RESUMO
A main challenge in the development of anticancer drugs that eradicate cancer cells specifically with minimal toxicity to normal cells is to identify the cancer-specific properties. Cancer cells sustain a higher level of reactive oxygen species, owing to metabolic and signaling aberrations and unrestrained growth. Cancer cells are also furnished with a powerful reducing environment, owing to the overproduction of antioxidants such as glutathione (GSH). Therefore, the altered redox balance is probably the most prevailing property of cancer cells distinct from normal cells, which could serve as a plausible therapeutic target. In this work, we developed a GSH-depleting pro-oxidant, benzoyloxy dibenzyl carbonate, termed B2C, which is capable of rapidly declining GSH and elevating oxidative stress to a threshold level above which cancer cells cannot survive. B2C was designed to release quinone methide (QM) that rapidly depletes GSH through esterase-mediated hydrolysis. B2C was able to rapidly deplete GSH and induce an overwhelming level of oxidative stress in cancer cells, leading to mitochondrial disruption, activation of procaspase-3 and PARP-1, and cleavage of Bcl-2. In the study of tumor xenograft models, intravenously injected B2C caused apoptotic cell death in tumors and significantly suppressed tumor growth. These findings provide a new insight into the design of more effective anticancer drugs, which exploit altered redox balance in cancer cells.
RESUMO
In this study, a double network hydrogel of a natural polysaccharide gellan gum (GG) hydrogel and a synthetic hydrogel poloxamer-heparin (PoH) hydrogel (PoH/GG DNH) is introduced to complement disadvantages of each hydrogel and improve the microenvironment for cell delivery. The microstructure, surface morphology, gelation temperature, swelling and weight loss, sol fraction, mechanical property and thermal stability was examined. The potential of the composite hydrogel for cell vehicle was demonstrated by encapsulation of bone marrow stem cells isolated from rabbits (rBMSCs) within the PoH/GG DNH in vitro. The results showed that the DNH system supported cell survival and retained rBMSCs morphology and phenotype. Moreover, cell distribution, adherence, and ECM production were supported by PoH/GG DNH in vivo. Overall results provide a potential opportunity to apply the composite hydrogels in tissue engineering purpose.
Assuntos
Células da Medula Óssea/citologia , Portadores de Fármacos/química , Heparina/química , Hidrogéis/química , Poloxâmero/química , Polissacarídeos Bacterianos/química , Animais , Sobrevivência Celular , Células Cultivadas , Coelhos , Engenharia TecidualRESUMO
A blood clot (thrombus) is formed as a final product of the hemostatic process with two major components, a mesh of cross-linked fibrin and platelets activated by high concentration of hydrogen peroxide (H2O2). Thrombus formation impedes blood flow to brain and heart and is a principle cause of life-threatening diseases such as stroke and myocardial infarction. Aspirin has been widely used for the treatment and prevention of various cardiovascular diseases, but is unable to target a thrombus and scavenge a high level of H2O2. In this study, we report thrombus targeting aspirin polyconjugate particles (T-APP) as a near infrared imaging agent and on-demand therapeutic agent for thrombotic vascular diseases. T-APP were formulated from H2O2-activatable aspirin polyconjugate, fibrin-specific peptides and fluorescent IR780. In mouse models of tail bleeding and arterial thrombosis, T-APP targeted the thrombosed vessels rapidly with excellent specificity. T-APP also exerted highly strong antithrombotic activity in the thrombosed vessel by suppressing anti-inflammatory cytokines and inhibiting platelet activation. Based on the unique features such as specific thrombus targeting, H2O2 scavenging, and on-demand therapeutic actions, the rationally engineered T-APP have important ramifications on imaging and on-demand therapy of thrombotic disorders.
Assuntos
Aspirina/farmacologia , Fibrinolíticos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Trombose/tratamento farmacológico , Animais , Aspirina/administração & dosagem , Citocinas/metabolismo , Modelos Animais de Doenças , Fibrinolíticos/administração & dosagem , Hemorragia/induzido quimicamente , Peróxido de Hidrogênio/metabolismo , Camundongos , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/administração & dosagem , Polímeros/químicaRESUMO
Cancer cells have a large amount of ROS (reactive oxygen species) because of disturbed ROS homeostasis. Cancer cells therefore undertake redox adaptation to drive proliferation in tumor environments and even survive during anticancer treatment by upregulating endogenous antioxidants. As one of antioxidant defense systems, heme oxygenase-1 (HO-1) acts as an essential role in tumor development by offering antioxidant bilirubin to protect cancer cells under stress conditions. It can be therefore reasoned that the combination of ROS generation and HO-1 inhibition would exert synergistic anticancer effects through the amplification of oxidative stress and provide a new opportunity for targeted anticancer therapy. To establish targeted anticancer therapy based on amplified oxidative stress, we developed molecularly engineered polymer, termed CZP, which incorporates ROS generating CA (cinnamaldehyde) and HO-1 inhibiting ZnPP (zinc protoporphyrin) in its backbone and could form stable micelles in aqueous solutions. CZP micelles not only elevated oxidative stress but also suppressed the expression of antioxidant HO-1, leading to apoptotic cell death. CZP micelles could also significantly suppress the tumor growth without body weight loss, tumor recurrence, and noticeable toxicity in organs. This study demonstrates that a combination of ROS generation and HO-1inhibition synergistically magnifies oxidative stress to kill cancer cells and oxidative stress amplifying CZP micelles may provide a promising strategy in anticancer treatment.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Heme Oxigenase-1/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Células A549 , Animais , Antioxidantes/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Oxirredução/efeitos dos fármacos , Protoporfirinas/metabolismoRESUMO
Curcumin is a major active phenolic component of turmeric and has gained great attention in pharmaceutics due to its potent antioxidant, anti-inflammatory and anticancer activity. Here, we developed poly(oxalate-co-curcumin) (POC) as a hydrogen peroxide (H2O2)-activatable polymeric prodrug of curcumin by incorporating curcumin in the backbone of H2O2-responsive polyoxalate. POC particles effectively scavenged H2O2 and released curcumin in a H2O2-triggered manner. POC particles exhibited excellent antioxidant and anti-inflammatory activity in activated cells. POC particles intravenously administrated into acetaminophen-intoxicated mice remarkably suppressed the level of alanine transaminase and inhibited apoptotic cell death in liver. Interestingly, POC particles could also enhance the ultrasound contrast in the intoxicated liver due to CO2 bubble generation through H2O2-triggered oxidation of peroxalate esters. Given their H2O2-responsiveness and highly potent antioxidant activity, POC particles hold great translational potential as theranostic agents for H2O2-associated diseases.
Assuntos
Curcumina/uso terapêutico , Peróxido de Hidrogênio/química , Falência Hepática Aguda/diagnóstico por imagem , Falência Hepática Aguda/tratamento farmacológico , Polímeros/química , Pró-Fármacos/uso terapêutico , Ultrassonografia/métodos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/uso terapêutico , Curcumina/química , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pró-Fármacos/química , Células RAW 264.7RESUMO
Heme oxygenase-1 (HO-1) is a stress-response protein with potent cytoprotective and antioxidant activity, and its expression in cancer cells is enhanced in response to chemotherapy and radiotherapy. HO-1 is known to serve as a shield to protect cancer cells from anticancer therapy and attenuate apoptotic signals. It can be therefore reasoned that inhibition of HO-1 reduces the antioxidant level, making cancer cells more sensitive to photothermal heating. In this work, we developed dual imaging-guided oxidative-photothermal combination nanotherapeutics (OPCN) consisting of amphiphilic polymers conjugated with zinc protoporphyrin as a HO-1 inhibitor and fluorescent IR820 as a photothermal agent. A combination of OPCN and near-infrared (NIR) laser irradiation markedly increased the temperature and exerted significant toxicity through induction of apoptosis. In a mouse model of xenografts, tumors were identified by the strong fluorescence and photoacoustic signals. OPCN combined with NIR laser irradiation resulted in effective and complete thermal ablation of tumors without discernable side effects and tumor recurrence. We believe that OPCN hold tremendous translational potential for dual imaging-guided oxidative-photothermal combination anticancer therapy.
Assuntos
Antineoplásicos/farmacologia , Hipertermia Induzida , Imageamento Tridimensional , Fototerapia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Humanos , Lasers , Camundongos Nus , Nanopartículas/química , Oxirredução , Protoporfirinas/farmacologia , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
There has been increasing interest in the development of pathological stimulus-activatable nanoplatforms with theranostic functions. Here, we report ketalized maltodextrin (KMD) nanoparticles which are able to deliver therapeutic and imaging functions to the acidic conditions simultaneously, as may be found in the site of inflammation. KMD was synthesized as a platform of the theranostic nanoparticles by conjugating acid-cleavable hydrophobic moieties to maltodextrin through carbonate bonds. KMD nanoparticles could undergo acid-triggered hydrolytic degradation to generate carbon dioxide (CO2) bubbles, amplifying the ultrasound signal. The potential of KMD nanoparticles as a drug carrier was evaluated using silymarin as a model drug. KMD nanoparticles displayed significantly enhanced ultrasound contrast at acidic pH and released drug payloads in acid-triggered manners. The translational potential of silymarin-loaded KMD (s-KMD) nanoparticles as ultrasound contrast agents and therapeutic agents was thoroughly evaluated using cell culture models and mouse models of acetaminophen (APAP)-induced acute liver failure. s-KMD nanoparticles exhibited significantly enhanced ultrasound contrast in the APAP-intoxicated liver and also remarkably suppressed the hepatic damages by inhibiting the expression of pro-inflammatory cytokines. These results suggest that KMD nanoparticles hold tremendous potential as theranostic agents for various inflammatory diseases.
Assuntos
Antioxidantes/administração & dosagem , Falência Hepática Aguda/diagnóstico por imagem , Falência Hepática Aguda/tratamento farmacológico , Nanopartículas/química , Polissacarídeos/química , Silimarina/administração & dosagem , Células 3T3 , Animais , Citocinas/metabolismo , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Falência Hepática Aguda/metabolismo , Camundongos , Camundongos Nus , Células RAW 264.7 , Espécies Reativas de Oxigênio/metabolismo , Distribuição Tecidual , Ultrassonografia/métodosRESUMO
Muscles of peripheral artery disease (PAD) patients are under oxidative stress associated with a significantly elevated level of reactive oxygen species (ROS) including hydrogen peroxide (H2O2). Curcumin is a major active constituent of turmeric and is well known for its highly potent antioxidant, anti-inflammatory and angiogenic effects. We previously reported antioxidant vanillyl alcohol-incorporated copolyoxalate (PVAX) which is designed to rapidly scavenge H2O2 and release bioactive vanillyl alcohol and CO2 in a H2O2-triggered manner. In this work, we developed curcumin-loaded PVAX (CUR-PVAX) nanoparticles as contrast-enhanced ultrasound imaging agents as well as on-demand therapeutic agents for ischemic injuries based on the hypothesis that PVAX nanoparticles generate echogenic CO2 bubbles through H2O2-triggered oxidation of peroxalate esters and the merger of curcumin and PVAX exerts H2O2-activatable synergistic therapeutic actions. CUR-PVAX nanoparticles also displayed the drastic ultrasound signal in ischemic areas by generating CO2 bubbles. CUR-PVAX nanoparticles exhibited significantly higher antioxidant and anti-inflammatory activities than empty PVAX nanoparticles and equivalent curcumin in vascular endothelial cells. A mouse model of ischemic injury was used to evaluate the potential of CUR-PVAX nanoparticles as ultrasound imaging agents and on-demand therapeutic agents. CUR-PVAX nanoparticles significantly suppressed the expression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). Moreover, CUR-PVAX nanoparticles significantly enhanced the level of vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1, also known as CD31), leading to blood perfusion into ischemic tissues. We, therefore, believe that CUR-PVAX nanoparticles hold great translational potential as novel theranostic agents for ischemic diseases such as PAD.
Assuntos
Peróxido de Hidrogênio/química , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/metabolismo , Polímeros/química , Animais , Anti-Inflamatórios/uso terapêutico , Antioxidantes/química , Antioxidantes/metabolismo , Apoptose/efeitos dos fármacos , Curcumina/uso terapêutico , Peróxido de Hidrogênio/metabolismo , Camundongos , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Doença Arterial Periférica/tratamento farmacológico , Espécies Reativas de Oxigênio/metabolismoRESUMO
The recent advances in nanotechnology have led to the development of smart nanomaterials that combine diagnostic and therapeutic functions and provide synergistic anticancer effects through the combination of different treatment modalities. Here, we report a promising theranostic nanoconstruct that can translate into multiple functionalities: fluorescence/photoacoustic imaging, acid-triggered generation of ROS (reactive oxygen species), heat and singlet oxygen production under near infrared (NIR) laser irradiation, and coupling oxidative anticancer therapy to dual imaging-guided photothermal/photodynamic therapy. An NIR dye-conjugated hydroxyl radical generating biodegradable polymer (HRGP-IR) is employed as a theranostic nanoplatform. HRGP-IR could self-assemble to form micelles and elevate oxidative stress by generating hydrogen peroxide and hydroxyl radical. Under the NIR (808 nm) laser irradiation, HRGP-IR micelles also generate heat and singlet oxygen to induce cancer cell death. In mouse xenograft models, HRGP-IR micelles accumulated in tumors preferentially and the tumor could be detected by dual imaging. Effective tumor ablation was achieved by HRGP-IR micelles (5 mg/kg) combined with NIR laser irradiation, demonstrating the synergistic anticancer effects of oxidative stress with photothermal heating. Given their dual imaging capability, anticancer phototherapy and highly potent synergistic anticancer activity with NIR laser irradiation, HRGP-IR micelles hold great potential as a nanotheranostic agent for cancer treatment.
Assuntos
Diagnóstico por Imagem , Micelas , Estresse Oxidativo , Fototerapia , Polímeros/química , Espectroscopia de Luz Próxima ao Infravermelho , Antineoplásicos/farmacologia , Materiais Biocompatíveis/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Radical Hidroxila/química , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cancer cells, compared with normal cells, are under oxidative stress associated with the increased generation of reactive oxygen species (ROS) including H2O2 and are also susceptible to further ROS insults. Cancer cells adapt to oxidative stress by upregulating antioxidant systems such as glutathione to counteract the damaging effects of ROS. Therefore, the elevation of oxidative stress preferentially in cancer cells by depleting glutathione or generating ROS is a logical therapeutic strategy for the development of anticancer drugs. Here we report a dual stimuli-responsive hybrid anticancer drug QCA, which can be activated by H2O2 and acidic pH to release glutathione-scavenging quinone methide and ROS-generating cinnamaldehyde, respectively, in cancer cells. Quinone methide and cinnamaldehyde act in a synergistic manner to amplify oxidative stress, leading to preferential killing of cancer cells in vitro and in vivo. We therefore anticipate that QCA has promising potential as an anticancer therapeutic agent.
Assuntos
Antineoplásicos/farmacologia , Compostos de Boro/farmacologia , Ésteres/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Compostos de Boro/síntese química , Compostos de Boro/química , Linhagem Celular , Cromatografia Líquida/métodos , Fragmentação do DNA , Ésteres/síntese química , Ésteres/química , Peróxido de Hidrogênio , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/tratamento farmacológico , Distribuição Aleatória , Espécies Reativas de Oxigênio , Espectrometria de Massas em TandemRESUMO
Efficient delivery of small interfering RNA (siRNA) is one of major challenges in the successful applications of siRNA in clinic. In the present study, we report a new acid-degradable poly(ketal amidoamine) (PKAA) as a siRNA carrier, which has high delivery efficiency and low cytotoxicity. PKAA was designed to have acid-cleavable ketal linkages in the backbone of cationic biodegradable poly(amidoamine). PKAA efficiently self-assembled with siRNA to form nanocomplexes with a diameter of ~200 nm and slightly positive charges, which are stable under physiological conditions, but rapidly release siRNA at acidic pH. PKAA exhibited sufficient buffering capability and endosomolytic activity due mainly to the presence of secondary amine groups in its backbone and rapid degradation in acidic endosomes, leading to the enhanced release of siRNA to cytoplasm. Cell culture studies demonstrated that PKAA is capable of delivering anti-TNF (tumor necrosis factor)-α siRNA to lipopolysaccharide (LPS)-stimulated macrophages and significantly inhibits the expression of TNF-α. A mouse model of acetaminophen (APAP)-induced acute liver failure was used to evaluate in vivo siRNA delivery efficacy of PKAA. PKAA/anti-TNF-α siRNA nanocomplexes significantly reduced the ALT (alanine transaminase) and the hepatic cellular damages in APAP-intoxicated mice. We anticipate that acid-degradable PKAA has great potential as siRNA carriers based on its excellent biocompatibility, pH sensitivity, potential endosomolytic activity, and high delivery efficiency.