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1.
Mater Sci Eng C Mater Biol Appl ; 128: 112261, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474820

RESUMO

Glioblastoma multiforme (GBM) remains a major cause of mortality because treatments are precluded by to the limited transport and penetration of chemotherapeutics across the blood-brain barrier. Pitavastatin (PTV) is a hydrophobic Food and Drug Administration (FDA)-approved anticholesterolemic agent with reported anti-GBM activity. In the present study, we encapsulate PTV in silica-coated polymeric micelles (SiO2 PMs) surface-modified with the cyclic peptide Arg-Gly-Asp-Phe-Val (cRGDfV) that actively targets the αvß3 integrin overexpressed in the BBB endothelium and GBM. A central composite design is utilized to optimize the preparation process and improve the drug encapsulation ratio from 131 to 780 µg/mL. The silica shell provides full colloidal stability upon extreme dilution and enables a better control of the release kinetics in vitro with 28% of the cargo released after 12 h. Furthermore, SiO2 PMs show excellent compatibility and are internalized by human BBB endothelial cells, astrocytes and pericytes, as shown by confocal laser scanning fluorescence microscopy and flow cytometry. Finally, the anticancer efficacy is assessed in a pediatric patient-derived glioma cell line expressing high levels of the integrin subunits αv, ß3 and ß5. This PTV-loaded nanocarrier triggers apoptosis by reducing the mRNA level of anti-apoptotic genes NF-kß, IL-6, BIRC1 and BIRC5 by 89%, 33%, 81% and 63%, respectively, and the cell viability by >60%. Overall, our results suggest the potential of these hybrid nanocarriers for the targeted therapy of GBM and other tumors overexpressing integrin receptors.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Criança , Células Endoteliais , Glioblastoma/tratamento farmacológico , Humanos , Integrinas , Micelas , Dióxido de Silício
2.
Mater Sci Eng C Mater Biol Appl ; 128: 112317, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34474868

RESUMO

Acid-triggered degradable polyprodrug P(DOX-AH) was designed for long-acting drug delivery with minimal leakage and enhanced antitumor efficacy. By facile polymerization of doxorubicin (DOX) and N-(tert-butoxycarbonyl)acryloylhydrazine (Boc-AH), P(DOX-AH) with drug as unique repeating unit was obtained, possessing an ultrahigh drug content. It was stable in the neutral media but could degrade completely into DOX-AH in the acidic media without any other by-product. The cleavage of the hydrazone linkage between the DOX-AH repeating units was revealed by the LC-MS/MS analysis. Furthermore, a slow solubility-controlled drug release performance was achieved in the acidic media because of the low solubility of the released DOX-AH. Even with the slow DOX-AH releasing, the enhanced antitumor efficacy was obtained than free DOX in the in vitro cellular experiments. These features demonstrated the promising potential of the proposed polyprodrug for long-acting drug delivery in future tumor chemotherapy.


Assuntos
Polímeros , Espectrometria de Massas em Tandem , Cromatografia Líquida , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Micelas
3.
Anal Chem ; 93(36): 12346-12352, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34469684

RESUMO

Synthetic DNA walkers are artificially designed DNA self-assemblies with the capability of performing quasi-mechanical movement at the micro/nanoscale and have shown extensive promise in biosensing, intracellular imaging, and drug delivery. However, DNA walkers are usually constructed by covalently or coordinately binding DNA strands specifically to hard surfaces, thereby greatly limiting their movement efficiency. Herein, we report an intraparticle and interparticle transferable DNA walker (dynamic micelle-supported DNA walker, DM-walker) constructed by immobilizing walking tracks and walking arms onto the corona of DNA micelles according to the principle of Watson-Crick base pairing. The DNAzyme-powered walking arm can drive the intraparticle and interparticle movements of the DM-walker due to the fact that the dynamic structure of the DNA micelle helps overcome the spatial barrier between the arms and tracks in the system, resulting in high walking efficiency. Moreover, the whole DM-walker can be constructed by self-assembly, getting rid of the tedious process and low efficiency of fixing DNA strands on hard surfaces. Taking miRNA-10b as a model target, the DM-walker demonstrates high walking efficiency (reaction duration of 20 min) and high sensitivity (LOD of 87 pM). The proposed DM-walker provides an avenue to develop novel DNA walkers on dynamic interfaces and holds great potential in clinical diagnosis.


Assuntos
Técnicas Biossensoriais , MicroRNAs , DNA , Limite de Detecção , Micelas , Andadores
4.
Nanoscale ; 13(32): 13758-13763, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34477650

RESUMO

Here, we report how the nature of the hydrophobic core affects the molecular interactions of DNA block copolymer assemblies. Three different amphiphilic DNA block copolymers, DNA-b-polystyrene (DNA-b-PS), DNA-b-poly(2-vinylpyridine) (DNA-b-P2VP), and DNA-b-poly(methyl acrylate) (DNA-b-PMA) were synthesized and assembled into spherical micelles composed of a hydrophobic polymer core and DNA corona. Interestingly, DNA block copolymer micelles having different hydrophobic cores exhibited markedly different molecular and biological interactions. DNA-b-PS exhibited higher melting temperature, sharper melting transition, higher stability to nuclease-catalyzed DNA degradation, and higher cellular uptake efficiency compared to DNA-b-P2VP and DNA-b-PMA. The investigation of the self-assembly behavior revealed a much higher aggregation number and DNA density for DNA-b-PS micelles, which explains the superior properties of DNA-b-PS. These results demonstrate that the type of the hydrophobic core polymer, which has been largely overlooked, has a profound impact on the molecular and biological interactions of the DNA shell.


Assuntos
Micelas , Polímeros , DNA , Interações Hidrofóbicas e Hidrofílicas , Poliestirenos
5.
Nanoscale ; 13(31): 13328-13343, 2021 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-34477739

RESUMO

Facing the barriers in each step of the in vivo delivery cascade, the low drug delivery efficiency remains problematic in tumor therapy. Although recently the nanofibril drug delivery systems have shown improved circulation and accumulation compared with nanoparticles, the poor deep penetration and cellular internalization hinder their application, especially for pancreatic cancer with dense stroma. To comprehensively address the hurdles in the delivery cascade, a matrix metalloproteinase 2 (MMP-2) responsive transformable beaded nanofibril, which integrates the merits of nanofibril and small-sized nanoparticles, is established. The beaded nanofibril (GD@PPF) is prepared by conjugating gemcitabine-loaded small-sized nanoparticles (GD) with fibrous PEG-PCL (PPF) via GPLGVRG, a substrate peptide of MMP-2. GD@PPF escapes the clearance of the reticuloendothelial system (RES), prolongs the circulation time, and increases the selective accumulation in the tumor as fibrous micelles. Once accumulated in the tumor, small positively-charged GD is released from the beaded nanofibrils in response to MMP-2 overexpression in the stroma of pancreatic cancer, enabling permeation in the dense tumor matrix and cellular internalization, which makes up for the shortcomings of fibrous micelles. Furthermore, the remaining fibrous PPF surround the tumor tightly to impede the efflux of drugs, leading to improved retention. GD@PPF is biocompatible and exhibits excellent antitumor effect in Pan 02 subcutaneous tumor models. Therefore, the MMP-2 responsive transformable beaded nanofibril, which enhances the delivery efficiency in multiple stage of the delivery cascade, presents a promising strategy for pancreatic cancer therapy.


Assuntos
Nanopartículas , Neoplasias Pancreáticas , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Metaloproteinase 2 da Matriz , Micelas , Neoplasias Pancreáticas/tratamento farmacológico
6.
Biomater Sci ; 9(18): 6108-6115, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34369491

RESUMO

Nanomedicines have been widely used in the effective delivery of chemotherapeutic drugs due to their advantages such as increasing the half-life of drugs, selectively targeting tumor tissues, and thus reducing systemic toxicity. However, the low drug entrapment rate and the difficulty of real-controlled release at tumor sites hinder their further clinical translations. Here we have developed biodegradable polyionic micelles (PD-M) to facilitate black phosphorus (BP) encapsulation (PD-M@BP) for improved drug loading. With the introduction of BP, PTX-loaded PD-M@BP (PD-M@BP/PTX) with sizes of 124-162 nm exhibited superior encapsulation efficiency over 94% and excellent colloidal stability. Meanwhile, PD-M well protected BP from fast degradation to show the good photothermal performance under near-infrared (NIR) irradiation, thus achieving the remotely controlled fast PTX release due to micelle core melting and dissociation, accompanied by the synergistic photothermal tumor therapy. The in vivo results demonstrated that the PD-M@BP/PTX nanosystem not only realized significant inhibition of multi-drug resistant (MDR) cervical tumors (HeLa/PTXR tumor) by remote NIR-regulation, but also reduced the potential damage of chemotherapeutic drugs to the whole body, rendering these hybrid nanosystems as great tools to treat MDR tumors synergistically.


Assuntos
Micelas , Neoplasias , Preparações de Ação Retardada , Humanos , Nanomedicina , Fósforo
7.
J Am Chem Soc ; 143(33): 13205-13211, 2021 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-34375093

RESUMO

The receptor binding and proteolysis of Spike of SARS-CoV-2 release its S2 subunit to rearrange and catalyze viral-cell fusion. This deploys the fusion peptide for insertion into the cell membranes targeted. We show that this fusion peptide transforms from intrinsic disorder in solution into a wedge-shaped structure inserted in bilayered micelles, according to chemical shifts, 15N NMR relaxation, and NOEs. The globular fold of three helices contrasts the open, extended forms of this region observed in the electron density of compact prefusion states. In the hydrophobic, narrow end of the wedge, helices 1 and 2 contact the fatty acyl chains of phospholipids, according to NOEs and proximity to a nitroxide spin label deep in the membrane mimic. The polar end of the wedge may engage and displace lipid head groups and bind Ca2+ ions for membrane fusion. Polar helix 3 protrudes from the bilayer where it might be accessible to antibodies.


Assuntos
Micelas , Peptídeos/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/química , COVID-19/patologia , COVID-19/virologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Peptídeos/química , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , SARS-CoV-2/isolamento & purificação , Glicoproteína da Espícula de Coronavírus/metabolismo
8.
Food Res Int ; 147: 110451, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399453

RESUMO

Skim milk concentrates have important applications in the dairy industry, often as intermediate ingredients. Concentration of skim milk by reverse osmosis membrane filtration induces water removal, which reduces the free volume between the colloidal components, in particular the casein micelles. Thermal treatment before or after concentration impacts the morphology of casein micelles. These changes affect the flow behavior and viscosity, but the consequences for supermicellar structure have not been elucidated. In the present study, skim milk concentrates with different total solid contents from 8.7% (control) up to 22.8% (w/w), prepared by reverse osmosis membrane filtration of non-heated and pasteurized skim milk, were heat treated at 75 °C for 18 s, and compared with non-heated concentrates. The structure of the concentrates was studied using Ultra Small Angle X-ray Scattering (USAXS), and the viscosity of concentrates was measured. The USAXS intensity I(q) was fitted at small and intermediate q-regions (0.0005 < q < 0.003 Å-1 and 0.0035 < q < 0.03 Å-1, respectively) with a power law. The value of the power law exponent was used to assess the heat- and concentration-induced aggregation of the milk solids and correlate it with the apparent viscosity. The results showed that increased viscosity of skim milk concentrates, due to water removal and heat-load, can be explained by increased aggregation of the casein micelles into elongated aggregates and increased smoothening of the casein micelle surface.


Assuntos
Caseínas , Micelas , Animais , Leite , Viscosidade , Raios X
9.
Biomater Sci ; 9(17): 5977-5987, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34338256

RESUMO

Nanodrug delivery systems have been used extensively to improve the tumor-targeting ability and reduce the side effects of anticancer drugs. In this study, nanomicelles responsive to dual stimuli were designed and developed as drug carriers for delivering doxorubicin (DOX). The hydrophobic group of the nanomicelles was composed of the photosensitizer protoporphyrin IX (PpIX) and the disulfide bond-containing alpha-lipoic acid (LA); the hydrophilic group was made up of the nuclear localization signal (NLS, CGGGPKKKRKVGG) peptide with a lysine linker. Furthermore, anionic cyclo-γ-polyglutamic acid (cyclo-γ-PGA) was coated on the surface of the cationic micelles to construct a multifunctional drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA). Cyclo-γ-PGA, as a biological coating material, notably improved the stability of the cationic micelles by reducing nonspecific reactions with anionic groups. Additionally, the cyclo-γ-PGA coating mediated active tumor targeting and enhanced the cellular uptake of micelles via the γ-glutamyl transpeptidase (GGT) pathway. The integrated micelles not only achieved photochemical internalization (PCI) and photodynamic therapy (PDT) via light-activated reactive oxygen species (ROS) but also realized controlled intracellular drug release via the glutathione (GSH)-responsive disulfide-bond cleavage. As a result, NLS-LA-PpIX-DOX@cyclo-γ-PGA exhibited excellent synergistic chemo-photodynamic antitumor activity and fewer side effects than other therapies both in vitro and in vivo. In conclusion, this new dual-responsive drug delivery system (NLS-LA-PpIX-DOX@cyclo-γ-PGA) with improved stability and enhanced tumor-targeting ability may facilitate the development of high-efficiency and low-toxicity nanotherapeutic approaches.


Assuntos
Fotoquimioterapia , Ácido Poliglutâmico , Doxorrubicina/farmacologia , Portadores de Fármacos , Liberação Controlada de Fármacos , Micelas , Ácido Poliglutâmico/análogos & derivados
10.
Soft Matter ; 17(33): 7769-7780, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34351343

RESUMO

The self-assembly in mixtures of the anionic bile salt surfactant sodium deoxycholate (NaDC) and the zwitterionic phospholipid 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) in physiological saline solution has been investigated using light scattering, small-angle X-ray scattering and cryo-transmission electron microscopy. Rather small tri-axial ellipsoidal NaDC-DMPC mixed micelles form at a high content of bile salt in the mixture, which increase in size as an increasing amount of DMPC is incorporated into the micelles. Eventually, the micelles begin to grow substantially in length to form long wormlike micelles. At higher mole fractions of DMPC, the samples become turbid and cryo-TEM measurements reveal the existence of large perforated vesicles (stomatosomes), coexisting with geometrically open disks. To our knowledge, stomatosomes have not been observed before for any bile salt-phospholipid system. Mixed micelles are found to be the sole aggregate structure in a very wide regime of bile salt-phospholipid compositions, i.e. up to about 77 mol% phospholipid in the micelles. This is much higher than the corresponding value of 25 mol% observed for the conventional surfactant hexadecyltrimethylammonium bromide (CTAB) mixed with DMPC in the same solvent. The enhanced ability of bile salt surfactants to solubilize phospholipid bilayers and form mixed micelles is rationalized using bending elasticity theory. From our theoretical analysis, we are able to conclude that amphiphilic molecules rank in the following order of increasing spontaneous curvature: phospholipids < conventional surfactants < bile salts. The bending rigidity of the different amphiphilic molecules increases according to the following sequence: bile salts < conventional surfactants < phospholipids.


Assuntos
Micelas , Fosfolipídeos , Ácidos e Sais Biliares , Ácido Desoxicólico , Tensoativos
11.
Eur J Pharm Sci ; 166: 105960, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34339828

RESUMO

Our study aimed to formulate a novel dexamethasone (DXM)-loaded, mixed polymeric micelle-based drug delivery system, focusing on the auspicious nose-to-brain pathway, as a key delivery route to treat central nervous system (CNS) associated diseases. Polymeric micelles might be a solution to deliver drugs to the place of action compared to conventional formulations. Due to low Z-average (89.92 ± 2.7 nm), a polydispersity index of 0.216 ± 0.014 and high surface polarity (52.23%), a significant increase in water solubility (14-fold) was experienced. This increase resulted in favourable dissolution profile at nasal and axonal conditions with high in vitro permeability value (14.6×10-6 cm/s) on polar brain (porcine) lipid extract. Modified Side-bi-side® type diffusion study confirmed rapid and efficient passive diffusion through the nasal mucosa contributed by strong mucoadhesive properties. The final formulation met all the requirements of a nasal drug delivery system with rapid onset of action, meaning DXM can reach the CNS and there it can exert its beneficial effects in pathological conditions.


Assuntos
Portadores de Fármacos , Micelas , Animais , Dexametasona , Sistemas de Liberação de Medicamentos , Tamanho da Partícula , Polímeros , Solubilidade , Suínos
12.
Eur J Pharm Sci ; 166: 105978, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34418574

RESUMO

The current research article focused on formulating an easily applied, water-based buccal film loaded with the antiepileptic drug, lamotrigine (LTG). The designed film can be comfortably administered by epileptic patients to ensure a controllable therapeutic efficacy against seizures. The solubility of LTG in water was significantly improved by micellar solubilization. Upon testing several surfactants, three of them (Synperonic PE/P84, Brij L23, and Brij 78) achieved maximum possible solubility for LTG and were characterized for their micellar size, cloud point, and % transmittance. Selected micellar systems were incorporated within a buccal film prepared using solvent casting method based on either gelatin or polyvinylpyrrolidone (3%w/v) with 1.5%w/v propylene glycol as a plasticizer. Different micellar films were characterized for their physicochemical characteristics, swelling index, folding endurance, drug content uniformity, and in vitro LTG release. From the tested formulations, one formulation; LTG-BF1 (in which Brij 78 was used for the micellar solubilization and gelatin as the matrix former), was selected as the optimum and extensively studied for mucoadhesion, ex vivo permeation studies by Franz diffusion cells and confocal laser scanning microscopy. Results showed superior enhanced permeation of micellar film. LTG-BF1 was evaluated for the in vivo performance using rats. Status epilepticus was induced in rats by injecting Pentylenetetrazol (PTZ) i.p. at an initial dose of 30 mg/kg, followed by 10 mg/kg every10 min till 60 min. A group of rats receiving the designed buccal formulation (20 mg/kg) was compared with a group receiving the same dose of the oral market product and the normal control and PTZ groups. Rats receiving LTG-BF1 recorded reduced seizure scores at all stages, longer latency time, and higher threshold PTZ dose compared to PTZ and market product groups. In addition, LTG-BF1 reduced brain concentrations of TNF-α and TGF-ß with an elevation of EAAT2 and GABA brain contents compared to PTZ and market product groups and ameliorated neuronal damage. In conclusion, LTG-loaded buccal micellar film proved a superior antiepileptic effect in PTZ induced acute epileptic model.


Assuntos
Micelas , Convulsões , Animais , Anticonvulsivantes/uso terapêutico , Humanos , Lamotrigina , Pentilenotetrazol , Ratos , Convulsões/tratamento farmacológico
13.
Molecules ; 26(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34443601

RESUMO

Surfactant aggregates have long been considered as a tool to improve drug delivery and have been widely used in medical products. The pH-responsive aggregation behavior in anionic gemini surfactant 1,3-bis(N-dodecyl-N-propanesulfonate sodium)-propane (C12C3C12(SO3)2) and its mixture with a cationic monomeric surfactant cetyltrimethylammonium bromide (CTAB) have been investigated. The spherical-to-wormlike micelle transition was successfully realized in C12C3C12(SO3)2 through decreasing the pH, while the rheological properties were perfectly enhanced for the formation of wormlike micelles. Especially at 140 mM and pH 6.7, the mixture showed high viscoelasticity, and the maximum of the zero-shear viscosity reached 1530 Pa·s. Acting as a sulfobetaine zwitterionic gemini surfactant, the electrostatic attraction, the hydrogen bond and the short spacer of C12C3C12(SO3)2 molecules were all responsible for the significant micellar growth. Upon adding CTAB, the similar transition could also be realized at a low pH, and the further transformation to branched micelles occurred by adjusting the total concentration. Although the mixtures did not approach the viscosity maximum appearing in the C12C3C12(SO3)2 solution, CTAB addition is more favorable for viscosity enhancement in the wormlike-micelle region. The weakened charges of the headgroups in a catanionic mixed system minimizes the micellar spontaneous curvature and enhances the intermolecular hydrogen-bonding interaction between C12C3C12(SO3)2, facilitating the formation of a viscous solution, which would greatly induce entanglement and even the fusion of wormlike micelles, thus resulting in branched microstructures and a decline of viscosity.


Assuntos
Reologia , Tensoativos/química , Cetrimônio/química , Glutamatos/química , Concentração de Íons de Hidrogênio , Micelas , Viscosidade
14.
Langmuir ; 37(32): 9701-9710, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34339198

RESUMO

The interfacial properties of surfactant solutions are closely related to the micellization of surfactants. Temperature, salt type and concentration, pH, and other parameters affecting the micellization of surfactants have all been extensively investigated previously. However, the effect of dissolved gas on surfactant micellization and associated interfacial properties' transformations is not completely understood yet. In this study, sodium oleate (NaOl) was chosen as the research object, and the role of gas/gas nucleation in NaOl micellization was systematically investigated. The results indicated that the solution changed to be more turbid and the dissolved oxygen content increased after NaOl solutions were subjected to compression-decompression treatments. Meanwhile, the surface tension of the NaOl solution was altered, which was more pronounced when the concentration of NaOl was close to the critical micelle concentration. Given that the surface tension was a good indicator of the assembly and distribution state of the soluble monomers and insoluble micelles of NaOl, interactions between nucleated bubbles originating from the gas nucleation and NaOl molecules were unveiled through the analysis of the size distribution and zeta potential of sub-micro- and nanoscale particles in bulk solutions. Finally, possible micellization models of NaOl molecules, fully considering the role of gas/gas nucleation, were proposed under varying NaOl concentration conditions.


Assuntos
Micelas , Ácido Oleico , Tensão Superficial , Tensoativos
15.
Macromol Rapid Commun ; 42(17): e2100312, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34347312

RESUMO

Amphiphilic diblock copolymers containing dopamine and zwitterions are synthesized via the RAFT polymerization method, which undergo temperature-mediated micellization in aqueous media. The presence of catechol moiety in dopamine is exploited to form pH-responsive cross-links with ferric ions (Fe3+ ) at different pH value. Herein, a comprehensive study of the effect of pH as well as temperature on the size and solution behavior of these cross-linked micelles is presented. These micelles cross-linked via metal-catechol coordination bonds can have several important biomedical applications such as degradable scaffolds for payload delivery.


Assuntos
Micelas , Polímeros , Polimerização , Temperatura
16.
Nat Commun ; 12(1): 4755, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362890

RESUMO

Some specific chemotherapeutic drugs are able to enhance tumor immunogenicity and facilitate antitumor immunity by inducing immunogenic cell death (ICD). However, tumor immunosuppression induced by the adenosine pathway hampers this effect. In this study, E-selectin-modified thermal-sensitive micelles are designed to co-deliver a chemotherapeutic drug (doxorubicin, DOX) and an A2A adenosine receptor antagonist (SCH 58261), which simultaneously exhibit chemo-immunotherapeutic effects when applied with microwave irradiation. After intravenous injection, the fabricated micelles effectively adhere to the surface of leukocytes in peripheral blood mediated by E-selectin, and thereby hitchhiking with leukocytes to achieve a higher accumulation at the tumor site. Further, local microwave irradiation is applied to induce hyperthermia and accelerates the release rate of drugs from micelles. Rapidly released DOX induces tumor ICD and elicits tumor-specific immunity, while SCH 58261 alleviates immunosuppression caused by the adenosine pathway, further enhancing DOX-induced antitumor immunity. In conclusion, this study presents a strategy to increase the tumor accumulation of drugs by hitchhiking with leukocytes, and the synergistic strategy of chemo-immunotherapy not only effectively arrested primary tumor growth, but also exhibited superior effects in terms of antimetastasis, antirecurrence and antirechallenge.


Assuntos
Tratamento Farmacológico , Imunoterapia , Leucócitos/efeitos dos fármacos , Micelas , Neoplasias/terapia , Animais , Doxorrubicina/farmacologia , Portadores de Fármacos/administração & dosagem , Liberação Controlada de Fármacos , Feminino , Hipertermia/terapia , Imunidade , Camundongos , Camundongos Endogâmicos BALB C , Micro-Ondas/uso terapêutico , Fototerapia
17.
Nutrients ; 13(7)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34371895

RESUMO

BACKGROUND: Curcumin, a natural polyphenol and the principal bioactive compound in Curcuma longa, was reported to have anti-inflammatory, anti-cancer, anti-diabetic and anti-rheumatic activity. Curcumin is not only considered for preventive, but also for therapeutic, purposes in cancer therapy, which requires a killing effect on cancer cells. A drawback, however, is the low bioavailability of curcumin due to its insolubility in water. To circumvent this limitation, curcumin was administered in different water-soluble formulations, including liposomes or embedded into nanoscaled micelles. The high uptake rate of micellar curcumin makes it attractive also for cancer therapeutic strategies. Native curcumin solubilised in organic solvent was previously shown to be cytotoxic and bears a genotoxic potential. Corresponding studies with micellar curcumin are lacking. METHODS: We compared the cytotoxic and genotoxic activity of native curcumin solubilised in ethanol (Cur-E) with curcumin embedded in micells (Cur-M). We measured cell death by MTT assays, apoptosis, necrosis by flow cytometry, senolysis by MTT and C12FDG and genotoxicity by FPG-alkaline and neutral singe-cell gel electrophoresis (comet assay). RESULTS: Using a variety of primary and established cell lines, we show that Cur-E and Cur-M reduce the viability in all cell types in the same dose range. Cur-E and Cur-M induced dose-dependently apoptosis, but did not exhibit senolytic activity. In the cytotoxic dose range, Cur-E and Cur-M were positive in the alkaline and the neutral comet assay. Genotoxic effects vanished upon removal of curcumin, indicating efficient and complete repair of DNA damage. For inducing cell death, which was measured 48 h after the onset of treatment, permanent exposure was required while 60 min pulse-treatment was ineffective. In all assays, Cur-E and Cur-M were equally active, and the concentration above which significant cytotoxic and genotoxic effects were observed was 10 µM. Micelles not containing curcumin were completely inactive. CONCLUSIONS: The data show that micellar curcumin has the same cytotoxicity and genotoxicity profile as native curcumin. The effective concentration on different cell lines, including primary cells, was far above the curcumin concentration that can be achieved systemically in vivo, which leads us to conclude that native curcumin and curcumin administered as food supplement in a micellar formulation at the ADI level are not cytotoxic/genotoxic, indicating a wide margin of safety.


Assuntos
Apoptose/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Curcumina/toxicidade , Dano ao DNA , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Curcumina/química , Relação Dose-Resposta a Droga , Composição de Medicamentos , Etanol/química , Humanos , Lipossomos , Micelas , Necrose , Medição de Risco , Solubilidade , Solventes/química
18.
Molecules ; 26(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206391

RESUMO

Rapid chromatographic procedure for quantification of five sulfonamides in medicated feeds are proposed. Satisfactory separation of sulfonamides from medicated feeds was achieved using a Zorbax Eclipse XDB C18 column (4.6 × 150 mm, 5 µm particle size) with a micellar mobile phase consisting of 0.05 M sodium dodecyl sulphate, 0.02 M phosphate buffer, and 6% propan-2-ol (pH 3). UV quantitation was set at 260 nm. The proposed procedure allows the determination of sulfaguanidine, sulfadiazine, sulfamerazine, sulfamethazine, and sulfamethoxazole in medicated feeds for pigs and poultry. Application of the proposed method to the analysis of five pharmaceuticals gave recoveries between 72.7% to 94.7% and coefficients of variations for repeatability and reproducibility between 2.9% to 9.8% respectively, in the range of 200 to 2000 mg/kg sulfonamides in feeds. Limit of detection and limit of quantification were 32.7-56.3 and 54.8-98.4 mg/kg, respectively, depending on the analyte. The proposed procedure for the quantification of sulfonamides is simple, rapid, sensitive, free from interferences and suitable for the routine control of feeds. In the world literature, we did not find the described method of quantitative determination of sulfonamides in medicated feeds with the use of micellar liquid chromatography.


Assuntos
Ração Animal/análise , Sulfonamidas/análise , Animais , Micelas , Suínos
19.
Macromol Rapid Commun ; 42(17): e2100298, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34242443

RESUMO

8-Shaped copolymers with two macrocycles connected together represent an interesting cyclic topology-derived polymer species due to the simultaneous incorporation of two cyclic moieties and the reported unique physical and chemical properties. To provide a proof-of-concept for a broad readership on biomedical polymers, a well-defined hetero-8-shaped amphiphilic copolymer, cyclic-poly(oligo(ethylene glycol)monomethyl ether methacrylate)-b-cyclic PCL (cPOEGMA-b-cPCL) is synthesized by an elegant integration of intrachain click cyclization and interchain click coupling. The potential of the self-assembled micelles of cPOEGMA-b-cPCL for controlled drug release is evaluated by in vitro drug loading and drug release, cellular uptake, cytotoxicity, and degradation studies. Most importantly, the micelles based on cPOEGMA-b-cPCL show much slower degradation profiles than the previously reported linear counterpart, POEGMA-b-PCL and tadpole-shaped analog, PEG-b-cPCL because of the presence of cyclic hydrophilic POEGMA segment. Therefore, this study not only develops a robust strategy for a universal precise synthesis of well-defined hetero-8-shaped copolymers based on diverse vinyl and ring-structured monomers, but also reveals the first modulation of polymer degradation property by topological control of the nondegradable moiety in the polymer construct through advanced macromolecular engineering.


Assuntos
Micelas , Polímeros , Portadores de Fármacos , Liberação Controlada de Fármacos , Substâncias Macromoleculares , Metacrilatos , Polietilenoglicóis
20.
Molecules ; 26(14)2021 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-34299617

RESUMO

Oligomeric surfactants display the novel properties of low surface activity, low critical micellar concentration and enhanced viscosity, but no CO2 switchable oligomeric surfactants have been developed so far. The introduction of CO2 can convert tertiary amine reversibly to quaternary ammonium salt, which causes switchable surface activity. In this study, epoxidized soybean oil was selected as a raw material to synthesize a CO2-responsive oligomeric surfactant. After addition and removal of CO2, the conductivity analyzing proves that the oligomeric surfactant had a good response to CO2 stimulation. The viscosity of the oligomeric surfactant solution increased obviously after sparging CO2, but returned to its initial low viscosity in the absence of CO2. This work is expected to open a new window for the study of bio-based CO2-stimulated oligomeric surfactants.


Assuntos
Dióxido de Carbono/química , Óleo de Soja/química , Soja/química , Tensoativos/química , Aminas/química , Micelas , Compostos de Amônio Quaternário/química , Viscosidade , Água/química
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