RESUMO
Despite the great potential of starving therapy caused by nanoreactor based on glucose oxidase (GOX) in tumor therapy, efficiency and uncontrolled reaction rates in vivo lead to inevitable toxicity to normal tissues, which seriously hindering their clinical conversion. Herein, a cascade nanoreactor (GOX/Mn/MPDA) was constructed by coating mesoporous polydopamine nanoparticles (MPDA) with MnO2 shell and then depositing GOX into honeycomb-shaped manganese oxide nanostructures to achieve a combination of ferroptosis, photothermal therapy and starving therapy. Upon uptake of nanodrugs to cancer cells, the MnO2 shell would deplete glutathione (GSH) and produce Mn2+, while a large amount of H2O2 generated from the catalytic oxidation of glucose by GOX would accelerate the Fenton-like reaction mediated by Mn2+, producing high toxic â¢OH. More importantly, the cascade reaction between GOX and MnO2 would be further strengthened by localized hyperthermia caused by irradiated by near-infrared laser (NIR), inducing significant anti-tumor effects in vitro and in vivo. Regarding the effectiveness of tumor treatment in vivo, the tumor inhibition rate achieved an impressive 64.33%. This study provided a new strategy for anti-tumor therapeutic by designing a photothermal-enhanced cascade catalytic nanoreactor.
Assuntos
Ferroptose , Glucose Oxidase , Indóis , Compostos de Manganês , Nanopartículas , Óxidos , Terapia Fototérmica , Polímeros , Terapia Fototérmica/métodos , Compostos de Manganês/química , Animais , Humanos , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Indóis/química , Polímeros/química , Glucose Oxidase/metabolismo , Glucose Oxidase/administração & dosagem , Nanopartículas/química , Camundongos , Óxidos/química , Linhagem Celular Tumoral , Peróxido de Hidrogênio/metabolismo , Camundongos Endogâmicos BALB C , Terapia Combinada/métodos , Feminino , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Camundongos NusRESUMO
Addressing the pervasive issue of bacteria and biofilm infections is crucial in the development of advanced antifouling wound dressings. In this study, a novel wound healing treatment using sulfobetaine (SBMA) decorated electrospun fibrous membrane based on polycaprolactone (PCL)/nitric oxide (NO) donors was developed. The fabrication involved a dual strategy, first integrating NO donors into mesoporous polydopamine (MPDA) and complexed with PCL/PEI to electrospin nanofibers. The fibrous membrane exhibited a potent antibacterial response upon irradiation at 808 nm, owing to a combination of NO and photothermal effect that effectively targets bacteria and disrupts biofilms. Surface functionalization of the membrane with PEI allowed for the attachment of SBMA via Michael addition, fabricating a zwitterionic surface, which significantly hinders protein adsorption and reduces biofilm formation on the wound dressing. In vitro and in vivo assessments confirmed the rapid bactericidal capabilities and its efficacy in biofilm eradication. Combining photothermal activity, targeted NO release and antifouling surface, this multifaceted wound dressing addresses key challenges in bacterial infection management and biofilm eradication, promoting efficient wound healing.
Assuntos
Antibacterianos , Bandagens , Betaína , Biofilmes , Indóis , Nanofibras , Poliésteres , Cicatrização , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Animais , Cicatrização/efeitos dos fármacos , Poliésteres/química , Indóis/química , Indóis/farmacologia , Betaína/química , Betaína/farmacologia , Betaína/análogos & derivados , Nanofibras/química , Polímeros/química , Óxido Nítrico/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Incrustação Biológica/prevenção & controle , Doadores de Óxido Nítrico/farmacologia , Doadores de Óxido Nítrico/química , Camundongos , Propriedades de Superfície , Escherichia coli/efeitos dos fármacos , Polietilenoimina/químicaRESUMO
Nitric oxide (NO) gas molecules have demonstrated remarkable anti-tumor effects and minimal susceptibility to drug resistance, establishing as a promising modality for effective tumor treatment. However, how to realize its stable and efficient delivery in vivo is still a challenge. In this study, we have developed a heat-responsive biomimetic nano erythrocyte (M/B@R) by loading a NO donor (BNN6) onto mesoporous Prussian blue (M-PB) and subsequently enveloping them with red blood cell membranes. The preserved integrity of the red blood cell membrane (RBCm) structure could ensure its excellent biosafety, prolong its circulation time within the bloodstream and then enhance the accumulation of BNN6 at tumor sites. When M/B@R is stimulated by near-infrared light (NIR-II, 808 nm) irradiation, the nanoparticle could generate significant heat for photothermal therapy (PTT) by the characteristic NIR absorption of M-PB and then NO could also be efficiently released. The generated NO further facilitates the formation of ONOO-, a highly toxic species to tumors, while also alleviating tumor hypoxia. Remarkably, M/B@R, with NIR as the excitation source, induces combined lethality through hyperthermia, DNA damage, and tumor hypoxia relief. This novel combination strategy provides a new avenue for PTT/NO-induced cancer therapy.
Assuntos
Ferrocianetos , Hipertermia Induzida , Neoplasias Nasofaríngeas , Humanos , Fototerapia , Óxido Nítrico , Carcinoma Nasofaríngeo , Membrana CelularRESUMO
Artesunate (ART) has potent anticancer activity but it suffers from poor stability and low bioavailability in vivo due to the special endoperoxide moiety in the molecules. In this work, we fabricated programmable enzyme/reactive oxygen species (ROS) responsive ART complex carriers with size and charge adaptive regulation in order to improve stability and overcome biochemical hurdles of solid tumor. The complex carries (ART/AA-PAMAM@HA) were created by electrostatic interaction between dendrimer-ART/arachidonic acid (AA) (ART/AA-PAMAM) and hyaluronic acid (HA), which can proactively penetrate deeply into tumors and selective drug release. Specifically, ART induced Fenton reaction and produced a mass of ROS and lipid peroxides (LPO), leading to the depressing of GSH level and glutathione peroxidase 4 (GPX4) activity. Meanwhile, exogenous AA further promoted the accumulation of LPO by cascade regulating ferroptosis pathway. In the anti-tumor efficacy in vivo, the tumor inhibition ratio was achieved to 46.92%. This work shows a new anti-tumor strategy triggering ferroptosis via regulating redox homeostasis.
Assuntos
Ferroptose , Neoplasias , Humanos , Artesunato/farmacologia , Espécies Reativas de Oxigênio , Disponibilidade Biológica , Ácido Hialurônico , Peróxidos LipídicosRESUMO
Indocyanine green (ICG) has been employed in medical diagnostics due to its superior photophysical characteristics. However, these advantages are offset by its quick body clearance and inferior photo-stability. In this work, programmable prodrug carriers for chemotherapy/PDT/PTT against nasopharyngeal carcinoma (NPC) were created in order to increase photo-stability and get around biochemical hurdles. The programmable prodrug carriers (PEG-PLA@DIT-PAMAM) that proactively penetrated deeply into NPC tumors and produced the deep phototherapy and selective drug release under laser irradiation was created by dendrimer-DOX/ICG/TPP (DIT-PAMAM) and PEGylated poly (α-lipoic acid) (PLA) copolymer. Long circulation times and minimal toxicity to mammalian cells are two benefits of PEG-coated carriers. The overexpressed GSH on the tumor cell or vascular endothelial cell of the NPC disintegrated the PEG-g-PLA chains and released the DIT-PAMAM nanoparticles after the carriers had reached the NPC tumor periphery. Small, positively charged DIT-PAMAM nanoparticles may penetrate tumors effectively and remain inside tumor for an extended period of time. In addition, the induced ROS cleaved the thioketal linkers for both DOX and nanoparticles and product hyperthermia (PTT) to kill cancer cells under laser irradiation, facilitating faster diffusion of nanoparticles and more effective tumor penetration with a programmable publication of DOX. The programmable prodrug carries showed high photo-stability high photo-stability, which enabled very effective PDT, PTT, and tumor-specific DOX release. With the goal of combining the effects of chemotherapy, PDT, and PTT against NPC, this research showed the great efficacy of programmable prodrug carriers.
Assuntos
Hipertermia Induzida , Neoplasias Nasofaríngeas , Pró-Fármacos , Animais , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Poliésteres , MamíferosRESUMO
Nasopharyngeal carcinoma (NPC) is one of the major causes of death in Southern China. Due to the insidious location of NPC, the therapeutic effect of locoregionally advanced NPC is still unsatisfactory. In this work, to improve the treatment efficiency, combining DOC and JS-K to inhibit NPC cells (HNE-1) in vitro was investigated, as well as its possible mechanisms. Moreover, the in vivo effects of DOC and JS-K combination treatment were also evaluated in a xenograft model with HNE-1 cells. In vitro experiments including cell proliferation, migration ability, apoptosis, and expression levels of apoptosis-associated proteins revealed that the combination of DOC and JS-K was able to enhance antitumor effects. In vivo results further confirmed a significant treatment effect without obvious toxicity on mice. The present work provides a promising idea for the treatment of locally advanced NPC.
Assuntos
Neoplasias Nasofaríngeas , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Humanos , Camundongos , Carcinoma Nasofaríngeo/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The development of novel wound dressings, such as aerogels, with rapid hemostasis and bactericidal capacities for pre-hospital care is necessary. To prevent the occurrence of bacterial resistance, antibacterial photodynamic therapy (aPDT) with broad-spectrum antibacterial ability and negligible bacterial resistance has been intensively studied. However, photosensitizers often suffer from poor water solubility, short singlet oxygen (1O2) half-life and restricted 1O2 diffusion distance. Herein, sodium alginate was covalently modified by photosensitizers and phenylboronic acid, and cross-linked by Ca(II) ions to generate SA@TPAPP@PBA aerogel after lyophilization as an antibacterial photodynamic wound dressing. Afterwards, its photodynamic and bacterial capture activities were intensively evaluated. Furthermore, its hemostasis and bactericidal efficiency against Staphylococcus aureus were assessed via in vitro and in vivo assays. First, chemical immobilization of photosensitizers led to an enhancement of its solubility. Moreover, it showed an excellent hemostasis capacity. Due to the formation of reversible covalent bonds between phenylboronic acid and diol groups on bacterial cell surface, the aerogel could capture S. aureus tightly and dramatically enhance aPDT. To sum up, the prepared aerogel illustrated excellent hemostasis capacity and antibacterial ability against S. aureus. Therefore, they have great potential to be utilized as wound dressing in clinical trials.
Assuntos
Alginatos , Fotoquimioterapia , Alginatos/química , Antibacterianos/química , Antibacterianos/farmacologia , Bandagens , Géis , Staphylococcus aureus , Ferimentos e Lesões/microbiologia , Ferimentos e Lesões/terapiaRESUMO
The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with ß-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.
Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Nanopartículas/administração & dosagem , Naftoquinonas/administração & dosagem , Neoplasias/tratamento farmacológico , Estresse Oxidativo , Pró-Fármacos/administração & dosagem , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Quitosana/administração & dosagem , Quitosana/química , Quitosana/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Humanos , Camundongos Endogâmicos BALB C , Mitocôndrias/fisiologia , Nanopartículas/química , Naftoquinonas/química , Naftoquinonas/farmacocinética , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organofosforados/administração & dosagem , Compostos Organofosforados/química , Compostos Organofosforados/farmacocinética , Oxirredução , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Espécies Reativas de Oxigênio/metabolismo , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Carga Tumoral/efeitos dos fármacosRESUMO
Hepatocellular carcinoma (HCC) is one of the major cancers with high mortality rate. Traditional drugs used in clinic are usually limited by the drug resistance and side effect and novel agents are still needed. Macrolide brefeldin A (BFA) is a well-known lead compound in cancer chemotherapy, however, with poor solubility and instability. In this study, to overcome these disadvantages, BFA was encapsulated in mixed nanomicelles based on TPGS and F127 copolymers (M-BFA). M-BFA was conferred high solubility, colloidal stability, and capability of sustained release of intact BFA. In vitro, M-BFA markedly inhibited the proliferation, induced G0/G1 phase arrest, and caspase-dependent apoptosis in human liver carcinoma HepG2 cells. Moreover, M-BFA also induced autophagic cell death via Akt/mTOR and ERK pathways. In HepG2 tumor-bearing xenograft mice, indocyanine green (ICG) as a fluorescent probe loaded in M-BFA distributed to the tumor tissue rapidly, prolonged the blood circulation, and improved the tumor accumulation capacity. More importantly, M-BFA (10 mg/kg) dramatically delayed the tumor progression and induced extensive necrosis of the tumor tissues. Taken together, the present work suggests that M-BFA has promising potential in HCC therapy.
Assuntos
Antineoplásicos/administração & dosagem , Brefeldina A/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Micelas , Nanoestruturas/administração & dosagem , Animais , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Brefeldina A/sangue , Brefeldina A/química , Brefeldina A/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Polietilenos/administração & dosagem , Polietilenos/química , Polipropilenos/administração & dosagem , Polipropilenos/química , Ratos Sprague-Dawley , Distribuição Tecidual , Vitamina E/administração & dosagem , Vitamina E/químicaRESUMO
As a compound from marine fungi, (+)-terrein showed significant anticancer activity. In this study, (+)-terrein was extracted from the marine-derived fungus and showed significant cytotoxicity against cancer cells, especially in A549 cells. To enhance its anticancer effects, redox-responsive nanocarriers based on folic acid-chitosan decorating the mesoporous silica nanoparticles were designed to control (+)-terrein target delivery into cancer cells. (+)-Terrein was loaded in the holes, and folic acid-chitosan worked as a gatekeeper by disulfide linkage controlling (+)-terrein release in the tumor microenvironment. The (+)-terrein drug delivery systems exhibited cytotoxicity toward A549 cells through induction of apoptosis. The apoptosis effect was confirmed by the increase in the expression of cleaved caspase-3, caspase-9, and PARP. Taken together, this work evaluates for the first time the (+)-terrein delivery system and provides a promising nanomedicine platform for (+)-terrein.
RESUMO
Efficient delivery of chemotherapeutic agents into tumor cells and reversal of chemoresistance are crucially important to enhance cancer therapy. We fabricated pH/redox dual responsive nanocarriers based on cell penetrating peptides (TAT) functionalized TPGS (cTAT-TPGS) and polypeptide (PEG-b-poly(aspartic-lipoic acid), PPAL) to reduce the permanent drug release and overcome multidrug resistance. TAT was used to functionalize TPGS and shielded by pH-responsive fatty acids, and polypeptides with lipoic acid side chains (PPAL) were synthesized. Reversibly crosslinked hybrid micelles (RCMs) were fabricated based on cTAT-TPGS and PPAL. RCMs nanocarriers exhibited acid-responsive charge reversal and redox-responsive drug release. The in vitro results showed that the RCMs could be efficiently internalized by the MCF-7/ADR cells in an acidic microenvironment and inhibited the DOX efflux, causing a higher cytotoxicity than non-crosslinked nanocarriers. Furthermore, the dual-responsive structure effectively prolonged the circulation time of RCM nanocarriers and achieved a high level of accumulation in cancer cells in vivo, leading to much more effective inhibition of tumor growth. The DOX-loaded RCMs also showed excellent biosafety, especially for the myocardium tissue. This novel strategy provided an effective platform for drug target delivery and reversal of MDR.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptose/efeitos dos fármacos , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Feminino , Fluorescência , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Micelas , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Vitamina E/farmacocinética , Vitamina E/uso terapêuticoRESUMO
PDT is a well-established therapeutic modality for many types of cancer. Photoluminescent cyclometalated iridium(III) complexes are one of the most commonly used classes of organometallic compounds with potential beneficial applications in bioimaging and as promising anticancer agents. In the present study, three new cyclometalated iridium(III) complexes (Ir1-Ir3) containing guanidinium ligands were found to exert excellent cytotoxic effects on different types of cancer cells upon light irradiation at 425â¯nm. Notably, Ir1 conferred almost no dark toxicity (IC50â¯>â¯100⯵M) to HepG2 cells, but the value decreased by 387-fold to 0.36⯵M following 10â¯min of light irradiation (425â¯nm). Further mechanistic investigation revealed that complex Ir1 could induce apoptosis via the activation of reactive oxygen species (ROS)-mediated mitochondrial signaling pathways in the presence or absence of light irradiation. In vivo studies demonstrated that Ir1 significantly inhibited tumor growth in HepG2 xenograft-bearing mice under light irradiation at 425â¯nm. Taken together, these findings indicate that designing PDT-based Ir(III) complexes may hold a great deal of promise for anticancer drug development.
Assuntos
Antineoplásicos/farmacologia , Guanidina/farmacologia , Irídio/farmacologia , Mitocôndrias/efeitos dos fármacos , Imagem Óptica , Compostos Organometálicos/farmacologia , Fármacos Fotossensibilizantes/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Guanidina/química , Células Hep G2 , Humanos , Irídio/química , Neoplasias Hepáticas Experimentais/diagnóstico por imagem , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Mitocôndrias/patologia , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/química , Relação Estrutura-AtividadeRESUMO
Hierarchical responsive nanocarriers have received much attention for targeted delivery of chemotherapeutics. In this study, we designed pH and redox dual-stage responsive nanocarriers in the different delivery stages for co-delivery phosphorylated curcumin (p-Cur) with doxorubicin (Dox). The MSNs nanocarriers were functionalized via specific cleavable PEGylation and hydrogel coating crosslinked by disulfide bonds: MSNs as core load Dox; p-Cur encapsulated in hydrogel coating. In blood circulation, PEGylation endow the nanocarriers with long time during blood circulation; while in tumor tissue, PEG shells could be cleaved due to the pH-sensitive bond and expose the cationic hydrogel coating to improve cell uptake; while inside tumor cells, hydrogel coating could be cleaved due to the GSH and release the drugs. The results showed that the dual-responsive shells endowed the nanocarriers with tumor extracellular pH-triggered cell uptake and specific cancer cell target release. The synergistic effects of the p-Cur and Dox enhanced cellular apoptosis in Hela cells.
Assuntos
Antineoplásicos/química , Curcumina/química , Doxorrubicina/química , Portadores de Fármacos , Nanopartículas/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Curcumina/farmacologia , Doxorrubicina/farmacologia , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Cinética , Nanopartículas/ultraestrutura , OxirreduçãoRESUMO
In this study, the electroactive hybrid gels with controllable sol-gel process were fabricated based on the water soluble polyaniline complex and water soluble silica precursor. ß-cyclodextrin grafted on chitosan (CSCD) acted as a template, a new route for the synthesis of water soluble polyaniline complex (PA@CSCD) was designed by in-situ polymerization. Then, the hybrid silica gels without severe shrinkage were prepared by mixing PA@CSCD complex with water soluble precursor (tetrakis(2-hydroxyethyl)orthosilicates, THEOS). By dynamic rheological measurements, it was found that PA@CSCD complex could trigger and accelerate the sol-gel transition of the silica precursor. The gelation time could be largely shortened with the increase of PA@CSCD complex amount. By SEM observation, the PA@CSCD complex could be well compatible with the silica matrix. Moreover, the hybrid gels showed the good redox electroactivity, which could be successfully applied in a HRP-based biosensor.
RESUMO
Accidental fires and open combustion are regarded as major potential contributors to the environmental release of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs). The characterization of PBDD/Fs emitted from thermal treatment of simulated polystyrene (PS) foam is reported in this study. PS, hexabromocyclododecane (HBCDD) and metals (or metallic compounds) composed the test samples, which imitated real extruded (XPS) and expanded (EPS) polystyrene thermal insulation foams. Test samples were subjected to thermal treatments under different experimental conditions. This study shows that the temperature, metal (metallic compound) content, and type of atmosphere are the key factors in the formation of congeners and PBDD/Fs during thermal processes. The total yield of polybrominated dibenzofurans (PBDFs) was greater than that of the polybrominated dibenzo-p-dioxins (PBDDs) during the test, and 1,2,3,7,8-PeBDF and 2,3,7,8-TBDF were the predominant congeners emitted during the thermal treatment experiments.
Assuntos
Benzofuranos/química , Dioxinas/química , Metais/química , Poliestirenos/químicaRESUMO
The nucleus is one of the most important cellular organelles, where gene encode and transcribe at that location. However, nucleus-targeting gene delivery are rare been reported. It is important to develop a high-efficiency nucleus-targeting gene vector that can deliver targeted gene into nucleus directly for destroy of cancer cells. Here, special nucleus-targeting and size changeable deliver system based on TAT-SS-PAMAM-D3 with TAT functional on the surface and disulfide linked between D2 and D3 is designed to perform highly efficient nucleus-targeting gene delivery for effective cancer cell killing in vitro. CLSM observations reveal that more TAT-SS-PAMAM-D3 are enter into the nucleus when compare to SS-PAMAM-D3. The TAT modified vector can also act as gene deliver to reach high gene transfection efficiencies, high apoptosis and low viability in HeLa cells. This TAT functionalized and disulfide linking in the carrier may become a prospective vector for cancer gene treatment and also offered a different strategy for designing a better gene delivery system.
Assuntos
Apoptose/fisiologia , Núcleo Celular/metabolismo , Sobrevivência Celular/fisiologia , Dendrímeros/química , Vetores Genéticos/química , Apoptose/genética , Sobrevivência Celular/genética , Técnicas de Transferência de Genes , Células HeLa , Humanos , Fragmentos de Peptídeos/química , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
We developed a high-efficiency nucleus-targeted co-delivery vector that delivers genes and drugs directly into the nucleus of cancer cells. The system is based on grafted poly-(N-3-carbobenzyloxy-lysine) (CPCL) with transactivator of transcription (TAT)- chitosan on the surface. It is designed to perform highly efficient nucleus- targeted gene and drug co-delivery. Confocal laser scanning microscopy (CLSM) revealed that more TAT-CPCL entered the nucleus than does CPCL alone. The TAT-modified vector serves as a gene and drug co-delivery mechanism to achieve high gene transfection efficiency, high apoptosis and low viability in HeLa cells. TAT-CPCL may become a vector for cancer gene treatment and a template for designing better co-deliver systems.
Assuntos
Núcleo Celular/efeitos dos fármacos , Quitosana/química , Portadores de Fármacos , Produtos do Gene tat/metabolismo , Técnicas de Transferência de Genes , Vetores Genéticos/química , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Núcleo Celular/metabolismo , Doxorrubicina/farmacologia , Produtos do Gene tat/genética , Vetores Genéticos/metabolismo , Células HeLa , Humanos , Micelas , Tamanho da Partícula , Polilisina/química , Propriedades de SuperfícieRESUMO
In this work, we developed a drug-conjugated nanocarrier with "zero premature release" property for actively targeted drug delivery. The pH and redox dual-responsive nanocarrier was fabricated based on hyaluronic acid (HA) modified the mesoporous silica nanoparticles (MSNs). Doxorubicin (DOX) was conjugated to MSNs via hydrazone bonds, which can be cleaved in tumor tissue (acidic conditions). To improve specific cellular uptake and stability of nanocarriers, HA was equipped with an outer shell on the nanoparticle surface via a disulfide crosslinker. Stimulus-induced release of the DOX was studied in the different pH and GSH, which showed the embedded DOX can be controlled release from MSN channels. The dual-triggered drug release system provides an efficient targeted drug delivery system into the cytosol of cancer cells. The results of flow cytometry and confocal laser scanning microscopy (CLSM) showed that the HA-functionalized DOX-conjugated nanoparticles presented much better cellular uptake and higher cytotoxicity to tumor cells. This drug delivery system has great potential for tumor-trigged drug release for cancer therapy.
Assuntos
Nanoestruturas , Doxorrubicina , Sistemas de Liberação de Medicamentos , Humanos , Ácido Hialurônico , Concentração de Íons de Hidrogênio , Oxirredução , Dióxido de SilícioRESUMO
The codelivery of drug and gene is a promising method for cancer treatment. In our previous works, we prepared a cationic micelles based on chitosan and poly-(N-3-carbobenzyloxylysine) (CS-g-PZLL), but transfection ratio of CS-g-PZLL to Hela cell was low. Herein, to improve the transfection efficiency of CS-g-PZLL, curcumin was loaded in the CS-g-PZLL micelle. After irradiation, the obtained curcumin loaded micelle showed a better transfection, and the p53 protein expression in Hela cells was higher. The apoptosis assay showed that the complex could induce a more significant apoptosis to Hela cells than that of curcumin or p53 used alone, and the curcumin loaded micelle inducing apoptosis was best after irradiation. Therefore, CS-g-PZLL is a safe and effective carrier for the codelivery of drug/gene, and curcumin could be used as a photosensitizer to induce a photoenhanced gene transfection, which should be encouraged in improving transfection and tumor therapy.
Assuntos
Curcumina/química , Quitosana , Células HeLa , Humanos , Micelas , Polilisina , TransfecçãoRESUMO
Dickkopf-1 (DKK1) is a powerful antagonist of canonical WNT signaling pathway, and is regarded as a biomarker for osteoporosis. Its expression is highly correlated with bone mass and osteoblasts maturation. In this study, mouse primary bone marrow cells and osteoblast cell lines were used. Luciferase reporter assay and western blotting methods were employed to validate if miRNA-433-3p epigenetically regulated DKK1 translation. Rat bone marrow derived osteoblasts were infected with lentivirus vector in which miR-433-3p was constructed. The authors constructed lentivirus mediated miRNA-433-3p stable expression and examined the alkaline phosphatase (ALP) activity and mineral deposition level in vitro. In situ hybridization method was used to observe miR-433-3p in primary osteoblasts. We built up an OVX rat model to mimic postmenopausal osteoporosis, and found aberrant circulating miR-433-3p and miR-106b, which were not reported previously. Results showed that miR-433-3p potentially regulated DKK1 mRNA, Furthermore, the correlation of serum DKK1 with circulating miR-433-3p level was significant (r = 0.7520, p = 0.046). In the luciferase reporter assay, we found that miR-433-3p siRNA decreased luminescence signal, indicating direct regulation of miR-433-3p on DKK1 mRNA. When the miR-433-3p binding site in DKK1 3'UTR was mutant, such reduction was prohibited. Western blotting result validated that miR-433-3p inhibited over 90% of DKK1 protein expression. Similarly, the change of protein expression was not observed in mutant group. The stable expression of lentivirus mediated miR-433-3p increased ALP activity and mineralization both in human and rat derived immortalized cells. We found that primary osteoblasts had higher miR-433-3p level compared with immortal cells through real-time PCR, as well as in situ hybridization experiment. Conclusively, our findings further emphasized the vital role of miR-433-3p in DKK1/WNT/ß-catenin pathway through decreasing DKK1 expression and inducing osteoblasts differentiation.