RESUMO
A novel drug delivery strategy featured with enhanced uptake of nanoparticles (NPs) by targeted tumor cells and subsequent intratumoral cellular hitchhiking of chemotherapy to deep tumor regions was described. The NP delivery system was obtained from assembly of poly(lactic acid-co-glycolic acid)-grafted hyaluronic acid (HA-g-PLGA) together with an anticancer drug, SN38, in aqueous phase, followed by implementing the NP surface with a layer of methoxypoly(ethylene glycol)-b-poly(histamine methacrylamide) (mPEG-b-PHMA) via hydrophobic association to improve the colloidal stability both in vitro and in vivo. Upon arrival of these PEGylated NPs at the acidic tumor site through the EPR effect, mPEG-b-PHMA became detached from the NP surface by the charge transition of the PHMA blocks from neutral (hydrophobic) to positively charged (hydrophilic) state via acid-induced protonation of their imidazole groups in tumor microenvironment. The exposure of HA shell on the naked NP thus resulted in enhanced uptake of NPs by CD44-expressed tumor cells, including cancer cells and tumor-associated macrophages (TAMs). Along with the TAMs being further chemotactically recruited by hypoxia cells, the engulfed nanotherapeutics was thus transported into the avascular area in which the anticancer action of chemotherapy occurred by virtue of the drug release alongside PLGA degradation, similar to those arising in other tumor nonhypoxia regions.
Assuntos
Camptotecina/análogos & derivados , Sistemas de Liberação de Medicamentos , Ácido Hialurônico/química , Macrófagos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Irinotecano , Macrófagos/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Poliésteres/química , Ácido Poliglicólico/química , Neoplasias da Próstata/patologia , Células Tumorais CultivadasRESUMO
To address the issue that a single coating agent cannot simultaneously enhance Li+-ion transport and electronic conductivity of Ni-rich cathode materials with surface modification, in the present study, we first successfully synthesized a LiNi0.8Co0.1Mn0.1O2 (NCM811) cathode material by a Taylor-flow reactor followed by surface coating with Li-BTJ and dispersion of vapor-grown carbon fibers treated with polydopamine (PDA-VGCF) filler in the composite slurry. The Li-BTJ hybrid oligomer coating can suppress side reactions and enhance ionic conductivity, and the PDA-VGCFs filler can increase electronic conductivity. As a result of the synergistic effect of the dual conducting agents, the cells based on the modified NCM811 electrodes deliver superior cycling stability and rate capability, as compared to the bare NCM811 electrode. The CR2032 coin-type cells with the NCM811@Li-BTJ + PDA-VGCF electrode retain a discharge specific capacity of â¼92.2% at 1C after 200 cycles between 2.8 and 4.3 V (vs Li/Li+), while bare NCM811 retains only 84.0%. Moreover, the NCM811@Li-BTJ + PDA-VGCF electrode-based cells reduced the total heat (Qt) by ca. 7.0% at 35 °C over the bare electrode. Remarkably, the Li-BTJ hybrid oligomer coating on the surface of the NCM811 active particles acts as an artificial cathode electrolyte interphase (ACEI) layer, mitigating irreversible surface phase transformation of the layered NCM811 cathode and facilitating Li+ ion transport. Meanwhile, the fiber-shaped PDA-VGCF filler significantly reduced microcrack propagation during cycling and promoted the electronic conductance of the NCM811-based electrode. Generally, enlightened with the current experimental findings, the concerted ion and electron conductive agents significantly enhanced the Ni-rich cathode-based cell performance, which is a promising strategy to apply to other Ni-rich cathode materials for lithium-ion batteries.
RESUMO
Hollow hybrid nanogels were prepared first by the coassembly of the citric acid-coated superparamagnetic iron oxide nanoparticles (SPIONs, 44 wt %) with the graft copolymer (56 wt %) comprising acrylic acid and 2-methacryloylethyl acrylate units as the backbone and poly(ethylene glycol) and poly(N-isopropylacrylamide) as the grafts in the aqueous phase of pH 3.0 in the hybrid vesicle structure, followed by in situ covalent stabilization via the photoinitiated polymerization of MEA residues within vesicles. The resultant hollow nanogels, though slightly swollen, satisfactorily retain their structural integrity while the medium pH is adjusted to 7.4. Confining SPION clusters to such a high level (44 wt %) within the pH-responsive thin gel layer remarkably enhances the transverse relaxivity (r2) and renders the MR imaging highly pH-tunable. For example, with the pH being adjusted from 4.0 to 7.4, the r2 value can be dramatically increased from 138.5 to 265.5 mM(-1) s(-1). The DOX-loaded hybrid nanogels also exhibit accelerated drug release in response to both pH reduction and temperature increase as a result of the substantial disruption of the interactions between drug molecules and copolymer components. With magnetic transport guidance toward the target and subsequent exposure to an alternating magnetic field, this DOX-loaded nanogel system possessing combined capabilities of hyperthermia and stimuli-triggered drug release showed superior in vitro cytotoxicity against HeLa cells as compared to the case with only free drug or hyperthermia alone. This work demonstrates that the hollow inorganic/organic hybrid nanogels hold great potential to serve as a multimodal theranostic vehicle functionalized with such desirable features as the guidable delivery of stimuli-mediated diagnostic imaging and hyperthermia/chemotherapies.
Assuntos
Antineoplásicos/farmacologia , Géis/química , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita/química , Neoplasias/tratamento farmacológico , Compostos Organometálicos/farmacologia , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Ácido Cítrico/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Férricos/química , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Neoplasias/diagnóstico , Compostos Organometálicos/química , Tamanho da Partícula , Polímeros/química , Porosidade , Relação Estrutura-Atividade , Propriedades de SuperfícieRESUMO
Dual stimuli-responsive hollow nanogel spheres serving as an efficient intracellular drug delivery platform were obtained from the spontaneous coassociation of two graft copolymers into the vesicle architecture in aqueous phase. Both copolymers comprise acrylic acid (AAc) and 2-methacryloylethyl acrylate (MEA) units as the backbone and either poly(N-isopropylacrylamide) (PNIPAAm) alone or both PNIPAAm and monomethoxypoly(ethylene glycol) (mPEG) chain segments as the grafts. The assemblies were then subjected to covalent stabilization within vesicle walls with ester-containing cross-links by radical polymerization of MEA moieties, thereby leading to hollow nanogel particles. Taking the advantage of retaining a low quantity of payload within polymer layer-enclosed aqueous chambers through the entire loading process, doxorubicin (DOX) in the external bulk phase can be effectively transported into the gel membrane and bound therein via electrostatic interactions with ionized AAc residues and hydrogen-bond pairings with PNIPAAm grafts at pH 7.4. With the environmental pH being reduced (e.g., from 7.4 to 5.0) at 37 °C, the extensive disruption of AAc/DOX complexes due to the reduced ionization of AAc residues within the gel layer and the pronounced shrinkage of nanogels enable the rapid release of DOX species from drug-loaded hollow nanogels. By contrast, the drug liberation at 4 °C was severally restricted, particularly at pH 7.4 at which the DOX molecules remain strongly bound with ionized AAc residues and PNIPAAm grafts. The in vitro characterizations suggest that the DOX-loaded hollow nanogel particles after being internalized by HeLa cells via endocytosis can rapidly release the payload within acidic endosomes or lysosomes. This will then lead to significant drug accumulation in nuclei (within 1 h) and a cytotoxic effect comparable to free drug. This work demonstrates that the novel DOX-loaded hollow nanogel particles show great promise of therapeutic efficacy for potential anticancer treatment.
Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Polietilenoglicóis/química , Polietilenoimina/química , Polímeros/química , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Estrutura Molecular , Nanogéis , Tamanho da Partícula , Porosidade , Solubilidade , Relação Estrutura-Atividade , Propriedades de Superfície , TemperaturaRESUMO
A solid-state lithium metal battery of low capacity fade is acquired using the electrolyte membrane of a polyurethane-acrylate-thiocarbonate (PUAT) oligomer, macromolecules, lithium salt, and an oxide additive. Two types of composite electrolytes have been prepared: the free-standing electrolyte (PUAT-FS) and the electrode-coated electrolyte (PUAT-EC). Featuring a less PUAT content and a finer granular size, PUAT-FS is less ion-conductive than PUAT-EC; 0.44 mS cm-1 in contrast to 0.51 mS cm-1 at room temperature. Nonetheless, the lithium iron phosphate battery of PUAT-FS is far superior to that of PUAT-EC in terms of cycling stability. When cycled at 0.1C and room temperature, the PUAT-FS battery reaches a maximum discharge capacity of 169.7 mAh g-1 at its 20th cycle and decreases to 141.0 mAh g-1 at the 500th cycle, 83.1% retention. The capacity fading rate of the PUAT-FS battery is 0.034% per cycle at 0.1C, significantly less than that of the PUAT-EC battery, 0.138% per cycle. Other maximum capacities and fading rates of the PUAT-FS battery are 152.5 mAh g-1 and 0.050% per cycle at 0.2C in 800 cycles and 126.1 mAh g-1 and 0.051% per cycle at 0.5C in 1000 cycles. These features of a low fading rate and high capacity are attributed to a balanced ratio of oligomer to macromolecule (1:1 w/w) in the free-standing electrolyte and the sulfur-containing oligomer.
RESUMO
Soluble amyloid-ß oligomers (oAß42)-induced neuronal death and inflammation response has been recognized as one of the major causes of Alzheimer's disease (AD). In this work, a novel strategy adopting silica-coated iron oxide stir bar (MSB)-based AD therapy system via magnetic stirring-induced capture of oAß42 into magnetic plaques (mpAß42) and activation of microglia on cellular plaque clearance was developed. With oAß42 being effectively converted into mpAß42, the neurotoxicity toward neuronal cells was thus greatly reduced. In addition to the good preservation of neurite outgrowth through the diminished uptake of oAß42, neurons treated with oAß42 under magnetic stirring also exhibited comparable neuron-specific protein expression to those in the absence of oAß42. The phagocytic uptake of mpAß42 by microglia was enhanced significantly as compared to the counterpart of oAß42, and the M1 polarization of microglia often occurring after the uptake of oAß42 restricted to an appreciable extent. As a result, the inflammation induced by pro-inflammatory cytokines was greatly alleviated.
RESUMO
Graft copolymer comprising acrylic acid (AAc) units as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts undergoes phase transition and supramolecular assembly into colloidal particles in water upon the thermally induced hydrophobic association. The structural characteristics of the polymeric assemblies made from the graft copolymer in water are strongly dependent on the copolymer concentration and the way that the copolymer solution is subjected to heating from 25 degrees C to the phase transition region (occurring in the range 30 approximately 35 degrees C). The resultant assemblies are characterized by forming hydrophobic PNIPAAm regions with the multicore architecture and intercore connections. Interesting enough, these colloidal systems obtained from the copolymer solutions at different concentrations (10.0 and 1.0 mg/mL) and heating methods (fast and slow heating) exhibit very different structural responses when subjected to further temperature increase (from 30 approximately 35 to 60 degrees C). The mutual interactions among the components (PAAc backbone and PNIPAAm and mPEG grafts) of the copolymer were shown to play a crucial role in the evolution of the ultimate assembly structure. A molecular packing model was proposed to illustrate the mechanisms of the thermally induced structural transformation processes for the amphiphilic graft copolymer in water.
Assuntos
Acrilamidas/química , Resinas Acrílicas/química , Polietilenoglicóis/química , Polímeros/química , Temperatura , Água/química , Espectroscopia de Ressonância Magnética , Microscopia Eletrônica de Transmissão , Estrutura Molecular , Tamanho da PartículaRESUMO
HYPOTHESIS: How to encapsulate poly(N-isopropylacrylamide) (PNIPAM) mesoglobule cores by silica shells greatly affects the resultant nanoparticle structures. Incorporation of acrylamide (AM) unit into PNIPAM in combination with 3-glycidyloxypropyltrimethoxysilane (GLYMO, as a coupling agent) effectively induces nucleation and growth of silica on PNIPAM core surfaces, where the -NH2 of acrylamide reacts with the epoxide of GLYMO while GLYMO further participates in subsequent sol-gel reaction of tetraethyl orthosilicate (TEOS), thereby leading to desirable particle morphology. EXPERIMENTS: PNIPAM-based core-silica shell nanoparticles were prepared by sol-gel reaction of TEOS and GLYMO in the presence of polymeric core particles. The major parameters investigated in a systematic fashion include acrylamide concentration and weight ratio of polymer:GLYMO:TEOS. GPC, DLS, DSC, FE-SEM, TEM, FTIR and TGA were then used to characterize polymeric cores and hybrid nanoparticles. FINDINGS: The particle morphology was governed primarily by the acrylamide content and the weight ratio of PNIPAM/AM:GLYMO:TEOS, and desirable hybrid nanoparticles with narrow particle size distribution were achieved. The LCST of PNIPAM-based mesoglobules increases with increasing acrylamide content. Encapsulation of PNIPAM-based mesoglobules with silica also reduces their thermo-sensitivity. This is the first report of developing a novel approach to prepare PNIPAM-based mesoglobule core-silica shell nanoparticles with controllable particle morphologies.
RESUMO
Solubilization kinetics experiments were developed to study the effects of the polyethylene glycol chain length of Triton X surfactants on their interactions with the cholesterol-containing phosphatidylcholine vesicles. An empirical liposome stability ratio was used to describe the vesicle solubilization process. The effectiveness of Triton X surfactants in solubilizing vesicles decreases with increasing polyethylene glycol chain length of surfactants. It was also shown that vesicles containing the intercalated surfactant molecules with the largest number of ethylene glycol units per molecule exhibited the exceedingly retarded solubilization behavior. Independent experiments based on a thermodynamic approach provide supporting evidence for the conclusions obtained from solubilization kinetics experiments.
Assuntos
Colesterol/química , Lipossomos/química , Octoxinol/química , Fosfatidilcolinas/química , Polietilenoglicóis/química , Tensoativos/química , Cinética , Propriedades de Superfície , Fatores de TempoRESUMO
Overcoming limitations often experienced in nanomedicine delivery toward hypoxia regions of malignant tumors remains a great challenge. In this study, a promising modality for active hypoxia drug delivery was developed by adopting tumortropic monocytes/macrophages as a cellular vehicle for co-delivery of echogenic polymer/C5F12 bubbles and doxorubicin-loaded polymer vesicles. Through the remote-controlled focused ultrasound (FUS)-triggered drug liberation, therapeutic monocytes show prominent capability of inducing apoptosis of cancer cells. The in vivo and ex vivo fluorescence imaging shows appreciable accumulation of cell-mediated therapeutics in tumor as compared to the nanoparticle counterpart residing mostly in liver. Inhibition of tumor recurrence with γ-ray pre-irradiated Tramp-C1-bearing mice receiving therapeutic monocytes intravenously alongside the FUS activation at tumor site was significantly observed. Immunohistochemical examination of tumor sections confirms successful cellular transport of therapeutic payloads to hypoxic regions and pronounced cytotoxic action against hypoxic cells. Following the intravenous administration, the cellular-mediated therapeutics can penetrate easily to a depth beyond 150 µm from the nearest blood vessels within pre-irradiated tumor while nanoparticles are severely limited to a depth of ca 10-15 µm. This work demonstrates the great promise of cellular delivery to carry therapeutic payloads for improving chemotherapy in hypoxia by combining external trigger for drug release.
Assuntos
Antineoplásicos/farmacologia , Hipóxia Celular/efeitos dos fármacos , Monócitos/metabolismo , Neoplasias/patologia , Polímeros/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Distribuição TecidualRESUMO
To achieve effective intracellular anticancer drug delivery, the polymeric vesicles supplemented with the pH-responsive outlayered gels as a delivery system of doxorubicin (DOX) were developed from self-assembly of the lipid/polypeptide adduct, distearin grafted poly(γ-glutamic acid) (poly(γ-GA)), followed by sequential deposition of chitosan and poly(γ-GA-co-γ-glutamyl oxysuccinimide)-g-monomethoxy poly(ethylene glycol) in combination with in situ covalent cross-linking on assembly surfaces. The resultant gel-caged polymeric vesicles (GCPVs) showed superior performance in regulating drug release in response to the external pH change. Under typical physiological conditions (pH 7.4 and 37 °C) at which the γ-GA/DOX ionic pairings remained mostly undisturbed, the dense outlayered gels of GCPVs significantly reduced the premature leakage of the uncomplexed payload. With the environmental pH being reduced from pH 7.4 to 4.7, the drug liberation was appreciably promoted by the massive disruption of the ionic γ-GA/DOX complexes along with the significant swelling of nanogel layers upon the increased protonation of chitosan chain segments. After being internalized by HeLa cells via endocytosis, GCPVs exhibited cytotoxic effect comparable to free DOX achieved by rapidly releasing the payload in intracellular acidic endosomes and lysosomes. This strongly implies the great promise of such unique GCPVs as an intracellular drug delivery carrier for potential anticancer treatment.
Assuntos
Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Espaço Intracelular/metabolismo , Lipídeos/química , Peptídeos/química , Polietilenoglicóis/química , Polietilenoimina/química , Morte Celular/efeitos dos fármacos , Quitosana/química , Doxorrubicina/química , Liberação Controlada de Fármacos/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Citometria de Fluxo , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Luz , Espectroscopia de Ressonância Magnética , Peso Molecular , Nanogéis , Peptídeos/síntese química , Polietilenoglicóis/síntese química , Polietilenoimina/síntese química , Ácido Poliglutâmico/análogos & derivados , Ácido Poliglutâmico/síntese química , Ácido Poliglutâmico/química , Espalhamento de Radiação , Eletricidade EstáticaRESUMO
A cationic lipid-embedded poly(acrylic acid) (PAAc) gel layer coated on chitosan/superparamagnetic iron oxide nanoparticle (SPION) nanohybrid surfaces effectively modulates drug release and MR imaging contrast by pH-responsive morphological transformation and hierarchical alignment of the lipid assemblies.
RESUMO
This work presents an important example of novel hybrid vesicles with pH-triggered transmembrane channels prepared by co-assembly of poly(acrylic acid)-g-poly(monomethoxy ethylene glycol) (PAAc-g-mPEG) with a cationic lipid, didodecyldimethylammonium bromide (DDAB), via electrostatic interaction for effective doxorubicin (DOX) release.
Assuntos
Resinas Acrílicas/química , Membrana Celular/metabolismo , Portadores de Fármacos/química , Polietilenoglicóis/química , Compostos de Amônio Quaternário/química , Preparações de Ação Retardada , Doxorrubicina/química , Doxorrubicina/metabolismo , Concentração de Íons de Hidrogênio , Modelos Moleculares , Conformação Molecular , Tamanho da PartículaRESUMO
Polymeric vesicles produced by spontaneous self-association of poly(acrylic acid-co-distearin acrylate) (poly(AAc-co-DSA)) with varying ratios of AAc and DSA units in aqueous solution of pH 5.0 exhibit the pH-regulated drug release behavior. Through the electrostatic interaction with ionized AAc residues, doxorubicin (DOX) molecules can be highly accommodated onto either the inner or outer surfaces of vesicles when the pH is adjusted from 5.0 to 7.4. The extent of DOX encapsulation is dependent largely on the structural transition of vesicles in response to the pH change. While the pH-evolved drug release profile varies to some extent with the distribution of DOX molecules within vesicles, the drug release from vesicles is accelerated significantly via the disruption of the electrostatic interaction of DOX species with ionized AAc moieties at pH 5.0. The DOX-loaded polymeric vesicles show promoted cellular uptake and cytotoxicity comparable to free DOX for HeLa cells. This indicates that they are probably taken up by the cells via the lipid raft-mediated endocytosis.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Nanopartículas , Acrilatos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Preparações de Ação Retardada , Diglicerídeos/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Endocitose , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Microdomínios da Membrana/metabolismo , Eletricidade EstáticaRESUMO
The effects of SDS on the structural changes of the thermally induced polymeric micelles from a graft copolymer comprising poly(acrylic acid) (PAAc) as the backbone and poly(N-isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) (mPEG) as the grafts in aqueous solution are studied. At low temperature, SDS micelles form via the hydrophobic association of SDS molecules with the PNIPAAm grafts at a critical aggregation concentration of SDS (cac(SDS)) much lower than its critical micelle concentration. Consequently, the critical aggregation temperature of the graft copolymer is elevated. The corresponding structure of the thermally induced polymeric micelles is characterized by an abrupt reduction in the particle size and an increased tendency toward formation of the monocore structure with a more compact and hydrophobic PNIPAAm microdomain being developed. On the other hand, upon the polymeric micelle formation at high temperature, the copolymer-bound SDS micelle structure is disrupted and the dissociated SDS molecules migrate to the core-shell interface with their alkyl chains residing in the liquidlike region of the hydrophobic PNIPAAm microdomain. The correlation between the polymeric particles and copolymer-bound micelles is further substantiated by showing the change of the colloidal particle size in response to changes in cac(SDS) via adjusting the pH of the aqueous copolymer/SDS solutions.