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The advancement of flexible electrodes triggered research on wearables and health monitoring applications. Metal-based bioelectrodes encounter low mechanical strength and skin discomfort at the electrode-skin interface. Thus, recent research has focused on the development of flexible surface electrodes with low electrochemical resistance and high conductivity. This study investigated the development of a novel, flexible, surface electrode based on a MXene/polydimethylsiloxane (PDMS)/glycerol composite. MXenes offer the benefit of featuring highly conductive transition metals with metallic properties, including a group of carbides, nitrides, and carbonitrides, while PDMS exhibits inherent biostability, flexibility, and biocompatibility. Among the various MXene-based electrode compositions prepared in this work, those composed of 15% and 20% MXene content were further evaluated for their potential in electrophysiological sensing applications. The samples underwent a range of characterization techniques, including electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), as well as mechanical and bio-signal sensing from the skin. The experimental findings indicated that the compositions demonstrated favorable bulk impedances of 280 and 111 Ω, along with conductivities of 0.462 and 1.533 mS/cm, respectively. Additionally, they displayed promising electrochemical stability, featuring charge storage densities of 0.665 mC/cm2 and 1.99 mC/cm2, respectively. By conducting mechanical tests, Young's moduli were determined to be 2.61 MPa and 2.18 MPa, respectively. The composite samples exhibited elongation of 139% and 144%, respectively. Thus, MXene-based bioelectrodes show promising potential for flexible and wearable electronics and bio-signal sensing applications.
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Eletrodos , Dispositivos Eletrônicos Vestíveis , Técnicas Biossensoriais/métodos , Técnicas Biossensoriais/instrumentação , Humanos , Dimetilpolisiloxanos/química , Espectroscopia Dielétrica , Condutividade Elétrica , Técnicas Eletroquímicas/métodos , Técnicas Eletroquímicas/instrumentação , Impedância Elétrica , Glicerol/química , Fenômenos Eletrofisiológicos , Monitorização Fisiológica/instrumentação , Monitorização Fisiológica/métodosRESUMO
This study focuses on the development of antimicrobial fibres for use in medical and healthcare textile industries. Carbon dots (CDs) were designed with boronic acid groups for the attachment to cellulose fibres found in cotton textiles and to enhance their attachment to glycogens on bacterial surfaces. Boronic acid-based and curcumin-based CDs were prepared and characterized using various techniques, showing a nanoscale size and zeta potential values. The CDs inhibited the growth of both Staphylococcus epidermidis and Escherichia coli bacteria, with UV-activated CDs demonstrating improved antibacterial activity. The antimicrobial activity of the CDs was then tested, revealing strong adherence to cellulose paper fibres with no CD diffusion and potent inhibition of bacterial growth. Cytotoxicity assays on human cell lines showed no toxicity towards cells at concentrations of up to 100 µg ml-1 but exhibited increased toxicity at concentrations exceeding 1000 µg ml-1. However, CD-modified cellulose paper fibres showed no toxicity against human cell lines, highlighting the antimicrobial properties of the CD-modified cellulose fibres are safe for human use. These findings show promising potential for applications in both industrial and clinical settings.
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Flexible electrodes are becoming a topic of interest for a range of applications including implantation. They can be used for neural signal recording and for electrical stimulation of atrophying muscles. Unlike the traditionally used metal electrodes that are harsh to the body's tissues, flexible electrodes conduct electricity while preserving the delicate tissues. Polydimethylsiloxane (PDMS), a non-conductive synthetic polymer characterized by its flexibility, low cost, biocompatibility, and durability during implantation, has been explored as a matrix for flexible electrodes. This study reports the synthesis of composite boronic acid-modified carbon dots (BA-CDs)/PDMS electrode materials. The performance of the composite electrode is evaluated electrochemically (for its conductivity and charge storage capacity) and mechanically (Young's modulus). Furthermore, the effect of increasing the PDMS crosslinking density on the electrode's performance is studied based on the hypothesis that a higher crosslinking will bring the BA-CDs closer together, thereby facilitating the movement of electrons. Results of this study showed that incorporating 10% BA-CDs dispersed with 16% glycerol in 74% PDMS with a higher crosslinking density resulted in a bulk impedance of 47.7 Ω and a conductivity of 2.68×10-3 S/cm, both of which surpassed that of the same composition with lower crosslinking. The synthesized flexible electrode material was capable of charge storage although the charge storage capacity (0.00365 mC/cm2) was lower than the safe limit for some tissue activation. Furthermore, the electrode maintained a modulus of elasticity (0.2322 MPa) that is compatible with biological soft tissues.Clinical Relevance- This study reports a conductive electrode that has a flexibility compatible with that of biological tissues for future purposes such as neural signal recording and tissue electrical stimulation (e.g. atrophying muscles). The reported BA-CD/PDMS electrode overcomes the limitations of the harsh metals previously used as implantable electrodes that harm the biological tissues due to their high rigidity.
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Carbono , Polímeros , Condutividade Elétrica , Eletrodos Implantados , Impedância Elétrica , MetaisRESUMO
Biological therapeutics are major contributors to the pharmaceutical pipeline and continue to grow in sales and scope. Additionally, the field's understanding of cancer biology has advanced such that biopharmaceuticals can harness the power of the immune system for oncology treatments. Several of these novel therapeutics are engineered versions of naturally occurring proteins designed to improve therapeutic properties including potency, target engagement and half-life extension. Cytokines, such as interferons and interleukins, are a broad class of signaling proteins which modulate the body's immune response; engineered cytokines have entered the clinic as promising new immuno-oncology therapies. While these therapies hold great promise, their additional structural complexity introduces analytical challenges, and traditional analytical platforms may be ill-suited to effectively assess product development risks. Further, the pharmaceutical industry relies on streamlining approaches for high-throughput experimentation to achieve speed and efficiency for the discovery and development of new modalities. These demands necessitate the use of state-of-the-art techniques to rapidly characterize these new modalities and guide process development and optimization. Matrix Assisted Laser Desorption Ionization Mass Spectrometry (MALDI-MS) is a rapid, sensitive and automatable technique amenable for high-throughput analysis of proteins. In this work, we have developed an automated MALDI-MS platform to prepare, acquire and analyze molecular degradation in engineered PEGylated cytokines formulation samples. This orthogonal technique integrated seamlessly with current developability risk assessment workflows, ultimately enabling selection of a final formulation strategy for clinical development.
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Ipatasertib (GDC-0068) is a potent, highly selective, small-molecule inhibitor of protein kinase B (Akt) being developed by Genentech/Roche as a single agent and in combination with other therapies for the treatment of cancers. To fully understand the absorption, metabolism, and excretion of ipatasertib in humans, an open-label study using 14C-radiolabeled ipatasertib was completed to characterize the absolute bioavailability (period 1) and mass balance and metabolite profiling (period 2). In period 1, subjects were administered a 200 mg oral dose of ipatasertib followed by an 80 µg (800 nCi) intravenous dose of [14C]-ipatasertib. In period 2, subjects received a single oral dose containing approximately 200 mg (100 µCi) [14C]-ipatasertib. In an integrated analytical strategy, accelerator mass spectrometry was applied to measure the 14C microtracer intravenous pharmacokinetics in period 1 and fully profile plasma radioactivity in period 2. The systemic plasma clearance and steady-state volume of distribution were 98.8 L/h and 2530 L, respectively. The terminal half-lives after oral and intravenous administrations were similar (26.7 and 27.4 hours, respectively) and absolute bioavailability of ipatasertib was 34.0%. After a single oral dose of [14C]-ipatasertib, 88.3% of the administered radioactivity was recovered with approximately 69.0% and 19.3% in feces and urine, respectively. Radioactivity in feces and urine was predominantly metabolites with 24.4% and 8.26% of dose as unchanged parent, respectively; indicating that ipatasertib had been extensively absorbed and hepatic metabolism was the major route of clearance. The major metabolic pathway was N-dealkylation mediated by CYP3A, and minor pathways were oxidative by cytochromes P450 and aldehyde oxidase. SIGNIFICANCE STATEMENT: The study provided definitive information regarding the absolute bioavailability and the absorption, metabolism, and excretion pathways of ipatasertib, a potent, novel, and highly selective small-molecule inhibitor of protein kinase B (Akt). An ultrasensitive radioactive counting method, accelerator mass spectrometry was successfully applied for 14C-microtracer absolute bioavailability determination and plasma metabolite profiling.
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Piperazinas , Proteínas Proto-Oncogênicas c-akt , Humanos , Disponibilidade Biológica , Proteínas Proto-Oncogênicas c-akt/análise , Taxa de Depuração Metabólica , Fezes/química , Administração OralRESUMO
All currently approved antibiotics are being met by some degree of resistance by the bacteria they target. Biofilm formation is one of the crucial enablers of bacterial resistance, making it an important bacterial process to target for overcoming antibiotic resistance. Accordingly, several drug delivery systems that target biofilm formation have been developed. One of these systems is based on lipid-based nanocarriers (liposomes), which have shown strong efficacy against biofilms of bacterial pathogens. Liposomes come in various types, namely conventional (charged or neutral), stimuli-responsive, deformable, targeted, and stealth. This paper reviews studies employing liposomal formulations against biofilms of medically salient gram-negative and gram-positive bacterial species reported recently. When it comes to gram-negative species, liposomal formulations of various types were reported to be efficacious against Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, and members of the genera Klebsiella, Salmonella, Aeromonas, Serratia, Porphyromonas, and Prevotella. A range of liposomal formulations were also effective against gram-positive biofilms, including mostly biofilms of Staphylococcal strains, namely Staphylococcus aureus, Staphylococcus epidermidis, and Staphylococcus saprophyticus subspecies bovis, followed by Streptococcal strains (pneumonia, oralis, and mutans), Cutibacterium acnes, Bacillus subtilis, Mycobacterium avium, Mycobacterium avium subsp. hominissuis, Mycobacterium abscessus, and Listeria monocytogenes biofilms. This review outlines the benefits and limitations of using liposomal formulations as means to combat different multidrug-resistant bacteria, urging the investigation of the effects of bacterial gram-stain on liposomal efficiency and the inclusion of pathogenic bacterial strains previously unstudied.
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With the urgent need for bio-nanomaterials to improve the currently available cancer treatments, gold nanoparticle (GNP) hybrid nanostructures are rapidly rising as promising multimodal candidates for cancer therapy. Gold nanoparticles (GNPs) have been hybridized with several nanocarriers, including liposomes and polymers, to achieve chemotherapy, photothermal therapy, radiotherapy, and imaging using a single composite. The GNP nanohybrids used for targeted chemotherapy can be designed to respond to external stimuli such as heat or internal stimuli such as intratumoral pH. Despite their promise for multimodal cancer therapy, there are currently no reviews summarizing the current status of GNP nanohybrid use for cancer theragnostics. Therefore, this review fulfills this gap in the literature by providing a critical analysis of the data available on the use of GNP nanohybrids for cancer treatment with a specific focus on synergistic approaches (i.e., triggered drug release, photothermal therapy, and radiotherapy). It also highlights some of the challenges that hinder the clinical translation of GNP hybrid nanostructures from bench to bedside. Future studies that could expedite the clinical progress of GNPs, as well as the future possibility of improving GNP nanohybrids for cancer theragnostics, are also summarized.
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With cancer research shifting focus to achieving multifunctionality in cancer treatment strategies, hybrid nanogels are making a rapid rise to the spotlight as novel, multifunctional, stimuli-responsive, and biocompatible cancer therapeutic strategies. They can possess cancer cell-specific cytotoxic effects themselves, carry drugs or enzymes that can produce cytotoxic effects, improve imaging modalities, and target tumor cells over normal cells. Hybrid nanogels bring together a wide range of desirable properties for cancer treatment such as stimuli-responsiveness, efficient loading and protection of molecules such as drugs or enzymes, and effective crossing of cellular barriers among other properties. Despite their promising abilities, hybrid nanogels are still far from being used in the clinic, and their available data remains relatively limited. However, many studies can be done to facilitate this clinical transition. This review is critically summarizing and analyzing the recent information and progress on the use of hybrid nanogels particularly inorganic nanoparticle-based and organic nanoparticle-based hybrid nanogels in the field of oncology and future directions to aid in transferring those results to the clinic. This work concludes that the future of hybrid nanogels is greatly impacted by therapeutic and non-therapeutic factors. Therapeutic factors include the lack of hemocompatibility studies, acute and chronic toxicological studies, and information on agglomeration capability and extent, tumor heterogeneity, interaction with proteins in physiological fluids, endocytosis-exocytosis, and toxicity of the nanogels' breakdown products. Non-therapeutic factors include the lack of clear regulatory guidelines and standardized assays, limitations of animal models, and difficulties associated with good manufacture practices (GMP).
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Nanopartículas , Neoplasias , Animais , Nanogéis , Sistemas de Liberação de Medicamentos/métodos , Endocitose , Neoplasias/tratamento farmacológicoRESUMO
Peptide therapeutics are a growing modality in the pharmaceutical industry and expanding these therapeutics to hit intracellular targets would require establishing cell permeability. Rapid measurement target-agnostic cell permeability of peptides is still analytically challenging. In this study, we demonstrate the development of a rapid high-throughput label-free methodology based on a MALDI-hydrogen-deuterium exchange mass spectrometry (MALDI-HDX-MS) approach to rank-order peptide cell membrane permeability using live THP-1 and AsPc-1 cells. Peptides were incubated in the presence of live cells and their permeability into the cells over time was measured by MALDI-HDX-MS. A differential hydrogen-deuterium exchange approach was used to distinguish the peptides outside of the cells from those inside. The peptides on the outside of the cells were labeled using sufficiently short exposure to deuterium oxide, while the peptides inside of the cells were protected from labeling as a result of permeation into the cells. The deuterium labeled and peak area ratios of unlabeled peptides were compared and plotted over time. The developed methodology, referred to as Cell-based Approach Membrane Permeability Assay (CAMPA), was applied to study an array of 24 diverse peptides including cell-penetrating peptides, stapled and macrocyclic peptides. The cell membrane permeability results observed by CAMPA were corroborated by previously reported in literature data. The CAMPA MALDI-MS analysis was fully automated including MS data processing using internally developed Python scripts. Moreover, CAMPA was demonstrated to be useful for differentiating passive and active cell transportation by using an endocytosis inhibitor in cell incubation media for selected peptides.
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Medição da Troca de Deutério , Espectrometria de Massa com Troca Hidrogênio-Deutério , Permeabilidade da Membrana Celular , Deutério/química , Medição da Troca de Deutério/métodos , Hidrogênio/química , Peptídeos , Permeabilidade , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodosRESUMO
The capture and safe storage of radioactive iodine (129I or 131I) are of a compelling significance in the generation of nuclear energy and waste storage. Because of their physiochemical properties, Porous Organic Polymers (POPs) are considered to be one of the most sought classes of materials for iodine capture and storage. Herein, we report on the preparation and characterization of two triazine-based, nitrogen-rich, porous organic polymers, NRPOP-1 (SABET = 519 m2 g-1) and NRPOP-2 (SABET = 456 m2 g-1), by reacting 1,3,5-triazine-2,4,6-triamine or 1,4-bis-(2,4-diamino-1,3,5-triazine)-benzene with thieno[2,3-b]thiophene-2,5-dicarboxaldehyde, respectively, and their use in the capture of volatile iodine. NRPOP-1 and NRPOP-2 showed a high adsorption capacity of iodine vapor with an uptake of up to 317 wt % at 80 °C and 1 bar and adequate recyclability. The NRPOPs were also capable of removing up to 87% of iodine from 300 mg L-1 iodine-cyclohexane solution. Furthermore, the iodine-loaded polymers, I2@NRPOP-1 and I2@NRPOP-2, displayed good antibacterial activity against Micrococcus luteus (ML), Escherichia coli (EC), and Pseudomonas aeruginosa (PSA). The synergic functionality of these novel polymers makes them promising materials to the environment and public health.
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Antibacterianos , Armazenamento de Medicamentos/métodos , Radioisótopos do Iodo , Compostos Orgânicos , Polímeros , Porosidade , Triazinas , Adsorção , Farmacorresistência Bacteriana , Escherichia coli/efeitos dos fármacos , Micrococcus luteus/efeitos dos fármacos , Nitrogênio , Compostos Orgânicos/farmacologia , Polímeros/farmacologia , Triazinas/farmacologia , VolatilizaçãoRESUMO
Recent advances in the field of cancer biology have accelerated the discovery and development of novel biopharmaceuticals. At the forefront of these drug development efforts are high-throughput screening, compressed timelines, and limited sample quantities, all characteristic of the discovery space. To meet program targets, large numbers of protein variants must be produced, screened, and characterized, presenting a daunting analytical challenge. Additionally, the higher-order structure is paramount for protein function and must be monitored as a critical quality attribute. Matrix-assisted laser desorption/ionization mass spectrometry has been utilized as an ultra-fast, automatable, sample-sparing analytical tool for biomolecules. Our group has published applications integrating hydrogen-deuterium exchange mass spectrometry with matrix-assisted laser desorption/ionization mass spectrometry for the rapid conformational characterization of small proteins, the current work expands this application to monoclonal and bi-specific antibodies. This study demonstrates the ability of the methodology, matrix-assisted laser desorption/ionization hydrogen-deuterium exchange mass spectrometry, to detect conformational differences between bi-specific antibodies from different expression hosts. These conformational differences were validated by orthogonal techniques including circular dichroism, nuclear magnetic resonance, and size-exclusion chromatography hydrogen-deuterium exchange mass spectrometry. This work demonstrates the utility of applying the developed methodology as a rapid conformational screening tool to triage samples for further analytical characterization.
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Medição da Troca de Deutério , Hidrogênio , Deutério/química , Deutério/metabolismo , Medição da Troca de Deutério/métodos , Hidrogênio/química , Lasers , Proteínas/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Cardiovascular diseases (CVDs) are one of the foremost causes of mortality in intensive care units worldwide. The development of a rapid method to quantify cardiac troponin I (cTnI)-the gold-standard biomarker of myocardial infarction (MI) (or "heart attack")-becomes crucial in the early diagnosis and treatment of myocardial infarction (MI). This study investigates the development of an efficient fluorescent "sandwich" immunoassay using liposome-based fluorescent signal amplification and thereby enables the sensing and quantification of serum-cTnI at a concentration relevant to clinical settings. The calcein-loaded liposomes were utilized as fluorescent nano vehicles, and these have exhibited appropriate stability and efficient fluorescent properties. The standardized assay was sensitive and selective towards cTnI in both physiological buffer solutions and spiked human serum samples. The novel assay presented noble analytical results with sound dynamic linearity over a wide concentration range of 0 to 320 ng/mL and a detection limit of 6.5 ng/mL for cTnI in the spiked human serum.
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Lipossomos/química , Infarto do Miocárdio/sangue , Troponina I/sangue , Biomarcadores/sangue , Diagnóstico Precoce , Fluoresceínas/química , Humanos , ImunoensaioRESUMO
Cardiovascular diseases are considered one of the major causes of human death globally. Myocardial infarction (MI), characterized by a diminished flow of blood to the heart, presents the highest rate of morbidity and mortality among all other cardiovascular diseases. These fatal effects have triggered the need for early diagnosis of appropriate biomarkers so that countermeasures can be taken. Cardiac troponin, the central key element of muscle regulation and contraction, is the most specific biomarker for cardiac injury and is considered the "gold standard". Due to its high specificity, the measurement of cardiac troponin levels has become the predominant indicator of MI. Various forms of diagnostic methods have been developed so far, including chemiluminescence, fluorescence immunoassay, enzyme-linked immunosorbent assay, surface plasmon resonance, electrical detection, and colorimetric protein assays. However, fluorescence-based immunoassays are considered fast, accurate and most sensitive of all in the determination of cardiac troponins post-MI. This review represents the strategies, methods and levels of detection involved in the reported fluorescence-based immunoassays for the detection of cardiac troponin I.
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Biomarcadores/sangue , Imunoensaio , Infarto do Miocárdio/sangue , Troponina I/isolamento & purificação , Fluorescência , Humanos , Infarto do Miocárdio/diagnóstico , Troponina I/sangueRESUMO
Targeted liposomes are designed to target specific receptors overexpressed on the surfaces of cancer cells. This technique ensures site-specific drug delivery to reduce undesirable side effects while enhancing the efficiency of the encapsulated therapeutics. Upon reaching the tumor site, these liposomes can be triggered to release their content in a controlled manner using ultrasound (US). In this study, drug release from pegylated calcein-loaded liposomes modified with transferrin (Tf) and triggered with US was evaluated. Low-frequency ultrasound at 20-kHz using three different power densities (6.2 mW/cm2, 9 mW/cm2 and 10 mW/cm2) was found to increase calcein release. In addition, transferrin-conjugated pegylated liposomes (Tf-PEG liposomes) were found to be more sonosensitive compared to the non-targeted (control) liposomes. Calcein uptake by HeLa cells was found to be significantly higher with the Tf-PEG liposomes compared to the non-targeted control liposomes. This uptake was further enhanced following the exposure to low-frequency ultrasound (at 35 kHz). These findings show that targeted liposomes triggered with US have promising potential as a safe and effective drug delivery platform.
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Sistemas de Liberação de Medicamentos/métodos , Lipossomos , Sonicação , Transferrina/química , Células HeLa , Humanos , Tamanho da PartículaRESUMO
Poly (lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer, is one of the most commonly used vehicles for controlled-release (CR) implantable dosage forms. Drug molecules formulated in such CR vehicles are released slowly over an extended period of time - often months to years - posing challenges for batch release and quality control testing. Thus, reliable and reproducible accelerated testing methods are required to bridge this gap during early formulation development. This work describes the development of an accelerated in vitro release testing method to predict the real-time in vitro release of a synthetic peptide from a 6-month CR PLGA implant formulation. While accelerated methods have been previously reported for PLGA-based formulations, this work describes a unique case of an aggregation-prone peptide, which required careful attention to the impact of different conditions on both release kinetics and peptide stability. This method describes a suitable combination of release conditions that could help in understanding the release profiles of such peptides prone to aggregation. Parameters including pH, buffer species, temperature, and addition of organic co-solvents and surfactants were evaluated separately and in combination for their ability to achieve complete peptide release within 2 weeks while accurately recapitulating release rate, profile and peptide stability. The accelerated release method that gave the best agreement with real-time release was a mixed media of co-solvent (5% tetrahydrofuran), surfactant (5% TritonX-100) and elevated temperature (50 °C) in a neutral buffer (PBS pH 7.4). This optimized accelerated release method achieved complete release of the peptide load within 14-21 days compared to 3- to 6-months of real-time release and could discriminate critical differences in release behavior between different CR formulations to guide formulation and process development.
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Química Farmacêutica/métodos , Implantes de Medicamento/farmacocinética , Excipientes/química , Peptídeos/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Implantes de Medicamento/administração & dosagem , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Microesferas , Peptídeos/administração & dosagem , Peptídeos/química , Reprodutibilidade dos TestesRESUMO
The functionalization of liposomes with monoclonal antibodies is a potential strategy to increase the specificity of liposomes and reduce the side-effects associated with chemotherapeutic agents. The active targeting of the Human Epidermal growth factor Receptor 2 (HER2), which is overexpressed in HER2 positive breast cancer cells, can be achieved by coating liposomes with an anti-HER2 monoclonal antibody. In this study, we synthesized calcein and Doxorubicin-loaded immunoliposomes functionalized with the monoclonal antibody Trastuzumab (TRA). Both liposomes were characterized for their size, phospholipid content and antibody conjugation. Exposing the liposomes to low-frequency ultrasound (LFUS) triggered drug release which increased with the increase in power density. Trastuzumab conjugation resulted in enhancing the sensitivity of the liposomes to LFUS. Compared to the control liposomes, TRA-liposomes showed higher cellular toxicity and higher drug uptake by the HER2 + cell line (SKBR3) which was further improved following sonication with LFUS. Combining immunoliposomes with LFUS is a promising technique in the field of targeted drug delivery that can enhance efficiency and reduce the cytotoxicity of antineoplastic drugs.
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Sistemas de Liberação de Medicamentos/métodos , Lipossomos/uso terapêutico , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Fluoresceínas/administração & dosagem , Fluoresceínas/uso terapêutico , Humanos , Imunoconjugados/metabolismo , Receptor ErbB-2/imunologia , Trastuzumab/administração & dosagem , Trastuzumab/uso terapêutico , Terapia por Ultrassom/métodosRESUMO
Constrained peptides (CPs) have emerged as attractive candidates for drug discovery and development. To fully unlock the therapeutic potential of CPs, it is crucial to understand their physical stability and minimize the formation of aggregates that could induce immune responses. Although amyloid like aggregates have been researched extensively, few studies have focused on aggregates from other peptide scaffolds (e.g., CPs). In this work, a streamlined approach to effectively profile the nature and formation pathway of CP aggregates was demonstrated. Aggregates of various sizes were detected and shown to be amorphous. Though no major changes were found in peptide structure upon aggregation, these aggregates appeared to have mixed natures, consisting of primarily non-covalent aggregates with a low level of covalent species. This co-existence phenomenon was also supported by two kinetic pathways observed in time- and temperature-dependent aggregation studies. Furthermore, a stability study with 8 additional peptide variants exhibited good correlation between aggregation propensity and peptide hydrophobicity. Therefore, a dual aggregation pathway was proposed, with the non-covalent aggregates driven by hydrophobic interactions, whereas the covalent ones formed through disulfide scrambling. Overall, the workflow presented here provides a powerful strategy for comprehensive characterization of peptide aggregates and understanding their mechanisms of formation.
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Amiloide , Peptídeos , Dissulfetos , Interações Hidrofóbicas e Hidrofílicas , Fragmentos de PeptídeosRESUMO
The successful targeting of tumors can be achieved by conjugating targeting moieties to nanoparticles. These modifications allow nannocarriers to achieve greater targeting specificity through binding to specific receptors overexpressed on the surface of the tumor cells. In this study, pegylated liposomes encapsulating the model drug/dye calcein and conjugated to hyaluronic acid (HA) molecules were successfully synthesized, and their ability to target HA receptors overexpressed on a breast cancer cell line was investigated in vitro. Low-frequency ultrasound (LFUS), applied at three different power densities (6.2, 9, and 10 mW/cm²) were used to trigger the release of the entrapped calcein. Both the control and HAconjugated liposomes showed similar release profiles. HA conjugation to the liposomes resulted in a significant increase in calcein uptake by the breast cancer cell line MDA-MB-231 known for its CD44 (HA receptor) overexpression, while such an effect was not recorded with NIH-3T3, an embryonic mouse fibroblast, with low levels of CD44 expression. The application of low LFUS showed a significant enhancement of calcein uptake by MDA-MB-231 cells from our liposome compared to calcein uptake without cell exposure to ultrasound. These findings suggest that combining HA-conjugated liposomes with ultrasound is a promising drug delivery platform in breast cancer treatment.
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Neoplasias da Mama , Lipossomos , Animais , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Ácido Hialurônico , Células MCF-7 , CamundongosRESUMO
The outbreak of coronavirus (COVID-19) has led to a broad use of chemical disinfectants in order to sterilize public spaces and prevent contamination. This paper surveys the chemicals that are effective in deactivating the virus and their mode of action. It presents the different chemical classes of disinfectants and identifies the chemical features of these compounds that pertain to their biocidal activity, relevant to surface/water disinfection.
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Betacoronavirus , Infecções por Coronavirus , Pandemias , Pneumonia Viral , COVID-19 , Desinfetantes/farmacologia , Humanos , SARS-CoV-2RESUMO
A novel triazene-anthracene-based fluorescent aminal linked porous organic polymer (TALPOP) was prepared via metal free-Schiff base polycondensation reaction of 9,10-bis-(4,6-diamino-S-triazin-2-yl)anthracene and 2-furaldehyde. The polymer has exceptional chemical and thermal stabilities and exhibit good porosity with Brunauer-Emmett-Teller surface area of 401 m2g-1. The combination of such porosity along with the highly conjugated heteroatom-rich framework enabled the polymer to exhibit exceptional iodine vapor uptake of up to 314 wt % and reversible iodine adsorption in solution. Because of the inclusion of the anthracene moieties, the TALPOP exhibited excellent detection sensitivity towards iodine via florescence quenching with Ksv value of 2.9 × 103 L mol-1. The cost effective TALPOP along with its high uptake and sensing of iodine, make it an ideal material for environmental remediation.