RESUMEN
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.
Asunto(s)
Ferroptosis , Glucosa Oxidasa , Indoles , Compuestos de Manganeso , Nanopartículas , Óxidos , Terapia Fototérmica , Polímeros , Terapia Fototérmica/métodos , Compuestos de Manganeso/química , Animales , Humanos , Ferroptosis/efectos de los fármacos , Ferroptosis/fisiología , Indoles/química , Polímeros/química , Glucosa Oxidasa/metabolismo , Glucosa Oxidasa/administración & dosificación , Nanopartículas/química , Ratones , Óxidos/química , Línea Celular Tumoral , Peróxido de Hidrógeno/metabolismo , Ratones Endogámicos BALB C , Terapia Combinada/métodos , Femenino , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Ratones DesnudosRESUMEN
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.
Asunto(s)
Antibacterianos , Vendajes , Betaína , Biopelículas , Indoles , Nanofibras , Poliésteres , Cicatrización de Heridas , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/administración & dosificación , Biopelículas/efectos de los fármacos , Animales , Cicatrización de Heridas/efectos de los fármacos , Poliésteres/química , Indoles/química , Indoles/farmacología , Betaína/química , Betaína/farmacología , Betaína/análogos & derivados , Nanofibras/química , Polímeros/química , Óxido Nítrico/metabolismo , Staphylococcus aureus/efectos de los fármacos , Incrustaciones Biológicas/prevención & control , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/química , Ratones , Propiedades de Superficie , Escherichia coli/efectos de los fármacos , Polietileneimina/químicaRESUMEN
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.
Asunto(s)
Ferroptosis , Neoplasias , Humanos , Artesunato/farmacología , Especies Reactivas de Oxígeno , Disponibilidad Biológica , Ácido Hialurónico , Peróxidos LipídicosRESUMEN
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.
Asunto(s)
Hipertermia Inducida , Neoplasias Nasofaríngeas , Profármacos , Animales , Profármacos/farmacología , Profármacos/uso terapéutico , Carcinoma Nasofaríngeo/tratamiento farmacológico , Neoplasias Nasofaríngeas/tratamiento farmacológico , Poliésteres , MamíferosRESUMEN
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.
Asunto(s)
Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Naftoquinonas/administración & dosificación , Neoplasias/tratamiento farmacológico , Estrés Oxidativo , Profármacos/administración & dosificación , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Quitosano/administración & dosificación , Quitosano/química , Quitosano/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Mitocondrias/fisiología , Nanopartículas/química , Naftoquinonas/química , Naftoquinonas/farmacocinética , Neoplasias/metabolismo , Neoplasias/patología , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Oxidación-Reducción , Profármacos/química , Profármacos/farmacocinética , Especies Reactivas de Oxígeno/metabolismo , Dióxido de Silicio/administración & dosificación , Dióxido de Silicio/química , Dióxido de Silicio/farmacocinética , Carga Tumoral/efectos de los fármacosRESUMEN
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.
Asunto(s)
Antineoplásicos/administración & dosificación , Brefeldino A/administración & dosificación , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Micelas , Nanoestructuras/administración & dosificación , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Brefeldino A/sangre , Brefeldino A/química , Brefeldino A/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patología , Línea Celular , Supervivencia Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones Endogámicos BALB C , Nanoestructuras/química , Polietilenos/administración & dosificación , Polietilenos/química , Polipropilenos/administración & dosificación , Polipropilenos/química , Ratas Sprague-Dawley , Distribución Tisular , Vitamina E/administración & dosificación , Vitamina E/químicaRESUMEN
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.
RESUMEN
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.
Asunto(s)
Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Péptidos de Penetración Celular/química , Péptidos de Penetración Celular/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/farmacocinética , Liberación de Fármacos , Femenino , Fluorescencia , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Micelas , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Vitamina E/farmacocinética , Vitamina E/uso terapéuticoRESUMEN
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.
Asunto(s)
Antineoplásicos/farmacología , Guanidina/farmacología , Iridio/farmacología , Mitocondrias/efectos de los fármacos , Imagen Óptica , Compuestos Organometálicos/farmacología , Fármacos Fotosensibilizantes/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Guanidina/química , Células Hep G2 , Humanos , Iridio/química , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Neoplasias Hepáticas Experimentales/tratamiento farmacológico , Neoplasias Hepáticas Experimentales/patología , Ratones , Mitocondrias/patología , Estructura Molecular , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
Antineoplásicos/química , Curcumina/química , Doxorrubicina/química , Portadores de Fármacos , Nanopartículas/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Curcumina/farmacología , Doxorrubicina/farmacología , Composición de Medicamentos/métodos , Liberación de Fármacos , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Cinética , Nanopartículas/ultraestructura , Oxidación-ReducciónRESUMEN
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.
RESUMEN
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.
Asunto(s)
Apoptosis/fisiología , Núcleo Celular/metabolismo , Supervivencia Celular/fisiología , Dendrímeros/química , Vectores Genéticos/química , Apoptosis/genética , Supervivencia Celular/genética , Técnicas de Transferencia de Gen , Células HeLa , Humanos , Fragmentos de Péptidos/química , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
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.
Asunto(s)
Núcleo Celular/efectos de los fármacos , Quitosano/química , Portadores de Fármacos , Productos del Gen tat/metabolismo , Técnicas de Transferencia de Gen , Vectores Genéticos/química , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Núcleo Celular/metabolismo , Doxorrubicina/farmacología , Productos del Gen tat/genética , Vectores Genéticos/metabolismo , Células HeLa , Humanos , Micelas , Tamaño de la Partícula , Polilisina/química , Propiedades de SuperficieRESUMEN
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.
Asunto(s)
Nanoestructuras , Doxorrubicina , Sistemas de Liberación de Medicamentos , Humanos , Ácido Hialurónico , Concentración de Iones de Hidrógeno , Oxidación-Reducción , Dióxido de SilicioRESUMEN
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.
Asunto(s)
Curcumina/química , Quitosano , Células HeLa , Humanos , Micelas , Polilisina , TransfecciónRESUMEN
Stimuli-responsive nanocarriers for anticancer drug and gene co-delivery are promising strategy in cancer therapy. The ultimate goal is to deliver high local concentration of therapeutic agents with no premature release and result in synergistic effects for combination therapies. In this work, we developed a redox stimuli-responsive and synergistic co-delivery system for anticancer drug DOX and p53 gene for potential cancer therapy. A dendronized chitosan derivative (CP) as a "gatekeeper" to control release the drug was used to modify MSNs via a disulfide linker and improve the gene transfection efficiency. Stimulus-induced release of the DOX was studied in the presence of glutathione (GSH), which showed that polymer shell was shed and accelerated the release of embedded drugs inside the tumor cells under a GSH-rich environment. The obtained nanoparticles showed good gene delivery ability in vitro by inducing an obvious increase in p53 protein expression in Hela cells. Apoptosis analysis confirmed that DOX and p53 could be co-delivered to the Hela cells by MSN-SS-CP nanocarriers and induced significant cell apoptosis. These results demonstrated that the dual delivery system resulted in synergistic effects and lead to an effective cancer cell apoptosis, which may be promising for cancer therapeutic application.
Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos/métodos , Técnicas de Transferencia de Gen , Nanopartículas/química , Proteína p53 Supresora de Tumor/farmacología , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Quitosano/química , Doxorrubicina/metabolismo , Composición de Medicamentos/métodos , Liberación de Fármacos , Sinergismo Farmacológico , Glutatión/química , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Cinética , Nanopartículas/ultraestructura , Oxidación-Reducción , Porosidad , Dióxido de Silicio/química , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Stimuli-responsive nanocarriers for anticancer drug and gene co-delivery are a promising strategy in cancer therapy due to their combination of chemotherapy and gene therapy. In this work, we developed a facile and effective method to fabricate stimuli-responsive nanocarriers for anticancer drug and gene co-delivery based on complexes of polyethylenimine (PEI) with an adenosine triphosphate (ATP) responsive aptamer duplex (ARAD). No chemical reactions or complex modifications were used in the construction processes. In this system, Doxorubicin-loaded aptamer duplex and plasmid DNA (p53) can be bound by PEI by electronic interactions to form stable complexes which effectively protect the aptamer and p53 from DNase degradation. The intercalated Dox can be released on-demand by a structural change in the aptamer duplex in an ATP-rich environment. The morphology and average size of the nanocarriers were characterized by zeta potential and transmission electron microscopy (TEM). The nanocarriers exhibit lower cell toxicity in HeLa cell lines relative to PEI. RT-PCR and Western blot analysis confirmed that p53 could be effectively delivered and expressed in HeLa cells by PEI/ARAD/p53 complexes. Moreover, the apoptosis percentage of HeLa cells treated with PEI/ARAD/Dox/p53 complex increased to 40.8%, compared to 24.7% for PEI/ARAD/Dox complex and 11.5% for PEI/ARAD/p53, respectively. The result demonstrated that the combinatorial delivery of Dox and p53 by nanocarriers could induce synergistic actions and lead to effective cancer cell apoptosis.
RESUMEN
Cationic micellar nanoparticles for chemotherapeutic drugs and therapeutic gene co-delivery were prepared based on a poly-(N-ε-carbobenzyloxy-l-lysine) (PZLL) and dendritic polyamidoamine (PAMAM) block copolymer (PZLL-D3). PZLL-D3 was synthesized by a copper-catalyzed azide alkyne cyclization (click) reaction between α-alkyne-PZLL and azide focal point PAMAM dendrons. Its structure was characterized by (1)H NMR and FTIR, and its buffering capability was determined by acid-base titration. MTT, agarose gel electrophoresis and flow cytometry studies showed that PZLL-D3 revealed low in vitro cytotoxicity, strong pDNA condensation ability, protection of pDNA against deoxyribonuclease I degradation and high gene transfection efficiency in 293T and HeLa cells. In addition, the micellar nanoparticles delivered pDNA and anticancer drug doxorubicin (DOX) simultaneously and efficiently to tumor cells, and the DOX loaded nanoparticles showed sustained in vitro release at pH=7.4 and 5.8.
Asunto(s)
Doxorrubicina/química , Sistemas de Liberación de Medicamentos/métodos , Micelas , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacología , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Cationes/química , Línea Celular Tumoral , Dendrímeros/química , Dendrímeros/farmacología , Desoxirribonucleasa I/metabolismo , Doxorrubicina/farmacología , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Espectroscopía de Resonancia Magnética , Polilisina/química , Polilisina/farmacología , Polímeros/química , Polímeros/farmacología , Espectroscopía Infrarroja por Transformada de Fourier , TransfecciónRESUMEN
In an attempt to develop a biofriendly sol-gel route for the rapid formation of biofunctional silica gels, a biopolymer with good biocompatibility was used to assist the gelation of glycol-modified tetraethoxysilane (GMT) in aqueous system without the addition of any organic solvents. It was found that the biopolymer used could act as an effective accelerator for the sol-gel transition of GMT and an increase of its amount could shorten greatly the gelation time. For such a gelation reaction, its apparent activation energy was determined to be 64.9 kJ/mol according to the Arrhenius equation. In particular, the kinetic mechanism for the formation of the silica gel was investigated by using dynamic theological data and a scaling fractal model. It was revealed that the biopolymer used could change the sol-gel transition mechanism from reaction-limited kinetics to diffusion-limited kinetics. Circular dichroism analyses confirmed the suitability of using the resultant silica gel for the in situ protein encapsulation.
Asunto(s)
Biopolímeros/química , Proteínas/química , Dióxido de Silicio/química , Animales , Materiales Biocompatibles/química , Bovinos , Quitosano/química , Dicroismo Circular , Difusión , Fractales , Cinética , Microscopía Electrónica de Rastreo , Reología/métodos , Albúmina Sérica/química , Gel de Sílice , Solubilidad , Solventes/químicaRESUMEN
To develop biocompatible sol-gel silica matrix for the encapsulation of biomolecules or drugs, a novel water-soluble silica precursor, tetrakis(2-hydroxyethyl)orthosilicates (THEOS), was used in combination with a water-soluble polysaccharide derivative, hydroxypropyl guar gum (HPGG). We found that the introduction of HPGG could trigger and accelerate the sol-gel transition of THEOS in water and induce rapid formation of homogeneous gel matrix without the addition of any organic solvents or catalysts. Moreover, added HPGG macromolecules had a great influence on the network structure and particle dimension in the silica gel matrix, as confirmed by scanning electron microscope (SEM) observation. From the time sweep rheological measurements, it was found that a higher HPGG amount could lead to shorter gelation time for the sol-gel transition. From the strain and frequency sweep rheological experiments, it was found that the resultant silica matrix containing a higher amount of HPGG exhibited a narrower linear viscoelastic region, a higher dynamic muduli, and greater complex viscosity. In particular, the gel strength of the silica matrix could be modulated by the amount of HPGG. By investigating the controlled release of vitamin B12 from the sol-gel silica matrixes, a strong dependence of the release profile on the amount of introduced HPGG was observed. In this case, a higher HPGG amount resulted in lower release rate.