RESUMO
The strategy of in vivo self-assembly has been developed for improved enrichment and long-term retention of anticancer drug in tumor tissues. However, most self-assemblies with non-covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling-induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation-responsive peptide-porphyrin conjugate P1 is synthesized, which self-assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2-fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria-targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.
RESUMO
The biofilm-mediated implant infections pose a huge threat to human health. It is urgent to explore strategies to reverse this situation. Herein, we design 3-amino-1,2,4-triazole-5-thiol (ATT)-modified gold nanoclusters (AGNCs) to realize biofilm-targeting and near-infrared (NIR)-II light-responsive antibiofilm therapy. The AGNCs can interact with the bacterial extracellular DNA through the formation of hydrogen bonds between the amine groups on the ATT and the hydroxyl groups on the DNA. The AGNCs show photothermal properties even at a low power density (0.5 W/cm2) for a short-time (5 min) irradiation, making them highly effective in eradicating the biofilm with a dispersion rate up to 90 %. In vivo infected catheter implantation model demonstrates an exceptional high ability of the AGNCs to eradicate approximately 90 % of the bacteria encased within the biofilms. Moreover, the AGNCs show no detectable toxicity or systemic effects in mice. Our study suggests the great potential of the AGNCs for long-term prevention and elimination of the biofilm-mediated infections.
Assuntos
Antibacterianos , Biofilmes , Ouro , Nanopartículas Metálicas , Biofilmes/efeitos dos fármacos , Ouro/química , Ouro/farmacologia , Nanopartículas Metálicas/química , Animais , Camundongos , Antibacterianos/farmacologia , Antibacterianos/química , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/fisiologia , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Raios Infravermelhos , Propriedades de SuperfícieRESUMO
Background: Dihydroartemisinin (DHA) has emerged as a promising candidate for anticancer therapy. However, the application of DHA in clinics has been hampered by several limitations including poor bioavailability, short circulation life, and low solubility, significantly restricting its therapeutic efficacy and leading to notable side effects during the treatment. Purpose: We present DHA-loaded zeolitic imidazolate framework-8 (D-ZIF) with controllable and targeted DHA release properties, leading to enhanced antitumor effects while reducing potential side effects. Methods: D-ZIF was prepared by one-pot synthesis method using methylimidazole (MIM), Zn(NO3)2â¢6H2O and DHA. We characterized the physical and chemical properties of D-ZIF by TEM, DLS, XRD, FT-IR, and TG. We measured the drug loading efficiency and the cumulative release of DHA in different pH conditions. We evaluated the cytotoxicity of D-ZIF on renal cell carcinoma (RCC786-O), glioma cells (U251), TAX-resistant human lung adenocarcinoma (A549-TAX) cells by CCK8 in vitro. We explored the possible antitumor mechanism of D-ZIF by Western blot. We evaluated the biocompatibility and hemolysis of D-ZIF and explored the in vivo antitumor efficiency in mice model by TUNEL testing and blood biomarker evaluations. Results: D-ZIF showed rhombic dodecahedral morphology with size of 129±7.2 nm and possessed a noticeable DHA encapsulation efficiency (72.9%). After 48 hours, D-ZIF released a cumulative 70.0% of the loaded DHA at pH 6.5, and only 42.1% at pH 7.4. The pH-triggered programmed release behavior of D-ZIF could enhance anticancer effect of DHA while minimizing side effects under normal physiological conditions. Compared with the free DHA group with 31.75% of A549-TAX cell apoptosis, the percentage of apoptotic cells was approximately 76.67% in the D-ZIF group. D-ZIF inhibited tumor growth by inducing tumor cell apoptosis through the mechanism of ROS production and regulation of Nrf2/HO-1 and P38 MAPK signaling pathways. D-ZIF showed potent effects in treating tumors with high safety in vivo. Conclusion: This pH-responsive release mechanism enhanced the targeting efficiency of DHA towards tumor cells, thereby increasing drug concentration in tumor sites with negligible side effects. Herein, D-ZIF holds great promise for curing cancers with minimal adverse effects.
Assuntos
Antineoplásicos , Artemisininas , Resistencia a Medicamentos Antineoplásicos , Imidazóis , Neoplasias Pulmonares , Estruturas Metalorgânicas , Espécies Reativas de Oxigênio , Artemisininas/química , Artemisininas/farmacologia , Artemisininas/farmacocinética , Animais , Humanos , Espécies Reativas de Oxigênio/metabolismo , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacocinética , Estruturas Metalorgânicas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Concentração de Íons de Hidrogênio , Células A549 , Liberação Controlada de Fármacos , Camundongos Nus , Apoptose/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Ensaios Antitumorais Modelo de Xenoenxerto , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Hemólise/efeitos dos fármacosRESUMO
Oral immunization can elicit an effective immune response and immune tolerance to specific antigens. When compared with the traditional injection route, delivering antigens via the gastrointestinal mucosa offers superior immune effects and compliance, as well as simplicity and convenience, making it a more optimal route for immunization. At present, various oral vaccine delivery systems exist. Certain modified bacteria, such as Salmonella, Escherichia coli and particularly Lactobacillus, are considered promising carriers for oral vaccines. These carriers can significantly enhance immunization efficiency by actively replicating in the intestinal tract following oral administration. The present review provided a discussion of the main mechanisms of oral immunity and the research progress made in the field of oral vaccines. Additionally, it introduced the advantages and disadvantages of the currently more commonly administered injectable COVID-19 vaccines, alongside the latest advancements in this area. Furthermore, recent developments in oral vaccines are summarized, and their potential benefits and side effects are discussed.
RESUMO
Multidrug-resistant (MDR) bacteria-caused infections have been a major threat to human health. The abuse of conventional antibiotics accelerates the generation of MDR bacteria and makes the situation worse. The emergence of nanomaterials holds great promise for solving this tricky problem due to their multiple antibacterial mechanisms, tunable antibacterial spectra, and low probabilities of inducing drug resistance. In this review, we summarize the mechanism of the generation of drug resistance, and introduce the recently developed nanomaterials for dealing with MDR bacteria via various antibacterial mechanisms. Considering that biosafety and mass production are the major bottlenecks hurdling the commercialization of nanoantibiotics, we introduce the related development in these two aspects. We discuss urgent challenges in this field and future perspectives to promote the development and translation of nanoantibiotics as alternatives against MDR pathogens to traditional antibiotics-based approaches.
RESUMO
Vancomycin is one of the last lines of defense against certain drug-resistant bacteria-caused infections. However, the high susceptibility to drug resistance and high toxicity seriously limit the application of vancomycin. Nanoantibiotics provide opportunities to solve these problems. Herein, we present mercaptophenylboronic acid (MBA)-modified gold nanoclusters with well-defined molecular formulas and structure (Au44(MBA)18) and excellent antibacterial activities against various drug-resistant bacteria such as vancomycin-resistant Enterococcus faecalis (VRE). Au44(MBA)18 interacts with bacteria by first attaching to teichoic-acid and destroying the cell wall and subsequently binding to the bacterial DNA. Au44(MBA)18 could be administered via multiple routes and has a high biosafety (500 mg/kg, no ototoxicity), overcoming the two major shortcomings of vancomycin (sole administration route and high ototoxicity). Our study is insightful for curing infections caused by multidrug-resistant bacteria using nanoantibiotics with high biosafety.
Assuntos
Enterococos Resistentes à Vancomicina , Vancomicina , Vancomicina/farmacologia , Enterococcus faecalis/genética , Ouro/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Enterococos Resistentes à Vancomicina/genética , Testes de Sensibilidade MicrobianaRESUMO
Sepsis is an acute systemic infectious syndrome with high fatality. Fast and accurate diagnosis, monitoring, and medication of sepsis are essential. We exploited the fluorescent metal-AIEgen frameworks (MAFs) and demonstrated the dual functions of protein detection and bacteria identification: (i) ultrasensitive point-of-care (POC) detection of sepsis biomarkers (100 times enhanced sensitivity); (ii) rapid POC identification of Gram-negative/positive bacteria (selective aggregation within 20 min). Fluorescent lateral flow immunoassays (LFAs) are convenient and inexpensive for POC tests. MAFs possess a large surface area, excellent photostability, high quantum yield (â¼80%), and multiple active sites serving as protein binding domains for ultrasensitive detection of sepsis biomarkers (IL-6/PCT) on LFAs. The limit of detection (LOD) for IL-6/PCT is 0.252/0.333 pg/mL. Rapid appraisal of infectious bacteria is vital to guide the use of medicines. The dual-functional fluorescent MAFs have great potential in POC tests for the clinical diagnosis of bacterial infections.
RESUMO
For epilepsy therapy, one-third of the patients worldwide are resistant to antiepileptic drugs mainly due to the existence of the blood-brain barrier (BBB) that prevents the drugs from reaching the epileptic lesions. Here, we design a double targeting nanoparticle carrying lamotrigine (LTG) to cross the BBB and further concentrate at the neurons. We prepare the nanoparticles on a microfluidic chip by encapsulating LTG in poly(lactic-co-glycolic acid) (PLGA) to form a core (PL) and capping the core with a shell of lipids conjugated with the D-T7 peptide (targeting the BBB) and Tet1 peptide (targeting the neuron) to form D-T7/Tet1-lipids@PL nanoparticles (NPs). In vitro and in vivo experiments show that D-T7/Tet1-lipids@PL NPs have excellent neuron targeting, antiepileptic, and protecting effects. Our approach provides a new strategy for improving the therapeutic efficacy of existing antiepileptic drugs.
RESUMO
The type II prokaryotic CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR/Cas9) adaptive immune system is a cutting-edge genome-editing toolbox. However, its applications are still limited by its inefficient transduction. Herein, we present a novel gene vector, the zwitterionic polymer-inspired material with branched structure (ZEBRA) for efficient CRISPR/Cas9 delivery. Polo-like kinase 1 (PLK1) acts as a master regulator of mitosis and overexpresses in multiple tumor cells. The Cas9 and single guide sgRNA (sgRNA)-encoded plasmid was transduced to knockout Plk1 gene, which was expected to inhibit the expression of PLK1. Our studies demonstrated that ZEBRA enabled to transduce the CRISPR/Cas9 system with large size into the cells efficiently. The transduction with ZEBRA was cell line dependent, which showed â¼10-fold higher in CD44-positive cancer cell lines compared with CD44-negative ones. Furthermore, ZEBRA induced high-level expression of Cas9 proteins by the delivery of CRISPR/Cas9 and efficient gene editing of Plk1 gene, and inhibited the tumor cell growth significantly. This zwitterionic polymer-inspired material is an effective and targeted gene delivery vector and further studies are required to explore its potential in gene delivery applications.
RESUMO
Aggregation is a key factor influencing the function of nanoparticles. Thioproline-modified gold nanoparticles show potent antibacterial activity, which is compromised by thioproline-mediated particle aggregation. By tuning the balance between the exposure and shielding of thioproline, a maximal antibacterial property of the gold nanoparticles is achieved.
Assuntos
Ouro , Nanopartículas Metálicas , Antibacterianos/farmacologia , Ouro/farmacologiaRESUMO
Multidrug-resistant (MDR) bacteria-infected wounds are challenging issues that threaten human health. Herein, L-thioproline (T) and Boc-capped L-thioproline (BT)-decorated gold nanoparticles (TBT-GNPs) with potent antibacterial activity against MDR bacteria are reported. The TBT-GNPs are composited with bacterial cellulose to form wound dressings which show excellent antimicrobial performance both in vitro and in vivo. Moreover, this dressing is both breathable and stretchable which is favorable for gas exchange to accelerate the wound healing. This work is insightful for developing multifunctional dressings to satisfy the clinical requirements.
Assuntos
Nanopartículas Metálicas , Infecção dos Ferimentos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bandagens , Ouro , Humanos , Nanopartículas Metálicas/uso terapêutico , Cicatrização , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologiaRESUMO
Multiple antibiotics and mycotoxins usually simultaneously exist in foods, which poses a serious threat to human health. How to detect them in one test with high sensitivity and fidelity is challenging. In this study, we develop a dual readout lateral flow immunodetection platform that can quantitatively detect five kinds of antibiotics and five kinds of mycotoxins within one sample. The platform is composed of a chip and a portable readout instrument where gold nanoparticle (AuNP)-based and chemiluminescence immunoassays could be performed to reach a maximum throughput of 220 analytes in one setting. For a rapid screen, qualitative analysis by detecting the color change of the deposited AuNPs on the chip could be realized. For quantitative results, chemiluminescence imaging and analysis can be completed within 15 min. Apart from the high throughput and high efficiency, this platform has a high detection sensitivity. For instance, the limit of detection (LOD) for thiamphenicol (a representative antibiotic) and fumonisins B1 (a representative mycotoxin) is 8 times and 40 times lower than those of the previously reported methods, respectively. Thus, this dual readout immunodetection platform is promising as a universal device for rapid and quantitative detection of multiple analytes with high throughput, high sensitivity, and high fidelity.
Assuntos
Nanopartículas Metálicas , Micotoxinas , Antibacterianos , Ouro , Humanos , Imunoensaio/métodos , Limite de Detecção , Micotoxinas/análiseRESUMO
Nanomaterials usually kill bacteria via multiple mechanisms which are not explicit to the same degree as those of conventional antibiotics. This situation may hinder the development of novel nanoscale antibiotics. Here, we present aminophenol (AP) to modify gold nanoparticles (AP_Au NPs) which show a broad antibacterial spectrum and potent antibacterial effects against multidrug-resistant (MDR) bacteria with clear antibacterial mechanisms. AP_Au NPs can not only damage bacterial cell walls but also bind to the 16S rRNA to block bacterial protein synthesis. Moreover, AP_Au NPs show excellent performance in curing abdominal bacterial infections in an in vivo model. AP_Au NPs thus have the potential to become a novel antibacterial agent for clinical applications.
Assuntos
Infecções Bacterianas , Nanopartículas Metálicas , Aminofenóis/farmacologia , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Bactérias , Infecções Bacterianas/tratamento farmacológico , Ouro/farmacologia , Humanos , Nanopartículas Metálicas/uso terapêutico , Testes de Sensibilidade Microbiana , RNA Ribossômico 16SRESUMO
Correction for 'Screening on-chip fabricated nanoparticles for penetrating the blood-brain barrier' by Qinghong Hou et al., Nanoscale, 2022, DOI: 10.1039/d1nr05825h.
RESUMO
The inability of drugs to cross the blood-brain barrier (BBB) makes it difficult to treat diseases in the central nervous system. It is known that peptides with or without specific receptors on the BBB showed different or even controversial neuron targeting capability in different reports. So, it is necessary to clarify how these peptides work as targeting molecules in the central nervous system. Herein, we evaluate and compare the performance of 6 kinds of peptides with (T7, D-T7, and GSH) or without (TGN, CGN, and TAT) BBB-specific receptors by conjugating these peptides on lipids to serve as a shell to encapsulate a core of PLGA and lamotrigine to form nanoparticles for targeted epilepsy therapy. In vitro assay shows that the TAT-modified nanoparticles show the highest internalization efficacy in the BBB model cell line bEnd·3 cells and hippocampal neurons. By contrast, experiments in mice show that the D-T7-modified nanoparticles have the highest brain targeting and epilepsy therapeutic efficiency. Thus, our experiments uncover the different performances of the 6 peptides at different levels (in vitro and in vivo), which is insightful for developing novel delivery systems for treating diseases in the central nervous system.
Assuntos
Neoplasias Encefálicas , Nanopartículas , Animais , Transporte Biológico , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Camundongos , Nanopartículas/químicaRESUMO
We report aminophenol (A)-modified gold nanoparticles (AGNPs), which have potent antibacterial effects against multidrug-resistant bacteria with a broad antibacterial spectrum. Moreover, a series of in vitro and in vivo models indicate that AGNPs are much less ototoxic than aminoglycosides. AGNPs thus have the potential to replace aminoglycosides as novel antibacterial agents for clinical applications.
Assuntos
Aminofenóis/química , Bactérias/efeitos dos fármacos , Ouro/química , Nanopartículas Metálicas/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cães , Escherichia coli/efeitos dos fármacos , Humanos , Larva/efeitos dos fármacos , Larva/fisiologia , Nanopartículas Metálicas/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Peixe-Zebra/crescimento & desenvolvimentoRESUMO
The replacement of dressings may cause secondary damage to the wounds; thus, the real-time monitoring of the state of wound dressings is crucial for evaluating wound care processes. Herein, we report a smart dressing to self-monitor residue nanomedicine on it during the application. We load aminobenzeneboronic acid (ABA)-modified gold nanoclusters (A-GNCs) on bacterial cellulose (BC) membranes as an antibacterial wound dressing to display the amount of residual nanomedicine (A-GNCs) by in situ colorimetry during the application in remedying multi-drug-resistant (MDR) bacteria-infected wounds. A-GNCs emit bright orange fluorescence under UV light, whereas the BC membrane is transparent at a humidified state on the wounds. Thus, the BC-A-GNCs nanocomposite (BGN) shows decreasing intensity of orange fluorescence with the release of the A-GNCs, indicating the appropriate time points for the replacement of the dressing. The BGN, which can realize accurate self-monitoring in a simple, low-cost, and efficient way, thus holds great promise for broad clinical applications.
Assuntos
Ouro , Nanocompostos , Ouro/química , Bandagens , Antibacterianos/farmacologia , Antibacterianos/química , Celulose/química , Nanocompostos/química , BactériasRESUMO
With the long-term and extensive abuse of antibiotics, bacteria can mutate into multidrug-resistant (MDR) strains, resist the existing antibiotics, and escape the danger of being killed. MDR bacteria-caused skin infections are intractable and chronic, becoming one of the most significant and global public-health issues. Thus, the development of novel antimicrobial materials is urgently needed. Non-antibiotic small molecule-modified gold nanoclusters (AuNCs) have great potential as a substitute for commercial antibiotics. Still, their narrow antibacterial spectrum hinders their wide clinical applications. Herein, we report that 4,6-diamino-2-pyrimidinethiol (DAPT)-modified AuNCs (DAPT-AuNCs) can fight against Gram-negative and Gram-positive bacterial strains as well as their MDR counterparts. By modifying DAPT-AuNCs on nanofibrous films, we develop an antibiotic film as innovative dressings for curing incised wounds, which exhibits excellent therapeutic effects on wounds infected by MDR bacteria. Compared to the narrow-spectral one, the broad-spectral antibacterial activity of the DAPT-AuNCs-modified film is more suitable for preventing and treating skin infections caused by various kinds of unknown bacteria. Moreover, the antibacterial films display excellent biocompatibility, implying the great potential for clinical applications.
Assuntos
Antibacterianos/uso terapêutico , Bandagens , Infecções por Escherichia coli/tratamento farmacológico , Nanopartículas Metálicas/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Animais , Antibacterianos/química , Antibacterianos/toxicidade , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/patologia , Feminino , Ouro/química , Ouro/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Pirimidinas/química , Pirimidinas/toxicidade , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/microbiologia , Pele/patologia , Infecções Cutâneas Estafilocócicas/patologia , Staphylococcus aureus/efeitos dos fármacos , Compostos de Sulfidrila/química , Compostos de Sulfidrila/toxicidade , Cicatrização/efeitos dos fármacosRESUMO
The pharmacokinetics is a critical factor determining the clinical applicability of nanomaterials. Systematic study of the pharmacokinetics of functional nanomaterials is thus significant for promoting their applications. Herein, we take aminophenylboronic acid and mercaptophenylboronic acid-co-modified gold nanoparticles (A/M-Au NPs) with potent and tunable antibacterial activity as an example to study their behaviors in vitro and in vivo. The maximum concentration (Cmax, 2 mg L-1), the time to reach the maximum concentration (Tmax, 6 h), and the half-life (T1/2, 12 h) in the plasma of mice reflect appropriate pharmacokinetics of the gold nanoparticles as an ideal nano-antibiotic. Strikingly, the A/M-Au NPs show an extremely high median lethal dose (920 mg kg-1), which is about 100 times their effective dose (7.2 mg kg-1), suggesting their outstanding biosafety. The adequate pharmacokinetic profile and the high biosafety of the gold nanoparticles pave the way for their potential biomedical applications.