (designated as CYC-1) is prepared by the self-assembly of chlorine e6 (Ce6) and 3-(5'-hydroxy-methyl-2'-furyl)-1-benzylindazole (YC-1) through π-π stacking and hydrophobic interactions. Of special note, carrier-free CYC-1 holds an extremely high drug loading rate and avoids excipient-triggered adverse reactions. Intravenously administered CYC-1 prefers to accumulate in the tumor tissue for effective cellular uptake. More importantly, it is verified that CYC-1 is capable of inhibiting the HIF-1α activity, thereby improving its PDT efficacy on tumor suppression. Besides, CYC-1 has the overwhelming superiority in restraining tumor proliferation over the combined administration of Ce6 and YC-1, which highlights the advantage of this self-remedied strategy in drug delivery and tumor therapy. This study sheds light on the development of self-delivery nanomedicine for efficient PDT against malignancies.
Assuntos
Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Nanomedicina , Nanopartículas/química , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
The development of photodynamic therapy (PDT) is severely limited by short half-life of singlet oxygen (1O2) and the hypoxic microenvironment. In this work, a plasma membrane targeted photodynamic O2 economizer (designated as P-POE) is developed to improve the subcellular delivery of photosensitizers and alleviate the tumor hypoxia for enhanced PDT effect. After self-assembly into nanomicelles, P-POE has a relatively high stability and a favorable photochemical performance, which are conducive to boosting the 1O2 production. Besides, the plasma membrane anchoring of P-POE contributes to enhancing the preferential retention and cellular accumulation of photosensitizers on tumor tissues and cells. More importantly, P-POE-induced mitochondrial respiratory depression is demonstrated to reduce the O2 consumption of tumor cells to relieve the hypoxia. Consequently, P-POE still exhibits a robust PDT effect against hypoxic tumors, which greatly inhibits the proliferation of breast cancer with low adverse reactions. This innovative combination of subcellular targeting and hypoxic alleviation would advance the development of individualized drug delivery systems for photodynamic therapy against hypoxic tumors.
Assuntos
Nanopartículas , Fotoquimioterapia , Linhagem Celular Tumoral , Membrana Celular , Humanos , Hipóxia/tratamento farmacológico , Oxigênio , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
Development of antitumor agents with high efficiency and low toxicity is one of the most important goals for biomedical research. However, most traditional therapeutic strategies were limited due to their non-specificity and abnormal tumor microenvironments, causing a poor therapeutic efficiency and severe side effects. In this paper, a tumor targeted self-synergistic nanoplatform (designated as PAO@PCN@HA) was developed for chemotherapy sensitized photodynamic therapy (PDT) against hypoxic tumors. The efficient drug loading of phenylarsine oxide (PAO) in porphyrinic metal organic framework of PCN-224 as well as the surface modification of hyaluronic acid (HA) improved the targeted drug delivery and reduced the side effects of PAO at the therapeutic dose. Particularly, PAO as an arsenical-based chemotherapeutic agent could not only induce cell apoptosis by generating reactive oxygen species (ROS), but also regulate tumor microenvironments to improve the PDT effect of PCN-224 by mitigating hypoxia and consuming cellular GSH. Both in vitro and in vivo investigations confirmed an effective self-synergy of PAO@PCN@HA in hypoxic tumor therapy with a low systemic toxicity. This integration of microenvironment adjustment with tumor targeted self-synergistic mechanism might provide a new insight for the development of arsenic-based antitumor strategy for clinical applications.
Assuntos
Antineoplásicos , Arsênio , Neoplasias , Fotoquimioterapia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Arsênio/uso terapêutico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , Fármacos Fotossensibilizantes/uso terapêutico , Microambiente TumoralRESUMO
In this paper, modulation of reflected wavefront out of the incident plane by a tunable acoustic metasurface is investigated based on the fully generalized Snell's law in the three-dimensional space. The metasurface is constructed by a square lattice of circular holes with gradient annular bumps. The phase shift is tuned by changing the volume of water filled in the holes. The acoustic wave steering out of the incident plane and the out-of-plane acoustic focusing with the oblique incidence at the subwavelength scale are demonstrated numerically by selecting suitable distributions of water depth. The numerical results show that the wavefront of the reflected wave can be manipulated over a wide frequency range; and the gradient design of the unit cells can suppress the parasitic reflection. The present work is relevant to the practical design of novel acoustic devices.
RESUMO
OBJECTIVE: To set up method for the quality control of carbonized Cortex Moutan. METHODS: The optimized processing technology of carbonized Cortex Moutan was selected by the time of blood coagulation. Besides, the contents of tannin, adsorbability, paeonol and peoniflorin were researched. RESULTS: To parch the pieces 5 minutes at the temperature of 22 degrees C was the optimized processing technology. CONCLUSION: This study provides a reference to the institution for the quality standard of carbonized Cortex Moutan.
Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/isolamento & purificação , Paeonia/química , Tecnologia Farmacêutica/métodos , Acetofenonas/análise , Animais , Benzoatos/análise , Coagulação Sanguínea/efeitos dos fármacos , Hidrocarbonetos Aromáticos com Pontes/análise , Carvão Vegetal , Cromatografia Líquida de Alta Pressão , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Glucosídeos/análise , Masculino , Camundongos , Monoterpenos , Casca de Planta/química , Raízes de Plantas/química , Controle de Qualidade , Taninos/análise , Tempo de Coagulação do Sangue TotalRESUMO
In this paper, anti-plane transverse wave propagation in nanoscale periodic layered piezoelectric structures is studied. The localization factor is introduced to characterize the wave propagation behavior. The transfer matrix method based on the nonlocal piezoelectricity continuum theory is used to calculate the localization factor. Additionally, the stiffness matrix method is applied to compute the wave transmission spectra. A cut-off frequency is found, beyond which the elastic waves cannot propagate through the periodic structure. The size effect or the influence of the ratio of the internal to external characteristic lengths on the cut-off frequency and the wave propagation behavior are investigated and discussed.