RESUMO
The present paper reports the fabrication of novel types of hybrid fibrous photocatalysts by combining block copolymer (BCP) templating, sol-gel processing, and coaxial electrospinning techniques. Coaxial electrospinning produces core-shell nanofibers (NFs), which are converted into hollow porous TiO2 NFs using an oxidative calcination step. Hybrid BCP micelles comprising a single plasmonic nanoparticle (NP) in their core and thereof derived silica-coated core-shell particles are utilized as precursors to generate yolk-shell type particulate inclusions in photocatalytically active NFs. The catalytic and photocatalytic activity of calcined NFs comprising different types of yolk-shell particles is systematically investigated and compared. Interestingly, calcined NFs comprising silica-coated yolk-shells demonstrate enhanced catalytic and photocatalytic performance despite the presence of silica shell separating plasmonic NP from the TiO2 matrix. Electromagnetic simulations indicate that this enhancement is caused by a localized surface plasmon resonance and a confinement effect in silica-coated yolk-shells embedded in porous TiO2 NFs. Utilization of the coaxially electrospun TiO2 NFs in combination with yolk-shells comprising plasmonic NPs reveals to be a potent method for the photocatalytic decomposition of numerous pollutants. It is worth noting that this study stands as the first occurrence of combining yolk-shells (Au@void@SiO2) with porous electrospun NFs (TiO2) for photocatalytic purposes and gaining an understanding of plasmon and confinement effects for photocatalytic performance. This approach represents a promising route for fabricating highly active and up-scalable fibrous photocatalytic systems.
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To develop new hybrid micelles with alkyl/polyaromatic core-shell structures, we synthesized umbrella-shaped amphiphiles bearing a bent anthracene dimer with a linear alkyl chain (i.e., octyl and hexadecyl groups). The amphiphiles quantitatively assemble into spherical micelles (~2-3â nm in core diameter), possessing an alkylated cavity surrounded by a polyaromatic framework, in water. The alkylation significantly enhances the stability of the micellar structures against dilution (up to 9â µM) and heat (up to >120 °C). The highly condensed hexadecyl core of the hybrid micelle, as indicated by solvatochromic guest probes, displays increased uptake ability toward large alkylated metallodyes. Interestingly, efficient uptake of aromatic macrocycles (i.e., [n]cycloparaphenylenes) by the present micelle provides pseudorotaxane-shaped host-guest composites with high emissivity (ΦF=up to 35 %). Internal multi-alkylation of an aromatic micelle can thus successfully enhance its assembly stability/guest uptake functions.
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Industrial-scale production of recombinant proteins for food products may become economically feasible but correct post-translational modification of proteins by microbial expression systems remains a challenge. For efficient production of hybrid products from bovine casein and recombinant casein, it is therefore of interest to evaluate the necessity of casein post-translational phosphorylation for the preparation of hybrid casein micelles and study their rennet-induced coagulation. Our results show that dephosphorylated casein was hardly incorporated into artificial casein micelles but was capable of stabilising calcium phosphate nanoclusters with an increased size through adsorption on their surface. Thereby, dephosphorylated casein formed larger colloidal particles with a decreased hydration. Furthermore, the presence of increasing amounts of dephosphorylated casein resulted in increasingly poor rennet coagulation behaviour, where dephosphorylated casein disrupted the formation of a coherent gel network by native casein. These results emphasise that post-translational phosphorylation of casein is crucial for their assembly into micelles and thereby for the production of dairy products for which the casein micelle structure is a prerequisite, such as many cheese varieties and yoghurt. Therefore, phosphorylation of future recombinant casein is essential to allow its use in the production of animal-free dairy products.
Assuntos
Queijo , Micelas , Animais , Bovinos , Caseínas/química , Fosforilação , Leite/químicaRESUMO
Diabetic nephropathy (DN) is an important complication of diabetes and is the main cause of end-stage renal disease. The pathogenesis of DN is complex, including glucose and lipid metabolism disorder, inflammation, and so on. Novel hybrid micelles loaded Puerarin (Pue) based on Angelica sinensis polysaccharides (ASP) and Astragalus polysaccharide (APS) were fabricated with pH-responsive ASP-hydrazone-ibuprofen (BF) materials (ASP-HZ-BF, SHB) and sialic acid (SA) modified APS-hydrazone-ibuprofen materials (SA/APS-HZ-BF, SPHB) by thin-film dispersion method. The SA in hybrid micelles can specifically bind to the E-selectin receptor which is highly expressed in inflammatory vascular endothelial cells. The loaded Pue could be accurately delivered to the inflammatory site of the kidney in response to the low pH microenvironment. Overall, this study provides a promising strategy for developing hybrid micelles based on natural polysaccharides for the treatment of diabetic nephropathy by inhibiting renal inflammatory reactions, and antioxidant stress.
Assuntos
Diabetes Mellitus Experimental , Neuropatias Diabéticas , Portadores de Fármacos , Selectina E , Isoflavonas , Concentração de Íons de Hidrogênio , Selectina E/metabolismo , Micelas , Neuropatias Diabéticas/tratamento farmacológico , Isoflavonas/administração & dosagem , Angelica sinensis/química , Astrágalo/química , Polissacarídeos/química , Rim , Inflamação/tratamento farmacológico , Ibuprofeno/química , Ácidos Siálicos/química , Ligação Proteica , Diabetes Mellitus Experimental/induzido quimicamente , Estreptozocina , Animais , Camundongos , Masculino , Camundongos Endogâmicos C57BLRESUMO
This study reports a facile and green synthesis of a new multifunctional nanotheranostic probe for the synergistic therapy of rheumatoid arthritis (RA) and in situ assessment of therapeutic response. The probe is synthesized through a one-step self-assembly of two exquisitely designed peptide-amphiphilic block copolymers (PEG-DTIPA-KGPLGVRK-MTX and Pal-GGGGHHHHD-TCZ) under mild conditions, requiring minimal energy input. The resultant probe demonstrates excellent biocompatibility, water solubility, and colloidal stability. It exhibits a strong IL-6R targeting ability toward inflamed joints, and releases drugs in an MMP-2-responsive manner. The co-loading of methotrexate(MTX) and tocilizumab (TCZ) into the probe enables synergistic RA therapy with improved efficacy by simultaneously decreasing the activity of adenosine synthetase and interfering with the binding of IL-6 to its receptor. In addition, the resultant probe exhibits a high r1 relaxation rate (7.00 mm-1 s-1 ) and X-ray absorption capability (69.04 Hu mm-1 ), enabling sensitive MR and CT dual-modal imaging for simultaneous evaluation of synovial thickness and bone erosion. Both in vitro experiments using lipopolysaccharide-treated RAW264.7 cells and in vivo experiments using collagen-induced arthritis mice demonstrate the probe's high effectiveness in synergistically inhibiting inflammation. This study provides new insights into RA theranostics, therapeutic monitoring, the design of multifunctional theranostic probes, and beyond.
Assuntos
Antirreumáticos , Artrite Reumatoide , Camundongos , Animais , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Metaloproteinase 2 da Matriz , Nanomedicina Teranóstica , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Tomografia Computadorizada por Raios XRESUMO
The ability of nanocarriers to enter tumor cells can be enhanced by positive surface charge. Nonetheless, the relationship between the spatial distributions of cationic groups and the endocytosis and tumor penetration of nanocarriers remains largely elusive. Here, using quaternary ammonium salt (QAS) as a model cationic group, a series of hybrid micelles (HMs) bearing QAS with different spatial distributions were prepared from star-shaped polymers with well-defined molecular architectures. The structural characteristics of HM, such as spatial location of QAS and local poly(ethylene glycol) (PEG) density near QAS, were investigated by both experimental techniques and dissipative particle dynamics (DPD) simulation. We show that the drug carriers with QAS extending to the micellar outer space allows QAS to facilitate cell surface binding with minimized hindrance, resulting in greatly enhanced endocytosis compared with nanocarriers with QAS attached onto the micellar surface or shielded by a PEG corona. This study offers cues for future development of tumor-penetrating drug delivery systems.
RESUMO
Carbon quantum dots (CDs) have attracted more and more attention in the field of biological imaging, while their applications are restricted due to their nonspecific fluorescence and small particle size. Herein, two pH-responsive carbon quantum dot-doxorubicin (DOX) conjugates were designed with maleic acid (MA, cis-butenedioic acid) and fumaric acid (FA, trans-butenedioic acid) as linker, respectively, which could self-assemble into unique hybrid micelles as tumor-specific carrier-free nanotheranostics. Owing to the acid-labile covalent modification with conjugated groups and the interaction with the surrounding DOX molecules, the fluorescence of CDs was completely quenched, while it could be recovered in the tumor intracellular microenvironment by acid-triggered cleavage of the fluorophore-drug conjugates, showing excellent turn-on fluorescence for effective cellular imaging. Especially, the trans conjugate with FA as linker possessed higher drug content, better drug release behavior and stronger inhibition of tumor cells than the cis one with MA as linker, demonstrating its promising potential as carrier-free nanotheranostics for future tumor treatment.
Assuntos
Micelas , Pontos Quânticos , Pontos Quânticos/química , Nanomedicina Teranóstica , Carbono/química , Fluorescência , Doxorrubicina/farmacologia , Doxorrubicina/química , Concentração de Íons de HidrogênioRESUMO
The aim of this study was to provide a new effective carrier for rescuing the sensitivity of drug-resistant in breast cancer cells. Nano-gold micelles loaded with Dox and Elacridar (FP-ssD@A-E) were chemically synthesised. With the increase in the amount of Dox and Elacridar, the encapsulation rate of FP-ssD@A-E gradually increased, and the drug loading rate gradually decreased. FP-ss@A-E had a sustained-release effect. Dox, Elacridar, FP-ss@AuNPs, and FP-ssD@A-E significantly improved cell apoptosis, in which, FP-ssD@A-E was the most significant. FP-ssD@A-E significantly decreased the cell viability and improved the Dox uptake. The levels of VEGFR-1, P-gp, IL-6, and i-NOS were significantly decreased after Dox, Dox + Elacridar, FP-ss@AuNPs, and FP-ssD@A-E treatment. It was worth noting that FP-ssD@A-E had the most significant effects. The prepared FP-ssD@A-E micelles, which were spherical in shape, uniform in particle size distribution, and had good drug loading performance and encapsulation efficiency.
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Neoplasias da Mama , Nanopartículas Metálicas , Humanos , Feminino , Micelas , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/farmacologia , Ouro , Resistência a Medicamentos , Portadores de Fármacos/uso terapêutico , Linhagem Celular TumoralRESUMO
We report on the effect of a hydrocarbon (n-dodecane) on the rheological properties and shapes of the hybrid wormlike micelles (WLMs) of a surfactant potassium oleate with an embedded polymer poly(4-vinylpyridine). With and without hydrocarbon solutions, the hybrid micelles exhibit the same values of viscosity at shear rates typical for hydraulic fracturing (HF) tests, as solutions of polymer-free WLMs. Therefore, similar to WLMs of surfactants, they could be applied as thickeners in HF fluids without breakers. At the same time, in the presence of n-dodecane, the hybrid micelles have much higher drag-reducing efficiency compared to microemulsions formed in polymer-free systems since they form "beads-on-string" structures according to results obtained using cryo-transmission electron microscopy (cryo-TEM), dynamic-light scattering (DLS), and small-angle X-ray scattering (SAXS). Consequently, they could also act as drag-reducing agents in the pipeline transport of recovered oil. Such a unique multi-functional additive to a fracturing fluid, which permits its concurrent use in oil production and oil transportation, has not been proposed before.
RESUMO
Salt-induced structural transformation of charged hybrid surfactant/polymer micelles formed by potassium oleate and poly(4-vinylpyridine) was investigated by cryo-TEM, SANS with contrast variation, DLS, and 2D NOESY. Cryo-TEM data show, that at small salt concentration beads-on-string aggregates on polymer chains are formed. KCl induces the transformation of those aggregates into rods, which is due to the screening of the electrostatic repulsion between similarly charged beads by added salt. In a certain range of salt concentration, the beads-on-string aggregates coexist with the rodlike ones. In the presence of polymer, the sphere-to-rod transition occurs at higher salt concentration than in pure surfactant system indicating that hydrophobic polymer favors the spherical packing of potassium oleate molecules. The size of micelles was estimated by DLS. The rods that are formed in the hybrid system are much shorter than those in polymer-free surfactant solution suggesting the stabilization of the semi-spherical endcaps of the rods by embedded polymer. 2D NOESY data evidence that in the spherical aggregates the polymer penetrates deep into the core, whereas in tighter packed rodlike aggregates it is located mainly at core/corona interface. According to SANS with contrast variation, inside the rodlike aggregates the polymer adopts more compact coil conformation than in the beads-on-string aggregates. Such adaptive self-assembled polymer-surfactant nanoparticles with water-insoluble polymer are very promising for various applications including drag reduction at transportation of fluids.
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Glucose oxidase (GOD)-based starvation therapy (ST), which inhibits the growth and proliferation of cancer cells by consuming glucose, has attracted intensive attention as an emerging non-invasive method for fighting cancers. However, the enzyme activity of GOD is greatly limited inâ vivo because of its optimal catalytic activity in the temperature range of 43-60 °C. Herein, a photothermal-enhanced starvation strategy is developed based on our engineered organosilica hybrid micelles (TiO2-x @POMs-GOD), in which the fluoride-doped TiO2-x with photothermal properties is encapsulated in the cores of organosilica cross-linked micelles and GOD is immobilized on the carboxyl groups of PAA segments. With its internalization by cancer cells, the conjugated GOD can effectively deplete glucose to achieve the ST effect, which can be remarkably enhanced by the loaded fluoride-doped TiO2-x with NIR laser irradiation, thus cooperatively contributing to the efficient treatment of TiO2-x @POMs-GOD on various cancer cells. This suggests great potential for TiO2-x @POMs-GOD in photothermal-enhanced ST inâ vivo.
Assuntos
Hipertermia Induzida , Nanopartículas , Neoplasias , Fluoretos , Glucose , Glucose Oxidase , Humanos , Micelas , Neoplasias/tratamento farmacológico , Fototerapia/métodosRESUMO
Since block copolymers are able to self-assemble into various polymeric architectures, it is intriguing to explore a unique self-assembly strategy for polymers. Two different metallic oxides [manganese dioxide (MnO2) and zinc oxide (ZnO)] are displayed herein to demonstrate this self-assembly mechanism of polymers. In situ generation of metallic oxides induces self-assembly of block copolymers to form polymeric hybrid micelles with tunable stability in aqueous solutions. These final ZnO-cross-linked polymeric micelles exhibited a high drug loading capacity of 0.41 mg mg-1 toward doxorubicin (DOX), whereas DOX-loaded ZnO-cross-linked polymeric micelles could be broken down into Zn2+ and polymer scraps, which facilitated drug release in tumor microenvironments. Both in vitro and in vivo investigations showed that the drug-loaded ZnO-cross-linked polymeric micelles effectively suppressed tumor growth. Accordingly, the present study demonstrates a novel strategy of polymer self-assembly for fabricating polymeric architectures that can potentially provide insight for developing other polymeric architectures.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Micelas , Neoplasias/tratamento farmacológico , Microambiente Tumoral/efeitos dos fármacos , Resinas Acrílicas/química , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Compostos de Manganês/química , Nanopartículas Metálicas/química , Camundongos Endogâmicos BALB C , Neoplasias/patologia , Óxidos/química , Polietilenoglicóis/química , Óxido de Zinco/químicaRESUMO
Building novel functional nanomaterials with a polymer is one of the most dynamic research fields at present. Here, three amphiphilic block copolymers of 8-hydroxyquinoline derivative motifs (MQ) with excellent coordination function were synthesized by Reversible Addition-Fragmentation Chain Transfer Polymerization (RAFT) polymerization. The coordination micelles were prepared through the self-assembly process, which the MQ motifs were dispersed in the hydrophobic polystyrene (PSt) blocks and hydrophilic Poly(N-isopropylacrylamide (PNIPAM)) blocks, respectively. The dual-emission micelles including the intrinsic red light emission of quantum dots (QDs) and the coordination green light emission of Zn2+-MQ complexes were built by introducing the CdSe/ZnS and CdTe/ZnS QDs in the core and shell precisely in the coordination micelles through the coordination-driven self-assembly process. Furthermore, based on the principle of three primary colors that produce white light emission, vinyl carbazole units (Polyvinyl Carbazole, PVK) with blue light emission were introduced into the hydrophilic PNIPAM blocks to construct the white light micelles that possess special multi-emission properties in which the intrinsic red light emission of QDs, the coordination green light of Zn2+-MQ complexes, and the blue light emission of PVK were synergized. The dual and multi-emission hybrid micelles have great application prospects in ratiometric fluorescent probes and biomarkers.
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Purpose: Methotrexate (MTX) is a first-line drug for rheumatoid arthritis (RA)therapy. However, MTX monotherapy often results in irreversible joint damage due to its slow onset of action and long duration. microRNA-124 (miR-124) has shown direct bone protection activity against RA. A co-delivery system for MTX and microRNA combination may provide therapeutic synergy. Methods: Methotrexate-conjugated polymer hybrid micelles (M-PHMs) were prepared by self-assembly of two functional amphiphilic polymers (MTX-PEI-LA and mPEG-LA) at an optimized weight ratio. Incorporation of microRNA was achieved through electrostatic interactions between microRNA and cationic polymer MTX-PEI-LA. Cellular uptake, endosome escape, biodistribution, and therapeutic efficacy of M-PHMs/miR-124 complexes were investigated and evaluated in RAW264.7 cells and a rat adjuvant-induced arthritis (AIA) model. Results: M-PHMs/miR-124 complexes exhibited folate receptor-mediated uptake in activated RAW264.7 cells. miR-124 was able to escape from the endosome and down-regulate nuclear factor of activated T cells cytoplasmic1 (NFATc1). M-PHMs/miR-124 complexes accumulated in inflamed joints of AIA rats and showed superior therapeutic efficacy through both anti-inflammatory effect and direct bone protective effect. Combination of miR-124 and MTX in these micelles induced disease remission. Conclusions: M-PHMs/miR-124 was highly effective against RA through therapeutic synergy. Additional studies are warranted to further investigate its therapeutic potential and delineate its mechanisms of action.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Micelas , MicroRNAs/metabolismo , Polímeros/química , Animais , Artrite Reumatoide/sangue , Morte Celular/efeitos dos fármacos , Citocinas/sangue , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Receptor 1 de Folato/metabolismo , Hemólise/efeitos dos fármacos , Mediadores da Inflamação/sangue , Articulações/patologia , Ácido Linoleico/síntese química , Lipopolissacarídeos , Metotrexato/farmacologia , Camundongos , MicroRNAs/genética , Fatores de Transcrição NFATC/metabolismo , Polietilenoglicóis/síntese química , Polietilenoimina/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Células RAW 264.7 , Ratos , Distribuição Tecidual/efeitos dos fármacosRESUMO
Currently, the simple integration of multiple therapeutic agents within a single nanostructure for combating multidrug resistance (MDR) tumors yet remains a challenge. Herein, we report a photoresponsive nanocluster (NC) system prepared by installing polydopamine (PDA) nanoparticle clusters on the surface of d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) (a drug efflux inhibitor) micelles solubilized with IR780 (a photosensitizer) to achieve a combined chemotherapy (CT)/photothermal therapy (PTT)/photodynamic therapy (PDT) for drug-resistant breast cancer. Mediated by the fluorescence resonance energy transfer and radical scavenging properties of PDA, NC shows prominently quenched fluorescence emission (â¼78%) and inhibited singlet oxygen generation (â¼67%) upon exposure to near-infrared (NIR) light (808 nm, 0.5 W cm-2), favoring a highly efficient PTT module. Meanwhile, the photothermal heat can also boost the release of doxorubicin hydrochloride whose intracellular accumulation can be greatly enhanced by TPGS. Interestingly, the first NIR irradiation and subsequent incubation (â¼24 h) can induce the gradual relocation and disintegration of PDA nanoparticles, thereby leading to activated PDT therapy under the second irradiation. Upon the temporally controlled sequential application of PTT/PDT, the developed NC exhibited a great potential to treat MDR cancer both in vitro and in vivo. These findings suggest that complementary interactions among PTT/PDT/CT modalities can enhance the efficiency of the combined therapy for MDR tumor.
Assuntos
Doxorrubicina/química , Indóis/química , Micelas , Nanopartículas/química , Polímeros/química , Animais , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Indóis/farmacologia , Indóis/uso terapêutico , Raios Infravermelhos , Camundongos , Camundongos Nus , Nanopartículas/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Fototerapia , Polietilenoglicóis/química , Espécies Reativas de Oxigênio/metabolismo , Transplante HeterólogoRESUMO
PURPOSE: To enhance therapeutic efficacy and prevent phlebitis caused by Asulacrine (ASL) precipitation post intravenous injection, ASL-loaded hybrid micelles with size below 40 nm were developed to improve drug retention and tumor penetration. METHODS: ASL-micelles were prepared using different weight ratios of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethyleneglycol-2000 (DSPE-PEG2000) and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) polymers. Stability of micelles was optimized in terms of critical micelle concentration (CMC) and drug release properties. The encapsulation efficiency (EE) and drug loading were determined using an established dialysis-mathematic fitting method. Multicellular spheroids (MCTS) penetration and cytotoxicity were investigated on MCF-7 cell line. Pharmacokinetics of ASL-micelles was evaluated in rats with ASL-solution as control. RESULTS: The ASL-micelles prepared with DSPE-PEG2000 and TPGS (1:1, w/w) exhibited small size (~18.5 nm), higher EE (~94.12%), better sustained in vitro drug release with lower CMC which may be ascribed to the interaction between drug and carriers. Compared to free ASL, ASL-micelles showed better MCTS penetration capacity and more potent cytotoxicity. Pharmacokinetic studies demonstrated that the half-life and AUC values of ASL-micelles were approximately 1.37-fold and 3.49-fold greater than that of free ASL. CONCLUSIONS: The optimized DSPE-PEG2000/TPGS micelles could serve as a promising vehicle to improve drug retention and penetration in tumor.
Assuntos
Amsacrina/análogos & derivados , Antineoplásicos/farmacocinética , Micelas , Fosfatidiletanolaminas/química , Polietilenoglicóis/química , Amsacrina/química , Amsacrina/farmacocinética , Amsacrina/uso terapêutico , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Técnicas de Cultura de Células , Sobrevivência Celular , Preparações de Ação Retardada , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Células MCF-7 , Masculino , Nanopartículas/química , Tamanho da Partícula , Permeabilidade , Ratos , Ratos Sprague-Dawley , Propriedades de Superfície , Vitamina E/químicaRESUMO
Therapeutic efficacy of conventional single PEGylated polymeric micelles is significantly reduced by limited endocytosis and intracellular drug release. To improve drug delivery efficiency, poly (ethylene glycol)-block-poly (l-lactic acid)/(Arg-Gly-Asp-Phe)-poly (aminoethyl ethylene phosphate)-block-poly (l-lactic acid) (PEG-PLLA/RGDF-PAEEP-PLLA) hybrid micelles with tunable active targeting and acid/phosphatase-stimulated drug release are developed. The optimized hybrid micelles with 6 wt % of RGDF have favorable in vitro and in vivo activities. The hybrid micelles could temporarily shield the targeting efficacy of RGDF at pH 7.4 due to the steric effect exerted by concealment of RGDF peptides in the PEG corona, which strongly decreases the clearance by mononuclear phagocyte system and consequently improves the tumor accumulation. Inside the solid tumor with a lower acidic pH, the hybrid micelles restore the active tumor targeting property with exposed RGDF on the surface of the micelles because of the increased protonation and stretching degree of PAEEP blocks. RGDF-mediated endocytosis improves the tumor cell uptake. The hybrid micelles would also enhance intracellular drug release because of the hydrolysis of the acid/phosphatase-sensitivity of PAEEP blocks in endo/lysosome. Systemic administration of the hybrid micelles significantly inhibits tumor growth by 96% due to the integration of enhanced circulation time, tumor accumulation, cell uptake and intracellular drug release.
Assuntos
Fosfatase Ácida/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Doxorrubicina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Micelas , Polímeros/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
It has been widely accepted that lymph nodes (LNs) are critical targets of cancer vaccines and particles sized between 10 and 100 nm with a neutral or negative surface charge are preferred for lymphatic transfer after subcutaneous or intradermal injection. However their limited uptake by antigen presenting cells (APCs) and inadequate retention within LNs undoubtedly restrains their strength on activating T cell immunity. Here, we address this issue by tailoring the physicochemical properties of polymeric hybrid micelles (HMs), which are self-assembled from two amphiphilic diblock copolymers, poly-(ethylene glycol) phosphorethanolamine (PEG-PE) and polyethylenimine-stearic acid conjugate (PSA) via hydrophobic and electrostatic interactions. We successfully encapsulate melanoma antigen peptide Trp2 and Toll-like receptor-9 (TLR-9) agonist CpG ODN into HMs with a size of sub-30 nm. Their surface characteristics which are found closely related to their in vivo kinetics can be modulated by simply adjusting the molar ratio of PEG-PE and PSA. Our results demonstrated the optimized HMs with an equal mol of PEG-PE and PSA can potently target proximal LNs where their cargos are efficiently internalized by DCs. Furthermore, HMs mediated Trp2/CpG delivery system greatly expands antigen specific cytotoxic T lymphocytes (CTLs) and offers a strong anti-tumor effect in a lung metastatic melanoma model.
Assuntos
Antígenos de Neoplasias/administração & dosagem , Vacinas Anticâncer/administração & dosagem , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Linfonodos/efeitos dos fármacos , Nanocápsulas/química , Polímeros/química , Animais , Vacinas Anticâncer/química , Linhagem Celular Tumoral , Emulsões/química , Feminino , Neoplasias Pulmonares/imunologia , Linfonodos/química , Camundongos , Camundongos Endogâmicos C57BL , Micelas , Nanocápsulas/administração & dosagem , Resultado do TratamentoRESUMO
One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Camptotecina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Peróxido de Hidrogênio/metabolismo , Neoplasias/metabolismo , Animais , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/química , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Camundongos Endogâmicos BALB C , Micelas , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Oxirredução , Polímeros/administração & dosagem , Polímeros/química , Polímeros/farmacologia , Polímeros/uso terapêuticoRESUMO
There are several obstacles in the process of successful treatment of malignant tumors, including toxicity to normal cells, inefficiency of drug permeation and accumulation into the deep tissue of solid tumor, and multidrug resistance (MDR). In this work, we prepared docetaxel (DTX)-loaded hybrid micelles with DSPE-PEG and TPGS (TPGS/DTX-M), where TPGS serves as an effective P-gp inhibitor for overcoming MDR, and active targeting hybrid micelles (FA@TPGS/DTX-M) with targeting ligand of folate on the hybrid micelles surface offering active targeting to folate receptor-overexpressed tumor cells. A systematic comparative evaluation of these micelles on cellular internalization, sub-cellular distribution, antiproliferation, mitochondrial membrane potential, cell apoptosis and cell cycle, permeation and inhibition on 3-dimensional multicellular tumor spheroids, as well as antitumor efficacy and safety assay in vivo were well performed between sensitive KB tumors and resistant KBv tumors, and among P-gp substrate or not. We found that the roles of folate and TPGS varied due to the sensitivity of tumors and the loaded molecules in the micelles. Folate and folate receptor-mediated endocytosis played a leading role in internalization, permeation and accumulation for sensitive tumors and non-substrates of P-gp. On the contrary, TPGS played the predominant role which dramatically decreased the efflux of drugs both when the tumor is resistant and for P-gp substrate. These findings are very meaningful for guiding the design of carrier delivery system to treat tumors. The antitumor efficacy in xenograft nude mice model and safety assay showed that the TPGS/DTX-M and FA@TPGS/DTX-M significantly exhibited higher antitumor activity against resistant KBv tumors than the marketed formulation and normal micelles owing to the small size (approximately 20 nm), hydrophilic PEGylation, TPGS inhibition of P-gp function, and folate receptor-modified endocytosis, permeation and accumulation in solid tumor, as well as synergistic effects of DTX-induced cell division inhibition, growth restraint and TPGS-triggered mitochondrial apoptosis in tumor cells. In conclusion, folate-modified TPGS hybrid micelles provide a synergistic strategy for effective delivery of DTX into KBv cells and overcoming MDR.