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Despite advances by recently approved antibody-drug conjugates in treating advanced gastric cancer patients, substantial limitations remain. Here, several key obstacles are overcome by developing a first-in-class ultrasmall (sub-8-nanometer (nm)) anti-human epidermal growth factor receptor 2 (HER2)-targeting drug-immune conjugate nanoparticle therapy. This multivalent fluorescent core-shell silica nanoparticle bears multiple anti-HER2 single-chain variable fragments (scFv), topoisomerase inhibitors, and deferoxamine moieties. Most surprisingly, drawing upon its favorable physicochemical, pharmacokinetic, clearance, and target-specific dual-modality imaging properties in a "hit and run" approach, this conjugate eradicated HER2-expressing gastric tumors without any evidence of tumor regrowth, while exhibiting a wide therapeutic index. Therapeutic response mechanisms are accompanied by the activation of functional markers, as well as pathway-specific inhibition. Results highlight the potential clinical utility of this molecularly engineered particle drug-immune conjugate and underscore the versatility of the base platform as a carrier for conjugating an array of other immune products and payloads.
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Mycobacterium tuberculosis is an etiological agent of tuberculosis (TB) known to be a highly contagious disease and is the major cause of mortality from a single infectious agent worldwide. Emergence of multi-drug resistant and extremely drug resistant strains of M. tuberculosis has made TB management extremely challenging eliciting the urgent need for alternative therapeutics. Peptide based therapeutic strategies are an emerging area that can be employed as a prospective alternative to the currently existing therapeutic regime for TB treatment. Here, we are reporting the anti-mycobacterial activity of two peptides, Tachyplesin and CyLoP-1, derived from marine horseshoe crab and snake toxin respectively, with potent anti-mycobacterial activity against various mycobacterium species. Both the peptides exhibit appreciable antimicrobial and anti-biofilm activities against mycobacterium species with minimum cytotoxicity towards macrophage cells. They are also effective in eliminating mycobacterium cells from infected macrophage cells. Tachyplesin acts on mycobacterium cells in a lytic manner with outer membrane disruption confirmed by propidium iodide uptake with slight membrane depolarization and reactive oxygen species (ROS) production. CyLoP-1, on the other hand, does not rupture the mycobacterium cells even at high concentrations. It seems to follow intracellular pathway of killing mycobacterium cells by production of more ROS and membrane depolarization. Both the peptides do not lead to apoptotic way of mycobacterium cell death. These results suggest an effective peptide-based antimicrobial strategy for development of future anti-TB therapeutics.
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Antiinfecciosos , Mycobacterium tuberculosis , Tuberculosis , Antiinfecciosos/farmacología , Péptidos Catiónicos Antimicrobianos/farmacología , Antituberculosos/farmacología , Proteínas de Unión al ADN , Humanos , Péptidos Cíclicos , Estudios Prospectivos , Especies Reactivas de Oxígeno , Tuberculosis/tratamiento farmacológicoRESUMEN
PURPOSE: Despite dramatic growth in the number of small-molecule drugs developed to treat solid tumors, durable therapeutic options to control primary central nervous system malignancies are relatively scarce. Chemotherapeutic agents that appear biologically potent in model systems have often been found to be marginally effective at best when given systemically in clinical trials. This work presents for the first time an ultrasmall (<8 nm) multimodal core-shell silica nanoparticle, Cornell prime dots (or C' dots), for the efficacious treatment of high-grade gliomas. EXPERIMENTAL DESIGN: This work presents first-in-kind renally clearable ultrasmall (<8 nm) multimodal C' dots with surface-conjugated doxorubicin (DOX) via pH-sensitive linkers for the efficacious treatment in two different clinically relevant high-grade glioma models. RESULTS: Optimal drug-per-particle ratios of as-developed nanoparticle-drug conjugates were established and used to obtain favorable pharmacokinetic profiles. The in vivo efficacy results showed significantly improved biological, therapeutic, and toxicological properties over the native drug after intravenous administration in platelet-derived growth factor-driven genetically engineered mouse model, and an EGF-expressing patient-derived xenograft (EGFR PDX) model. CONCLUSIONS: Ultrasmall C' dot-drug conjugates showed great translational potential over DOX for improving the therapeutic outcome of patients with high-grade gliomas, even without a cancer-targeting moiety.
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Glioma , Nanopartículas , Animales , Línea Celular Tumoral , Doxorrubicina , Sistemas de Liberación de Medicamentos/métodos , Glioma/tratamiento farmacológico , Humanos , Ratones , Dióxido de Silicio , Índice TerapéuticoRESUMEN
We report mesoporous bioactive glasses (MBGs) with different pore architecture synthesized using the supramolecular chemical approach using acid assisted sol-gel method followed by evaporation induced self-assembly (EISA) process. The surfactant of non-ionic block co-polymer used in the present work act as structure directing agent (SDA) with varying amount, which brings different textural properties. As prepared glasses possess wormhole-like mesostructure with different textural characteristics and it varies with surfactant concentrations. The pristine MBGs have been characterized by various analytical techniques before and after immersing in simulated body fluid (SBF). The textural properties show non-monotonous variations with varying the surfactant concentrations. We have quantified the various structural species present in the glass sample by using local structural probe such as nuclear magnetic resonance technique. Invitro studies on the MBGs revealed the influence of textural characteristics on the formation of nano-crystalline hydroxycarbonated apatite (HCA) layer. The biodegradability is largely related to the pore architecture and it affects the biocompatibility as well as bone formation. In-vitro studies reveals that there are serious negative effects that have been observed in the case of larger pore sized samples due to rapid degradation. We found that MBG with pore sizes of few nano meters exhibit favorable biocompatibility in vitro behavior and found to be promising candidate in the field of biomaterials including tissue regeneration and drug storage.
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Apatitas , Carbonatos , Cerámica , Ensayo de Materiales , Nanopartículas/química , Tensoactivos , Apatitas/química , Apatitas/farmacología , Carbonatos/química , Carbonatos/farmacología , Línea Celular Tumoral , Cerámica/química , Cerámica/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Porosidad , Tensoactivos/química , Tensoactivos/farmacologíaRESUMEN
ZnO nanoparticles of different sizes were functionalized with an amphipathic peptide, and its effect on nanoparticle stabilization and UV photoprotective activity was studied in this article. The peptide-modified nanoparticles exhibited lower aggregation, significant reduction in Zn2+ leaching in vitro and even inside the cells for smaller particle sizes, reduced photocatalytic activity, and reduced cellular toxicity under UV-B treated conditions. In addition, the peptide-modified 60 nm ZnO nanoparticles showed lower genotoxicity, lower oxidative stress induction levels, less DNA damage responses, and less immunogenic potential than the bare counterparts in the presence of UV-B rays. They localized more in the stratum corneum and epidermis ex vivo, indicating better retention in epidermis, and demonstrated improved UV-B protection and/or skin integrity in SKH-1 mice in vivo compared to unmodified nanoparticles and commercial UV-protective agents tested. To our knowledge, this is the first report on the application of peptide-modified ZnO nanoparticles for improved photoprotection.
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Daño del ADN , Epidermis/metabolismo , Nanopartículas , Péptidos , Protectores Solares , Rayos Ultravioleta/efectos adversos , Óxido de Zinc , Epidermis/patología , Humanos , Masculino , Nanopartículas/química , Nanopartículas/uso terapéutico , Péptidos/química , Péptidos/farmacología , Protectores Solares/química , Protectores Solares/farmacología , Óxido de Zinc/química , Óxido de Zinc/farmacologíaRESUMEN
Zinc oxide (ZnO) nanoparticles have been shown in the literature to have antibacterial properties and have been widely used in antibacterial formulations. However, one of the problems with ZnO nanoparticles is their tendency to aggregate, thereby causing damage to normal cells and lowering their antibacterial efficacy during application. In this work, we have attempted to avoid this by using a combination of ZnO nanoparticles and ionic liquids, a class of low melting salts containing organic cations and organic/inorganic anions that show antibacterial property as well, and tested the antibacterial activity of this dispersion. ZnO nanoparticles of 60 nm were dispersed in two different ionic liquids-choline acetate (IL1) and 1-butyl-3-methylimidazolium chloride (IL2)-to achieve high dispersibility, whereas ZnO dispersed in phosphate-buffered saline was taken as a control. These dispersions were tested on four strains- Escherichia coli, Bacillus subtilis, Klebsiella pneumoniae, and Staphylococcus epidermidis. Maximum efficiency was obtained for ZnO nanoparticles dispersed in imidazolium-based ionic liquids against skin-specific S. epidermidis. Skin infections induced by S. epidermidis are prevalent in hospital-acquired diseases. In most cases, traditional antibiotic-based therapies fail to combat such infections. Our strategy of developing a dispersion of ZnO nanoparticles in ionic liquids shows superior antibacterial efficacy in comparison to that shown individually by ZnO nanoparticles or ionic liquids. We have also established that the mechanism of killing this skin-specific bacterium is possibly through the production of reactive oxygen species leading to bacterial cell lysis. Further, we showed that this formulation is biocompatible and nontoxic to normal keratinocyte cells even under coculture conditions.
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Nanopartículas , Antibacterianos , Antiinfecciosos , Líquidos Iónicos , Óxido de ZincRESUMEN
The development of a new generation of biomaterials includes a sol-gel process to obtain glass foams, which is a well established method for CaO-SiO2-P2O5 compositions, but is not yet recognized for Bioglass® containing sodium oxide. In this study, we report, for the first time, the synthesis of a mesoporous 45S5 bioactive glass with superior textural characteristics and its in vitro dissolution and biomineralization behavior. Wormhole-like bioactive mesostructured 45S5 glass has been synthesized by an acid assisted sol-gel method followed by an evaporation induced self-assembly process. The virgin mesoporous 45S5 bioactive glass has been characterized by various analytical methods before and after soaking in simulated body fluid (SBF). The factors affecting the glass formation have been discussed in terms of the critical micelle concentration (CMC) at a particular temperature followed by a specified time interval. In vitro studies on the mesostructured 45S5 glass sample reveal the rapid formation of carbonated hydroxyapatite (HCA) with nano sized crystals. The mesostructured glass showed an excellent cell proliferation response without toxicity up to the concentration of 50 µg ml-1. Furthermore, we show that the 45S5 glass with superior textural parameters is extremely useful within the family of bioactive materials as it has accelerated formation kinetics of the apatite phase as compared to other bioactive glass compositions.
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The effect of cetyltrimethylammonium bromide (CTAB) concentration as a sacrificial template on tunable mesostructure textured bioactive glass nanoparticles has been explored and characterized. For the 10 mM CTAB concentration templated sample, smart bioactive glass nanoassembly (nBGA) has been tailored for dual antibiotic sustained release against osteomyelitis disease. The loading of two different drugs on the bioglass has been controlled through a thin chitosan sheath. To our knowledge, for the first time synergistic co-drug delivery of two antibiotics, namely sodium ampicillin and gentamicin sulfate, through bioglass nanoassembly, along with bone regeneration has been considered. Sustained co-release kinetics of dual anti-biotic drugs at different time points was evaluated. In addition to this, the in situ loss in bacterial viability with time of the dual drug loaded bioglass nanoassembly has been quantified against two different mono- and co-bacterial cultures by live/dead BacLight bacterial viability kit. Additionally, osteoblast like osteosarcoma cells proliferation on the dual drug loaded bioglass nanoassembly surface has been quantified in the presence and absence of bacterial challenge. This study provides a new insight into the application of bioactive glass as an efficient co-drug delivery vehicle for osteomyelitis.