RESUMEN
A novel star-shaped polymer, porphyrin-poly(L-lysine) dendrons (PP-PLLD), is synthesized by the click reaction between azido-modified porphyrin and propargyl focal point poly(L-lysine) dendrons. Its chemical structure is characterized by (1) H nuclear magnetic resonance, Fourier transform infrared spectroscopy, and gel permeation chromatography (GPC) is analyses etc. Due to its amphiphilic property, the obtained PP-PLLD has a low critical micelle concentration in an aqueous solution, and can load doxorubicin (DOX) with a loading amount of 64 µg mg(-1) . By in vitro toxicity assay, PP-PLLD has no dark cytotoxicity but has significant phototoxicity. Moreover, DOX-loaded PP-PLLD shows a higher cytotoxicity under the light condition than PP-PLLD or DOX alone, suggesting PP-PLLD has a potential application in combined photodynamic therapy and chemotherapy.
Asunto(s)
Dendrímeros/química , Portadores de Fármacos/síntesis química , Polilisina/química , Porfirinas/síntesis química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Química Clic , Doxorrubicina/química , Doxorrubicina/farmacología , Portadores de Fármacos/farmacología , Composición de Medicamentos , Humanos , Luz , Estructura Molecular , Fotoquimioterapia , Porfirinas/farmacologíaRESUMEN
Transition metal salts were employed as the catalysts to improve the selective degradation of the α-O-4 lignin model compound (benzyl phenyl ether (BPE)) in the solvothermal system. The results concluded that most of the transition metal salts could enhance BPE degradation. Among which, NiSO4·6H2O exhibited the highest performance on BPE degradation (90.8%) for 5 h and phenol selectivity (53%) for 4 h at 200 °C. In addition, the GC-MS analysis indicated that the intermediates during BPE degradation included a series of aromatic compounds, such as phenol, benzyl methyl ether and benzyl alcohol. Furthermore, the mechanisms for BPE degradation and phenol selectivity in the NiSO4·6H2O system involved the synergetic effects between the acid catalysis and coordination catalysis, which caused the effective and selective cleavage of the C-O bonds.
RESUMEN
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
The nucleus is one of the most important cellular organelles. Chitosan-grafted poly-(N-3-carbobenzyloxy-lysine) (CCL) decorated with human immunodeficiency virus-1 transactivator of transcription (TAT) can co-deliver p53 and doxorubicin into the nucleus simultaneously, such that their antitumor functions are exerted. However, TAT-CCL has been shown to have an anti-tumor effect only in vitro; the effect in vivo was unsatisfactory. Here, a unique nucleus-targeted delivery system based on amidized TAT (aTAT)-CCL with aTAT functional on the surface was designed to achieve a highly efficient nucleus-targeting gene and drug delivery system for effective cancer cell elimination in vitro and in vivo. In this delivery system, TAT is amidized to inhibit its nonspecific interactions. Confocal laser scanning microscopy observations revealed that if aTAT-CCL was incubated in pH 5.0 acetate buffer solution for 24â¯h before use (named aTAT-CCL-HB), more aTAT-CCL-HB entered the nucleus compared with aTAT-CCL or CCL. aTAT-CCL-HB can also achieve high gene transfection and drug delivery efficiencies and low viability in HepG2 cells. However, only aTAT-CCL achieved extensive circulation in the blood compartment and high antitumor activity in vivo. Amidization of TAT in vectors may become a promising strategy for nucleus-targeted delivery systems, especially in in vivo applications.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Núcleo Celular/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Neoplasias/tratamiento farmacológico , Proteína p53 Supresora de Tumor/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Quitosano/administración & dosificación , Doxorrubicina/administración & dosificación , Técnicas de Transferencia de Gen , Células Hep G2 , Humanos , Ratones Desnudos , Neoplasias/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
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
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
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
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
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 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
New heparin-indomethacin conjugate with an ester linkage was prepared by the carbodiimide-mediated condensation reaction, and then characterized by FTIR and (1)HNMR analyses. Due to its amphiphilic character, such a conjugate could self-aggregate into spherical nanoparticles in aqueous system, as confirmed by fluorescence spectroscopy, dynamic light scattering and transmission electron microscopy. By the in vitro drug release tests, the resultant conjugate nanoparticles were found to have a sustained and esterase-sensitive release behavior for conjugated indomethacin. In addition, the uptake of these conjugate nanoparticles into human nasopharyngeal carcinoma CNE1 cells was confirmed by fluorescence microscopy.
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Sistemas de Liberación de Medicamentos , Ésteres/química , Heparina/síntesis química , Indometacina/síntesis química , Línea Celular Tumoral , Heparina/química , Humanos , Indometacina/química , Espectroscopía de Resonancia Magnética , Microscopía Fluorescente , Nanopartículas/ultraestructura , Tamaño de la Partícula , Espectrofotometría InfrarrojaRESUMEN
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
To develop a multifunctional polymeric carrier for gene and drug co-delivery, a new cyclodextrin derivative containing poly(L-lysine) dendrons was prepared by the click conjugation of per-6-azido-ß-cyclodextrin with propargyl focal point poly(L-lysine) dendron of third generation and then characterized by FTIR, (1)H NMR, and GPC analyses. It was found that such a conjugate could form colloidally stable nanocomplexes with plasmid DNA in aqueous system and exhibited high gene transfection efficiency. Moreover, it could load efficiently methotrexate drug with anticancer activity and showed a sustained release behavior. Different from commonly used amphiphilic copolymers with cationic character, the as obtained cyclodextrin derivative may be used directly for the combinatorial delivery of nucleic acid and lipophilic anticancer drugs without a complicated micellization process.
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Ciclodextrinas/química , ADN/química , Dendrímeros/química , Portadores de Fármacos , Técnicas de Transferencia de Gen , Plásmidos/química , Polilisina/química , Antineoplásicos/administración & dosificación , Coloides/química , Humanos , Células MCF-7 , Metotrexato/administración & dosificación , Nanotecnología , Polímeros/química , TransfecciónRESUMEN
A star-shaped polymer (PP-PLLD) consisting of a porphyrin (PP) core and poly(L-lysine) dendron arms (PLLD) is synthesized by the click reaction, and its ability to deliver pEGFP is investigated in this paper. It is found that PP-PLLD has a good buffer capacity and can form compact complexes with pEGFP. In vitro assay indicates that PP-PLLD shows photoenhanced gene transfection efficiency. PP-PLLD consisting of only third generation PLLD shows a higher transfected cell number than PEI under a Xe lamp at the N/P ratio of 20, and meanwhile shows a neglectable cytotoxicity to HeLa cells. Therefore, PP-PLLD with suited irradiation is a promising nontoxic and photoinducible effective gene delivery strategy, which should be encouraged in gene therapy.