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The dense stroma of desmoplastic tumor limits nanotherapeutic penetration and hampers the antitumor immune response. Here, we report a denaturation-and-penetration strategy and the use of tin monosulfide nanoparticles (SnSNPs) as nano-sonosensitizers that can overcome the stromal barrier for the management of desmoplastic triple-negative breast cancer (TNBC). SnSNPs possess a narrow bandgap (1.18 eV), allowing for efficient electron (e-)-hole (h+) pair separation to generate reactive oxygen species under US activation. More importantly, SnSNPs display mild photothermal properties that can in situ denature tumor collagen and facilitate deep penetration into the tumor mass upon near-infrared irradiation. This approach significantly enhances sonodynamic therapy (SDT) by SnSNPs and boosts antitumor immunity. In mouse models of malignant TNBC and hepatocellular carcinoma (HCC), the combination of robust SDT and enhanced cytotoxic T lymphocyte infiltration achieves remarkable anti-tumor efficacy. This study presents an innovative approach to enhance SDT and antitumor immunity using the denaturation-and-penetration strategy, offering a potential combined sono-immunotherapy approach for the cancer nanomedicine field.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Nanopartículas , Neoplasias , Neoplasias de Mama Triplo Negativas , Terapia por Ultrassom , Humanos , Animais , Camundongos , Carcinoma Hepatocelular/terapia , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias Hepáticas/terapia , Neoplasias/terapia , Espécies Reativas de Oxigênio , Nanopartículas/uso terapêutico , Linhagem Celular TumoralRESUMO
Messenger RNA (mRNA)-based therapeutics are transforming the landscapes of medicine, yet targeted delivery of mRNA to specific cell types while minimizing off-target accumulation remains challenging for mRNA-mediated therapy. In this study, we report an innovative design of a cationic lipid- and hyaluronic acid-based, dual-targeted mRNA nanoformulation that can display the desirable stability and efficiently transfect the targeted proteins into lung tissues. More importantly, the optimized dual-targeted mRNA nanoparticles (NPs) can not only accumulate primarily in lung tumor cells and inflammatory macrophages after inhalation delivery but also efficiently express any desirable proteins (e.g., p53 tumor suppressor for therapy, as well as luciferase and green fluorescence protein for imaging as examples in this study) and achieve efficacious lung tissue transfection in vivo. Overall, our findings provide proof-of-principle evidence for the design and use of dual-targeted mRNA NPs in homing to specific cell types to up-regulate target proteins in lung tissues, which may hold great potential for the future development of mRNA-based inhaled medicines or vaccines in treating various lung-related diseases.
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Nanopartículas , Neoplasias , RNA Mensageiro/genética , Transfecção , Pulmão , MacrófagosRESUMO
Tumor-associated macrophages (TAMs) play a critical role in the immunosuppressive solid tumor microenvironment (TME), yet in situ engineering of TAMs for enhanced tumor immunotherapy remains a significant challenge in translational immuno-oncology. Here, we report an innovative nanodrug-delivering-drug (STNSP@ELE) strategy that leverages two-dimensional (2D) stanene-based nanosheets (STNSP) and ß-Elemene (ELE), a small-molecule anticancer drug, to overcome TAM-mediated immunosuppression and improve chemo-immunotherapy. Our results demonstrate that both STNSP and ELE are capable of polarizing the tumor-supportive M2-like TAMs into a tumor-suppressive M1-like phenotype, which acts with the ELE chemotherapeutic to boost antitumor responses. In vivo mouse studies demonstrate that STNSP@ELE treatment can reprogram the immunosuppressive TME by significantly increasing the intratumoral ratio of M1/M2-like TAMs, enhancing the population of CD4+ and CD8+ T lymphocytes and mature dendritic cells, and elevating the expression of immunostimulatory cytokines in B16F10 melanomas, thereby promoting a robust antitumor response. Our study not only demonstrates that the STNSP@ELE chemo-immunotherapeutic nanoplatform has immune-modulatory capabilities that can overcome TAM-mediated immunosuppression in solid tumors, but also highlights the promise of this nanodrug-delivering-drug strategy in developing other nano-immunotherapeutics and treating various types of immunosuppressive tumors.
Assuntos
Melanoma , Nanopartículas , Neoplasias , Camundongos , Animais , Macrófagos Associados a Tumor , Macrófagos/metabolismo , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Melanoma/patologia , Nanopartículas/uso terapêutico , Microambiente TumoralRESUMO
Due to the fact that mRNA technology allows the production of diverse vaccines and treatments in a shorter time frame and with reduced expense compared to conventional approaches, there has been a surge in the use of mRNA-based therapeutics in recent years. With the aim of encoding tumour antigens for cancer vaccines, cytokines for immunotherapy, tumour suppressors to inhibit tumour development, chimeric antigen receptors for engineered T cell therapy or genome-editing proteins for gene therapy, many of these therapeutics have shown promising efficacy in preclinical studies, and some have even entered clinical trials. Given the evidence supporting the effectiveness and safety of clinically approved mRNA vaccines, coupled with growing interest in mRNA-based therapeutics, mRNA technology is poised to become one of the major pillars in cancer drug development. In this Review, we present in vitro transcribed mRNA-based therapeutics for cancer treatment, including the characteristics of the various types of synthetic mRNA, the packaging systems for efficient mRNA delivery, preclinical and clinical studies, current challenges and future prospects in the field. We anticipate the translation of promising mRNA-based treatments into clinical applications, to ultimately benefit patients.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Imunoterapia , Neoplasias/genética , Neoplasias/terapia , CitocinasRESUMO
Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.
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With the integration of nanotechnology into the medical field at large, great strides have been made in the development of nanomedicines for tackling different diseases, including cancers. To date, various cancer nanomedicines have demonstrated success in preclinical studies, improving therapeutic outcomes, prolonging survival, and/or decreasing side effects. However, the translation from bench to bedside remains challenging. While a number of nanomedicines have entered clinical trials, only a few have been approved for clinical applications. In this review, we highlight the most recent progress in cancer nanomedicine, discuss current clinical advances and challenges for the translation of cancer nanomedicines, and provide our viewpoints on accelerating clinical translation. We expect this review to benefit the future development of cancer nanotherapeutics specifically from the clinical perspective.
Assuntos
Nanopartículas , Neoplasias , Humanos , Nanomedicina , Neoplasias/terapia , Nanotecnologia , PrevisõesRESUMO
Despite extensive efforts to realize effective photodynamic therapy (PDT), there is still a lack of therapeutic approaches concisely structured to mitigate the major obstacles of PDT in clinical applications. Herein, we report a molecular strategy exploiting ascorbate chemistry to enhance the efficacy of PDT in cancer cells overexpressing glucose transporter 1 (GLUT1). AA-EtNBS, a 5-O-substituted ascorbate-photosensitizer (PS) conjugate, undergoes a reversible structural conversion of the ascorbate moiety in the presence of reactive oxygen species (ROS) and glutathione (GSH), thereby promoting its uptake in GLUT1-overexpressed KM12C colon cancer cells and perturbing tumor redox homeostasis, respectively. Due to the unique pro-oxidant role of ascorbate in tumor environments, AA-EtNBS effectively sensitized KM12C cancer cells prior to PS-mediated generation of superoxide radicals under near-infrared (NIR) illumination. AA-EtNBS successfully exhibited GLUT1-targeted synergistic therapeutic efficacy during PDT both in vitro and in vivo. Therefore, this study outlines a promising strategy employing ascorbate both as a targeting unit for GLUT1-overexpressed cancer cells and redox homeostasis destruction agent, thereby enhancing therapeutic responses towards anticancer treatment when used in conjunction with conventional PDT.
Assuntos
Neoplasias , Fotoquimioterapia , Ácido Ascórbico/farmacologia , Linhagem Celular Tumoral , Transportador de Glucose Tipo 1 , Glutationa/metabolismo , Humanos , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Espécies Reativas de Oxigênio/metabolismoRESUMO
In vivo imaging in the second near-infrared window (NIR-II, 1000-1700 nm), which enables us to look deeply into living subjects, is producing marvelous opportunities for biomedical research and clinical applications. Very recently, there has been an upsurge of interdisciplinary studies focusing on developing versatile types of inorganic/organic fluorophores that can be used for noninvasive NIR-IIa/IIb imaging (NIR-IIa, 1300-1400 nm; NIR-IIb, 1500-1700 nm) with near-zero tissue autofluorescence and deeper tissue penetration. This review provides an overview of the reports published to date on the design, properties, molecular imaging, and theranostics of inorganic/organic NIR-IIa/IIb fluorophores. First, we summarize the design concepts of the up-to-date functional NIR-IIa/IIb biomaterials, in the order of single-walled carbon nanotubes (SWCNTs), quantum dots (QDs), rare-earth-doped nanoparticles (RENPs), and organic fluorophores (OFs). Then, these novel imaging modalities and versatile biomedical applications brought by these superior fluorescent properties are reviewed. Finally, challenges and perspectives for future clinical translation, aiming at boosting the clinical application progress of NIR-IIa and NIR-IIb imaging technology are highlighted.
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Nanotubos de Carbono , Medicina de Precisão , Corantes Fluorescentes , Humanos , Imagem Molecular , Imagem Óptica/métodosRESUMO
Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione-pi (GST-pi) is a key enzyme that militates against ROS-mediated apoptosis. We report herein a new construct, EA-BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST-pi inhibitor. Photoirradiation of EA-BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST-pi inhibition. Relative to BPS alone, an enhanced cell-killing effect is seen under hypoxic conditions both inâ vitro and inâ vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions.
Assuntos
Compostos de Boro/química , Ácido Etacrínico/química , Fármacos Fotossensibilizantes/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Apoptose/efeitos dos fármacos , Hipóxia Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Glutationa S-Transferase pi/antagonistas & inibidores , Glutationa S-Transferase pi/metabolismo , Halogenação , Humanos , Luz , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Transplante HeterólogoRESUMO
Reported here is a molecular construct (K1) designed to overcome hurdles associated with delivering active drugs to heterogeneous tumor environments. Construct K1 relies on two cancer environment triggers (GSH and H2O2) to induce prodrug activation. It releases an active drug form (SN-38) under conditions of both oxidative and reductive stress in vitro. Specific uptake of K1 in COX-2 positive aggressive colon cancer cells (SW620 and LoVo) was seen, along with enhanced anticancer activity compared with the control agent SN-38. These findings are attributed to environmentally triggered drug release, as well as simultaneous scavenging of species giving rise to intracellular redox stress. K1 serves to downregulate various cancer survival signaling pathways (AKT, p38, IL-6, VEGF, and TNF-α) and upregulate an anti-inflammatory response (IL-10). Compared with SN-38 and DMSO as controls, K1 also displayed an improved in vivo therapeutic efficacy in a xenograft tumor regrowth model with no noticeable systematic toxicity at the administrated dose. We believe that the strategy described here presents an attractive approach to addressing solid tumors characterized by intratumoral heterogeneity.
Assuntos
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Linhagem Celular Tumoral , Neoplasias do Colo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Irinotecano/química , Irinotecano/farmacologia , Camundongos , Camundongos Nus , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Concurrently, manipulation of mitochondrial activity and its monitoring have enormous significance in cancer therapy and diagnosis. In this context, a fluorescent probe MitoDP has been developed for validating H2S mediated protonophore (2,4-dinitrophenol, DNP) induced mitochondrial membrane potential change, ROS formation and ATP depletion in cancer cells. The extent of protonophore activation for mitochondrial dysfunction is monitored through fluorescence signalling at 450 nm. The current study provides a proof for the concept of endogenous H2S-mediated controlled and spatial release of bioactive agents, or toxins specifically in mitochondria of cancer cells.
Assuntos
2,4-Dinitrofenol/farmacologia , Corantes Fluorescentes/farmacologia , Sulfeto de Hidrogênio/farmacologia , Mitocôndrias/efeitos dos fármacos , 2,4-Dinitrofenol/química , Células 3T3 , Animais , Proliferação de Células/efeitos dos fármacos , Corantes Fluorescentes/química , Células HCT116 , Células HeLa , Humanos , Sulfeto de Hidrogênio/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Mitocôndrias/metabolismo , Estrutura Molecular , Imagem Óptica , Espécies Reativas de Oxigênio/metabolismo , Espectrometria de FluorescênciaRESUMO
Hypoxia is a state of low oxygen tension found in numerous solid tumours. It is typically associated with abnormal vasculature, which results in a reduced supply of oxygen and nutrients, as well as impaired delivery of drugs. The hypoxic nature of tumours often leads to the development of localized heterogeneous environments characterized by variable oxygen concentrations, relatively low pH, and increased levels of reactive oxygen species (ROS). The hypoxic heterogeneity promotes tumour invasiveness, metastasis, angiogenesis, and an increase in multidrug-resistant proteins. These factors decrease the therapeutic efficacy of anticancer drugs and can provide a barrier to advancing drug leads beyond the early stages of preclinical development. This review highlights various hypoxia-targeted and activated design strategies for the formulation of drugs or prodrugs and their mechanism of action for tumour diagnosis and treatment.
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Antineoplásicos/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Hipóxia Celular , Desenho de Fármacos , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias/patologia , Pró-Fármacos/uso terapêutico , Microambiente TumoralRESUMO
A theranostic, small-molecule-based prodrug, designed to be activated programmatically against hypoxic tumors, was successfully developed. The prodrug was stimulated to release the active chemotherapeutic drug in concurrent with a rhodol fluorophore in artificial hypoxia mimic conditions or an in vitro hypoxic environment. The extent of prodrug activation was monitored under the hypoxia condition by monitoring a fluorescence signal at 543 nm. The excellent therapeutic response and selective fluorescence labeling of biotin receptor overexpressed cancer cells ensured that the prodrug could be an effective strategy for the therapy of chronic hypoxic tumors.
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Herein, we report an amphiphilic fluorescent probe consisting of a dansyl fluorophore as a reporter and a hydrophobic cetyl chain bridged by a triazole unit. The cetyl-based probe can self-assemble to form nanoaggregates in aqueous solution, as confirmed by Tyndall effect, dynamic light scattering (DLS), and transmission electron microscopy (TEM) measurements. This probe exhibited an "on-off" fluorescence quenching response toward Hg2+ ions in aqueous solution over other tested metal ions. In contrast, the analogous methyl-based probe barely exhibits Hg2+ ion sensing behavior under the same conditions. Moreover, the resulting complex of the cetyl-based probe and Hg2+ (1-Hg2+, 1:1 stoichiometry) exhibited an efficient fluorescence "off-on" sensing for thiol-containing amino acids, including cysteine (Cys), homocysteine (Hcy), and glutathione (GSH). This nanoprobe exhibited minimal cytotoxicity with excellent cell permeability and was efficiently tested for the imaging of intracellular Hg2+ and cysteine in live cells.
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As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, 1 and 2, conjugated to SBE13 (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, and in vitro and in vivo imaging experiments all supported the selective targeting and visualization of PLK1 expressing cells by probes 1 and 2, and probe 2 was successfully demonstrated to image PLK1-upregulated tumors with remarkable signal-to-background ratios. These findings represent the first example of small-molecule based fluorescent imaging of tumors using PLK1 as a target, which could provide new avenues for tumor diagnosis and precision therapeutics.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Corantes Fluorescentes/química , Imagem Molecular/métodos , Neoplasias/diagnóstico por imagem , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Razão Sinal-Ruído , Humanos , Processamento de Imagem Assistida por Computador/métodos , Microscopia de Fluorescência , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Células Tumorais Cultivadas , Quinase 1 Polo-LikeRESUMO
A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors.
Assuntos
Anidrase Carbônica IX/química , Sistemas de Liberação de Medicamentos , Fotoquimioterapia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Anidrase Carbônica IX/metabolismo , Feminino , Células HeLa , Humanos , Hipóxia , Microscopia ConfocalRESUMO
We report on a mitochondria-specific combinational theranostic agent, 1. This system contains a chlorambucil prodrug and an aggregation induced emission dye. In addition, compound 1 bears both an intracellular thiol-triggered moiety and a mitochondria targeting unit (triphenylphosphonium). Glutathione (GSH) is the most abundant thiol and its concentrations are significantly higher in a great number of cancer cell lines, compared to normal cells. The GSH-induced prodrug 1 upon activation releases chlorambucil and exhibits mitochondria targeted aggregation induced emission (AIE) fluorescence, resulting in cell apoptosis via the caspase pathway due to mitochondrial dysfunction.
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Antineoplásicos/farmacologia , Clorambucila/farmacologia , Corantes/farmacologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Terapia de Alvo Molecular , Pró-Fármacos/farmacologia , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Clorambucila/química , Corantes/química , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Quimioterapia Combinada , Glutationa/metabolismo , Humanos , Mitocôndrias/metabolismo , Estrutura Molecular , Pró-Fármacos/química , Relação Estrutura-AtividadeRESUMO
The advances in genomics, proteomics, and bioinformatics have directed the development of new anticancer agents to reduce drug abuse and increase safe and specific drug treatment. Theranostics, combining therapy and diagnosis, is an appealing approach for chemotherapy in medicine which exhibits improved biodistribution, selective cancer targeting ability, reduced toxicity, masked drug efficacy, and minimum side effects. The role of diagnosis tools in theranostics is to collect the information of the diseased state before and after specific treatment. Magnetic particle-, mesoporous silica-, various carbon allotrope-, and polymer nanoparticle-based theranostic systems are well accepted and clinically significant. Currently, small conjugate-based systems have received much attention for cancer treatment and diagnosis. The structural architecture of these systems is relatively simple, compact, biocompatible, and unidirectional. In this tutorial review, we summarize the latest developments on small conjugate based theranostic agents for tumor treatment and diagnosis using fluorescence and magnetic resonance imaging (MRI).
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Antineoplásicos/uso terapêutico , Portadores de Fármacos , Nanoconjugados/uso terapêutico , Neoplasias , Pró-Fármacos/uso terapêutico , Nanomedicina Teranóstica/métodos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Humanos , Imageamento por Ressonância Magnética , Estrutura Molecular , Nanoconjugados/administração & dosagem , Nanoconjugados/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/químicaRESUMO
Rhodamine-labelled dieckol (1) synthesized through a click reaction was found to be localized in the endoplasmic reticulum (ER) of RAW 264.7 cells. Anti-inflammatory activity of compound was considerably greater than that of dieckol itself.