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Multiresponsive hydrogels are valuable as biomaterials due to their ability to respond to multiple biologically relevant stimuli, i.e., temperature, pH, or reactive oxygen species (ROS), which can be present simultaneously in the body. In this work, we synthesize triple-responsive hydrogels through UV light photopolymerization of selected monomer compositions that encompass thermoresponsive N-isopropylacrylamide (NIPAM), pH-responsive methacrylic acid (MAA), and a tailor-made ROS-responsive diacrylate thioether monomer (EG3SA). As a result, smart P[NIPAMx-co-MAAy-co-(EG3SA)z] hydrogels capable of being manufactured by digital light processing (DLP) 4D printing are obtained. The thermo-, pH-, and ROS-response of the hydrogels are studied by swelling tests and rheological measurements at different temperatures (25 and 37 °C), pHs (3, 5, 7.4, and 11), and in the absence or presence of ROS (H2O2). The hydrogels are employed as matrixes for the encapsulation of ketoprofen (KET), an anti-inflammatory drug that shows a tunable release, depending on the hydrogel composition and stimuli applied. The cytotoxicity properties of the hydrogels are tested in vitro with mouse embryonic fibroblasts (NIH 3T3) and RAW 264.7 murine macrophage (RAW) cells. Finally, the anti-inflammatory properties are assessed, and the results exhibit a ≈70% nitric oxide reduction up to base values of pro-inflammatory RAW cells, which highlights the anti-inflammatory capacity of P[NIPAM80-co-MAA15-co-(EG3SA)5] hydrogels, per se, without being necessary to encapsulate an anti-inflammatory drug within their network. It opens the route for the fabrication of customizable 4D printable scaffolds for the effective treatment of inflammatory pathologies.
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Fabrication of batch-wise efficient, user- and environmentally-friendly, and well-defined yield methods for the synthesis of graphite oxide, the main precursor to graphene oxide and its reduced derivative, is an essential and robust research field, yet is sparingly investigated or innovated in recent years. This Concept review showcases recent advances in the fabrication of electrochemical set ups that meet aforementioned design parameters, wherein working electrode construction is seen to play a key role in shaping the yield characteristics and aiding the mechanistic understanding of efficiency of adopted methods. Particularly, these advances pave the way for new and various tunable design parameters by fabricating different methods of encapsulating graphite powder instead of using conventional bare monolith forms of graphite as working electrode. Encapsulation geometry, pressure, and matrix material, as well as powder size are examples of such tunable design parameters, absent in the monolith methods. The encapsulation validates authenticity of real-time monitoring of electrochemical intercalation, exfoliation, and oxidation of graphite powder, thereby offering excellent and well-defined control on yield.
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This study presents an optimized microwave-assisted method for the green synthesis of silver nanoparticles (AgNPs) using a root extract obtained from Pelargonium sidoides DC. The influence of temperature, reagent concentration, and irradiation time was systematically investigated to enhance synthesis yield. Characterization techniques including XRD, UV-vis, FTIR, XPS, and zetametry were employed to confirm the successful formation of nanoparticles with a metallic silver core (â¼17 nm) functionalized with organic molecules derived from the plant extract. The cytotoxicity of AgNPs was assessed using a cell viability assay, while the Minimum Inhibitory Concentration (MIC) of nanoformulation against pathogenic bacteria, including Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and the carbapenem-resistant Klebsiella pneumoniae (KPC), was determined using the Broth microdilution method. The nanoformulation synthesized with P. sidoides extract exhibited a dose-dependent response, demonstrating superior antimicrobial efficacy compared to the pure plant extract in most cases. The MIC values ranged from 0.85 to 17.1 µg mL-1, with particularly strong performance against the drug resistant KPC strain. The enhanced antimicrobial effect is attributed to the synergistic action of the metallic silver core and phytochemicals from P. sidoides on the surface of nanoparticles, which also contribute to notable colloidal stability of AgNPs at physiological pH levels.
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Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects synovial joints and that frequently involves extra-articular organs. A multiplicity of interleukins (IL) participates in the pathogenesis of RA, including IL-6, IL-1ß, transforming growth factor-beta (TGF-ß), and tumor necrosis factor (TNF)-α; immune cells such as monocytes, T and B lymphocytes, and macrophages; and auto-antibodies, mainly rheumatoid factor and anti-citrullinated protein antibodies (ACPAs). Skeletal muscle is also involved in RA, with many patients developing muscle wasting and sarcopenia. Several mechanisms are involved in the myopenia observed in RA, and one of them includes the effects of some interleukins and myokines on myocytes. Myostatin is a myokine member of the TGF-ß superfamily; the overproduction of myostatin acts as a negative regulator of growth and differentiates the muscle fibers, limiting their number and size. Recent studies have identified abnormalities in the serum myostatin levels of RA patients, and these have been found to be associated with muscle wasting and other manifestations of severe RA. This review analyzes recent information regarding the relationship between myostatin levels and clinical manifestations of RA and the relevance of myostatin as a therapeutic target for future research.
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The Cu-glutathione (GSH) redox system, essential in biology, is designed here as a supramacromolecular assembly in which the tetrahedral 18e Cu(I) center loses a thiol ligand upon adsorption onto ZIF-8, as shown by EXAFS and DFT calculation, to generate a very robust 16e planar trigonal single-atom Cu(I) catalyst. Synergy between Cu(I) and ZIF-8, revealed by catalytic experiments and DFT calculation, affords CO2 conversion into high-value-added chemicals with a wide scope of substrates by reaction with terminal alkynes or propargyl amines in excellent yields under mild conditions and reuse at least 10â times without significant decrease in catalytic efficiency.
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HYPOTHESIS: Renal calculi (kidney stones) are mainly made by calcium oxalate and can cause different complications including malfunction of the kidney. The most important urinary stone inhibitors are citrate molecules. Unfortunately, the amount of citrate reaching the kidney after oral ingestion is low. We hypothesized that nanoparticles of polyallylamine hydrochloride (CIT-PAH) carrying citrate ions could simultaneously deliver citrates while PAH would complex oxalate triggering dissolution and removal of CaOx nanocrystals. EXPERIMENTS: We successfully prepared nanoparticles of citrate ions with polyallylamine hydrochloride (CIT-PAH), PAH with oxalate (OX-PAH) and characterize them by Small Angle X ray Scattering (SAXS), Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS) and NMR. Dissolution of CaOx nanocrystals in presence of CIT-PAH have been followed with Wide Angle Xray Scattering (WAXS), DLS and Confocal Raman Microscopy. Raman spectroscopy was used to study the dissolution of crystals in synthetic urine samples. The release of citrate from CIT-PAH was followed by diffusion NMR. Molecular dynamics (MD) simulations were carried out to study the interaction of CIT and OX ions with PAH. FINDINGS: CIT-PAH nanoparticles dissolves CaOx nanocrystals as shown by NMR, DLS, TEM and WAXS in water and by Raman spectroscopy in artificial human urine. WAXS and Raman show that the crystal structure of CaOx disappears in the presence of CIT-PAH. DLS shows that the time required for CaOX dissolution will depend on the concentration of CIT-PAH NPs. NMR proves that citrate ions are released from the CIT PAH NPs during CaOX dissolution, MD simulations showed that oxalates exhibit a stronger interaction for PAH than citrate, explaining the removal of oxalate ions and replacement of the citrate in the polymer nanoparticles.
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Oxalato de Calcio , Ácido Cítrico , Nanopartículas , Poliaminas , Nanopartículas/química , Poliaminas/química , Oxalato de Calcio/química , Ácido Cítrico/química , Humanos , Tamaño de la Partícula , Solubilidad , Simulación de Dinámica Molecular , Portadores de Fármacos/químicaRESUMEN
A hybrid cellulose-based programmable nanoplatform for applications in precision radiation oncology is described. Here, sugar heads work as tumor targeting moieties and steer the precise delivery of radiosensitizers, i.e. gold nanoparticles (AuNPs) into triple negative breast cancer (TNBC) cells. This "Trojan horse" approach promotes a specific and massive accumulation of radiosensitizers in TNBC cells, thus avoiding the fast turnover of small-sized AuNPs and the need for high doses of AuNPs for treatment. Application of X-rays resulted in a significant increase of the therapeutic effect while delivering the same dose, showing the possibility to use roughly half dose of X-rays to obtain the same radiotoxicity effect. These data suggest that this hybrid nanoplatform acts as a promising tool for applications in enhancing cancer radiotherapy effects with lower doses of X-rays.
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Celulosa , Oro , Nanopartículas del Metal , Fármacos Sensibilizantes a Radiaciones , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Fármacos Sensibilizantes a Radiaciones/química , Oro/química , Celulosa/química , Humanos , Nanopartículas del Metal/química , Nanopartículas del Metal/uso terapéutico , Nanopartículas del Metal/efectos de la radiación , Línea Celular Tumoral , Femenino , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Nanopartículas/química , Supervivencia Celular/efectos de los fármacosRESUMEN
Radiolabeling and nuclear imaging techniques are used to investigate the biodistribution patterns of the soft and hard protein corona around poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) after administration to healthy mice. Soft and hard protein coronas of 131I-labeled BSA or 131I-labeled serum are formed on PLGA NPs functionalized with either polyehtylenimine (PEI) or bovine serum albumin (BSA). The exchangeability of hard and soft corona is assessed in vitro by gamma counting exposing PLGA NPs with corona to non-labeled BSA, serum, or simulated body fluid. PEI PLGA NPs form larger and more stable coronas than BSA PLGA NPs. Soft coronas are more exchangeable than hard ones. The in vivo fate of PEI PLGA NPs coated with preformed 18F-labeled BSA hard and soft coronas is assessed by positron emission tomography (PET) following intravenous administration. While the soft corona shows a biodistribution similar to free 18F BSA with high activity in blood and kidney, the hard corona follows patterns characteristic of nanoparticles, accumulating in the lungs, liver, and spleen. These results show that in vivo fates of soft and hard corona are different, and that soft corona is more easily exchanged with proteins from the body, while hard corona is largely retained on the nanoparticle surface.
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HYPOTHESIS: The anticancer drug doxorubicin hydrochloride (DX) shows a high solubility in aqueous media thanks to the positive charge in the ammonium group. This feature, however, affects the drug encapsulation in the hydrophobic domains of polymeric micelles (PMs) used for the targeted delivery of the drug. At basic pH, DX deprotonates but also acquires a negative charge in the phenolic groups of the anthracycline structure. Both the efficiency and the rate of encapsulation will be increased by choosing an appropriate pH such that the drug molecule is in neutral form. EXPERIMENTS: An optimal pH for the encapsulation of the DX in PMs based on commercial poloxamers and on the diblock copolymer methoxy-poly(ethylene glycol)17-b-poly(ε-caprolactone)9 was determined by fluorescence spectroscopy, following the time evolution of both the intensity ratio of the first and the second emission bands of DX and its fluorescence lifetime, both sensitive to the environment polarity. Intracellular delivery of PMs encapsulated drug was followed by Confocal Scanning Laser Microscopy (CSLM). Cell viability was assessed with the sulforhodamine B (SRB) assay. FINDINGS: By adjusting pH to 8.1 a high yield of incorporation of DX in the PMs was achieved coupled to an appreciable increase (one order of magnitude) in the drug encapsulation rate. In-vitro tests in selected cancer cell lines showed the slow release of the drug and a delay in the cytotoxic response in comparison to free DX as detected by CSLM and SRB assay. The proposed methodology paves the way for a greener, faster and more efficient encapsulation of DX in PMs.
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Antineoplásicos , Micelas , Poliésteres/química , Doxorrubicina/farmacología , Doxorrubicina/química , Polímeros/química , Antineoplásicos/farmacología , Antineoplásicos/química , Polietilenglicoles/química , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Sistemas de Liberación de MedicamentosRESUMEN
Gene therapy can potentially treat a great number of diseases, from cancer to rare genetic disorders. Very recently, the development and emergency approval of nucleic acid-based COVID-19 vaccines confirmed its strength and versatility. However, gene therapy encounters limitations due to the lack of suitable carriers to vectorize therapeutic genetic material inside target cells. Nanogels are highly hydrated nano-size crosslinked polymeric networks that have been used in many biomedical applications, from drug delivery to tissue engineering and diagnostics. Due to their easy production, tunability, and swelling properties they have called the attention as promising vectors for gene delivery. In this review, nanogels are discussed as vectors for nucleic acid delivery aiming to enlarge gene therapy's therapeutic window. Recent works highlighting the optimization of inherent transfection efficiency and biocompatibility are reviewed here. The importance of the monomer choice, along with the internal structure, surface decoration, and responsive features are outlined for the different transfection modalities. The possible sources of toxicological endpoints in nanogels are analyzed, and the strategies to limit them are compared. Finally, perspectives are discussed to identify the remining challenges for the nanogels before their translation to the market as transfection agents.
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Vacunas contra la COVID-19 , Ácidos Nucleicos , Humanos , Nanogeles , Sistemas de Liberación de Medicamentos , Terapia GenéticaRESUMEN
Reactive oxygen species (ROS) play a key role in several biological functions like regulating cell survival and signaling; however, their effect can range from beneficial to nondesirable oxidative stress when they are overproduced causing inflammation or cancer diseases. Thus, the design of tailor-made ROS-responsive polymers offers the possibility of engineering hydrogels for target therapies. In this work, we developed thioether-based ROS-responsive difunctional monomers from ethylene glycol/thioether acrylate (EGnSA) with different lengths of the EGn chain (n = 1, 2, 3) by the thiol-Michael addition click reaction. The presence of acrylate groups allowed their photopolymerization by UV light, while the thioether groups conferred ROS-responsive properties. As a result, smart PEGnSA hydrogels were obtained, which could be processed by four-dimensional (4D) printing. The mechanical properties of the hydrogels were determined by rheology, pointing out a decrease of the elastic modulus (G') with the length of the EG segment. To enhance the stability of the hydrogels after swelling, the EGnSA monomers were copolymerized with a polar monomer, 2-hydroxyethyl acrylate (HEA), leading to P[(EGnSA)x-co-HEAy] with improved compatibility in aqueous media, making it a less brittle material. Swelling properties of the hydrogels increased in the presence of hydrogen peroxide, a kind of ROS, reaching values of ≈130% for P[(EG3SA)7-co-HEA93] which confirms the stimuli-responsive properties. Then, the P[(EG3SA)x-co-HEAy] hydrogels were employed as matrixes for the encapsulation of a chemotherapeutic drug, 5-fluorouracil (5FU), which showed sustained release over time modulated by the presence of H2O2. Finally, the effect of the 5-FU release from P[(EG3SA)x-co-HEAy] hydrogels was tested in vitro with melanoma cancer cells B16F10, pointing out B16F10 growth inhibition values in the range of 40-60% modulated by the EG3SA percentage and the presence or absence of ROS agents, thus confirming their excellent ROS-responsive properties for the treatment of localized pathologies.
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Hypertension is one of the main risk factors related to cardiovascular mortality, being the levels of blood pressure (BP) related to a variety of personal, anthropometric, biochemical and psychological variables; however, the study evaluating the association of all these factors in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a sample of relatively healthy subjects has not been performed. The aim of the study was to determine the main variables associated with SBP and DPB in a sample of relatively healthy subjects. A total of 171 participants were included, in which personal, anthropometric, positive and negative psychological variables and biochemical variables were measured. We observed that men showed higher levels of SBP and DBP than women, with more differences for SBP. Among the biochemical factors and SBP, we found that albumin and monocytes were positively correlated with it, while potassium, phosphorus and eosinophils were negatively correlated with it. Additionally, schooling was a constant variable negatively correlated with SBP in all samples (global, men and women). Among psychological variables, we observed that emotional perception was negatively correlated with SBP in men's and women's samples, while autonomy was positively correlated with SBP in the men's sample; however, their association was less when compared with the personal and biochemical variables included in the multivariate model. With regard to DBP, we observed that the biochemical variables, hemoglobin, sodium, uric acid and glucose, were positively correlated with DBP in the global sample, while chloride and BUN were negatively correlated with it. In addition, many personal and behavioral variables, including BMI, age and smoking consumption frequency, also correlated with DBP in the global sample. In conclusion, BP is affected by different factors, and these affect each sex differently.
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Oxidative stress (OS) has been linked to cell damage and chronic disease development; however, the study of psychological factors related with OS has been limited, as has its relationship with biochemical and personal variables. Therefore, the aim of this study was to evaluate the association between a wide variety of personal, psychological, and biochemical factors with OS in a sample of healthy Mexican people. A total of 134 participants, from which 70 (52%) were women, without known chronic conditions were included in the study, and the molecule 8-hydroxy-2'-deoxyguanosine (8-OHdG) was also measured as a marker of OS. We observed in the multivariate analysis of the whole sample that depressive symptoms (measured with CES-D scale) were the only psychological variable significantly associated (positively) with 8-OHdG. In addition, the following sociodemographic variables were associated with 8-OHdG: age, schooling (positively correlated), and the frequency of vitamins/antioxidant consumption (negatively correlated). The biochemical variables of erythrocytes in urine and amylase were positively correlated with 8-OHdG, while glucose was negatively correlated with it. Additional biochemical variables were associated in the multivariate analysis of each sex, including the positive correlation of LDL-cholesterol, LDH enzyme, lymphocytes, and the negative correlation of phosphorus and eosinophils in women's samples, as well as the positive correlation of potassium, uric acid, and leucocytes in urine and the negative correlation of erythrocytes and lipase in the men's samples. In conclusion, depression was the only psychological variable positively correlated with 8-OHdG after adjusting for confounders, and new associations with biochemical variables were found with some differences between sexes.
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A deeper knowledge on the formation and biological fate of polymer based gene vectors is needed for their translation into therapy. Here, polyplexes of polyethyleneimine (PEI) and silencing RNA (siRNA) are formed with theoretical N/P ratios of 2, 4 and 12. Fluorescence correlation spectroscopy (FCS) is used to study the formation of polyplexes from fluorescently labelled PEI and siRNA. FCS proves the presence of free PEI. From the analysis of the autocorrelation functions it was possible to determine the actual stoichiometry of polyplexes. FCS and fluorescence cross correlation spectroscopy (FCCS) are used to follow the fate of the polyplexes intracellularly. Polyplexes disassemble after 1 day inside cells. Positron emission tomography (PET) studies are conducted with radiolabelled polyplexes prepared with siRNA or PEI labelled with 2,3,5,6-tetrafluorophenyl 6-[18F]-fluoronicotinate ([18F]F-PyTFP). PET studies in healthy mice show that [18F]siRNA/PEI and siRNA/[18F]PEI polyplexes show similar biodistribution patterns with limited circulation in the bloodstream and accumulation in the liver. Higher activity for [18F]PEI in the kidney and bladder suggests the presence of free PEI.
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Polietileneimina , ARN Bicatenario , Animales , Ratones , Polietileneimina/química , ARN Interferente Pequeño/química , Distribución Tisular , Espectrometría de Fluorescencia , Tomografía de Emisión de PositronesRESUMEN
The present study focuses on the elaboration of magnetic nanocomposites by the in situ incorporation of magnetite (Fe3O4) nanoparticles (NPs) with spherical and nanoflower-like morphologies in graphitic carbon nitride (g-C3N4) sheets using two different synthetic routes. Nanomaterials are characterized by TEM, SEM, XRD, FTIR, BET, zetametry, vibrating sample magnetometry, and UV-vis absorption spectroscopy. The decoration of the carbon nitride matrix with the magnetic NPs enhanced optical and textural properties. The influence of the morphology of the magnetic NPs on the adsorptive and photocatalytic properties of the nanocomposites under different pH conditions (4.5, 6.9, and 10.6) was assessed from batch tests to remove methylene blue (MB) from aqueous solutions. In extreme pH conditions, the nanocomposites exhibited lower or equivalent MB removal capacity compared to the pure g-C3N4. However, at neutral medium, the nanocomposite with incorporated Fe3O4 nanoflowers showed a significantly higher removal efficiency (80.7%) due to the combination of a high adsorption capacity and a good photocatalytic activity in this pH region. The proposed nanocomposite is a promising alternative to remove cationic dyes from water by magnetic assistance, since no pH adjustment of the polluted effluent is required, reducing costs and environmental impact in the dyeing industry.
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N-Acetylgalactosamine-6-sulfatase (GALNS) is an enzyme whose deficiency is related to the lysosomal storage disease Morquio A. For the development of effective therapeutic approaches against this disease, the design of suitable enzyme enhancers (i.e. pharmacological chaperones) is fundamental. The natural substrates of GALNS are the glycosaminoglycans keratan sulfate and chondroitin 6-sulfate, which mainly display repeating units of sulfated carbohydrates. With a biomimetic approach, gold nanoparticles (AuNPs) decorated with simple monosaccharides, sulfated ligands (homoligand AuNPs), or both monosaccharides and sulfated ligands (mixed-ligand AuNPs) were designed here as multivalent inhibitors of GALNS. Among the homoligand AuNPs, the most effective inhibitors of GALNS activity are the ß-D-galactoside-coated AuNPs. In the case of mixed-ligand AuNPs, ß-D-galactosides/sulfated ligands do not show better inhibition than the ß-D-galactoside-coated AuNPs. However, a synergistic effect is observed for α-D-mannosides in a mixed-ligand coating with sulfated ligands that reduced IC50 by one order of magnitude with respect to the homoligand α-D-mannoside-coated AuNPs. SAXS experiments corroborated the association of GALNS with ß-D-galactoside AuNPs. These AuNPs are able to restore the enzyme activity by almost 2-fold after thermal denaturation, indicating a potential chaperoning activity towards GALNS. This information could be exploited for future development of nanomedicines for Morquio A. The recent implications of GALNS in cancer and neuropathic pain make these kinds of multivalent bionanomaterials of great interest towards multiple therapies.
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Condroitinsulfatasas , Nanopartículas del Metal , Oro , Acetilgalactosamina , Monosacáridos , Ligandos , Sulfatos , Dispersión del Ángulo Pequeño , Difracción de Rayos X , LisosomasRESUMEN
Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/genética , Cadenas HLA-DRB1/genética , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , GenotipoRESUMEN
An electrochemical exfoliation method for the production of graphene oxide and its characterization by electrochemical techniques are presented here. Graphite rods are used as working electrode in a three-electrode electrochemical cell, and electro-exfoliation is achieved by applying anodic polarization in a sulfuric acid solution. The electrochemical process involved two steps characterized by an intercalation at lower potential and an exfoliation at higher potential. The electrochemical behavior of the produced GO is studied through cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). X ray Photoelectronic Spectroscopy (XPS), Raman spectroscopy, Transmission Electron Microscopy (TEM), and Atomic Force Microscopy (AFM) are employed to characterize the structural and chemical properties of the exfoliated GO. The results demonstrate that the electrochemical exfoliation method yields GO materials with varying degrees of oxidation, defect density, and crystallite size, depending on the applied potential and acid concentration. The graphene oxide samples exhibited distinct electrochemical properties, including charge transfer resistance, interfacial capacitance, and relaxation times for the charge transfer, as revealed by CV and EIS measurements with a specifically selected redox probe. The comprehensive characterization performed provides valuable insights into the structure-property relationships of the GO materials synthesized through electrochemical exfoliation of graphite.
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Polyamine-based vectors offer many advantages for gene therapy, but they are hampered by a limited knowledge on their biological fate and efficacy for nucleic acid delivery. The 18 F radiolabeled siRNA is complexed with poly(allyl amine) hydrochloride (PAH), PEGylated PAH (PAHPEG ), or oleic acid-modified PAH (PAHOleic ) to form polyplexes, and injected them intravenously into healthy rodents. The biodistribution patterns obtained by positron emission tomography (PET) imaging vary according to the polymer used for complexation. Free siRNA is quickly eliminated through the bladder. PAH and oleic acid modify PAH polyplexes accumulate in the lungs and liver. No elimination through the bladder is observed for PAH and PAHOleic within 2 h after administration. PAHPEG polyplexes accumulate in kidneys and are eliminated through the bladder. Polyplexes prepared with 18 F-labeled oleic acid-modified PAH and non-labeled siRNA show similar biodistribution to those prepared with labeled siRNA, but with more accumulation in the lungs due to the presence of non-complexed polymer. Intravenous administration of PAHOleic polyplexes in tumor models results in a limited availability of siRNA. When PAHOleic polyplexes are administered intratumorally in tumor bearing rodents, ≈40% of the radioactivity is retained in the tumor after 180 min while free siRNA is completely eliminated.
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Neoplasias , Ácido Oléico , Humanos , ARN Interferente Pequeño , Distribución Tisular , Tomografía de Emisión de Positrones , Polímeros , PoliaminasRESUMEN
The gold standard drug for colorectal cancer (CRC) treatment, 5-Fluorouracil (5-FU), induces pharmacological tolerance in long-term management. The transcriptional factor nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) plays a key role in 5-FU resistance. The aim of this work is to study the capability of polyelectrolytes complex nanoparticles of dermatan sulfate (DS) and chitosan (CS), loaded with the anti-inflammatory tripeptide IRW, to sensitize colorectal cancer cells to 5-FU. Fluorescence and flow cytometry studies confirmed the recognition by the nanoformulation, of the cluster of differentiation 44 (CD44) receptor, involved in the initiation and progression of colorectal tumors. Dynamic light scattering (DLS) and flow cytometry reinforced the importance of DS and CD44 receptor in the interaction, as the addition of DS or anti-CD44 antibody blocked the binding. Moreover, the nanoformulation also interacts with 3D colon cancer cultures, namely colonospheres, enriched in cancer stem cells (CSC), subpopulation responsible for drug resistance and metastasis. To evaluate the consequences of this interaction, the subcellular distribution of the transcriptional factor NFκB, is determined by immunofluorescence analysis. Internalization and the intracellular release of IRW inhibited nuclear translocation of NFκB and increased cellular sensitivity to 5-FU. Altogether, the nanoformulation could provide a selective delivery platform for IRW distribution to colorectal tumors, being an innovative strategy toward overcoming 5-FU resistance in CRC therapy.