Targeted delivery of chemotherapeutics to tumors has the potential to reach a high dose at the tumor while minimizing systemic exposure. Incorporation of antibody within a micellar platform ...represents a drug delivery system for tumor-targeted delivery of antitumor agents. Such modified immunomicelles can result in an increased accumulation of antitumor agents and enhanced cytotoxicity toward cancer cells. Here, mixed dendrimer micelles (MDM) composed of PEG2k-DOPE-conjugated generation 4 polyamidoamine dendrimer G4-PAMAM-PEG2k-DOPE and PEG5k-DOPE were coloaded with doxorubicin and siMDR-1. This formulation was further modified with monoclonal antibodies 2C5 with nucleosome-restricted specificity that effectively recognized cancer cells via the cell-surface-bound nucleosomes. Micelles with attached 2C5 antibodies significantly enhanced cellular association and tumor killing in both monolayer and spheroid tumor models as well as in vivo in experimental animals compared to the nontargeted formulations.
Nano silver is one of the most widely used engineering nanomaterials with antimicrobial activity against bacteria, fungi, and viruses. However, the widespread application of nano silver preparations ...in daily life raises concerns about public health. Although several review articles have described the toxicity of nano silver to specific major organs, an updated comprehensive review that clearly and systematically outlines the harmful effects of nano silver is lacking. This review begins with the routes of exposure to nano silver and its distribution in vivo. The toxic reactions are then discussed on three levels, from the organ to the cellular and subcellular levels. This review also provides new insights on adjusting the toxicity of nano silver by changing their size and surface functionalization and their combination with other materials to form a composite formulation. Finally, future development, challenges, and research directions are discussed.
With the passage of years and the progress of research on ribonucleic acids, the range of forms in which these molecules have been observed grows. One of them, discovered relatively recently, is ...circular RNA - covalently closed circles (circRNA). In recent years, there has been a huge increase in the interest of researchers in this group of molecules. It entailed a significant increase in the state of knowledge about them, which in turn caused a dramatic change in their perception. Rather than seeing circular RNAs as curiosities that represent a minor information noise in a cell or a result of RNA misprocessing, they came to be regarded as a common, essential, and potentially extremely useful group of molecules. Nevertheless, the current state of the art of circRNA is full of white cards. A lot of valuable information has been obtained from high-throughput methods to study whole transcriptomes, but many issues related to circular RNAs still need to be clarified. Presumably, each answer obtained will raise several new questions. However, circRNAs have a wealth of potential applications, including therapeutic applications.
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Neutrophil extracellular traps (NETs) are structures consisting of decondensed chromatin with associated proteins, including histones and antimicrobial peptides, released from activated neutrophils. ...They are believed to be one of the body's first lines of defense against infectious agents. Despite their beneficial effect on the immune response process, some studies indicate that their excessive formation and the associated accumulation of extracellular DNA (eDNA) together with other polyelectrolytes (F-actin) plays an important role in the pathogenesis of many diseases. Thus NETs formation and removal are clinically significant. The monoclonal antibody 2C5 has strong specificity for intact nucleohistones (NS) and targets NS in NETs as we previously confirmed. Creation of a nano preparation that can specifically recognize and destroy NETs represents the aim for treatment many diseases. 2C5 antibody functionalized micelles coated with DNase I were created to achieve this aim.
Schematic illustration of the 2C5 targeted MDM (mixed DNase I micelles) components (created by http://Biorender.com). Display omitted
Breast cancer is potentially a lethal disease and a leading cause of death in women. Chemotherapy and radiotherapy are the most frequently used treatment options. Drug resistance in advanced breast ...cancer limits the therapeutic output of treatment. The leading cause of resistance in breast cancer is endocrine and hormonal imbalance, particularly in triple negative and HER2 positive breast cancers. The efflux of drugs due to p-gp’s activity is another leading cause of resistance. Breast cancer resistant protein also contributes significantly. Strategies used to combat resistance include the use of nanoparticles to target drug delivery by co-delivery of chemotherapeutic drugs and genes (siRNA and miRNA) that help to down-regulate genes causing resistance. The siRNA is specific and effectively silences p-gp and other proteins causing resistance. The use of chemosensitizers is also effective in overcoming resistance. Chemo-sensitizers sensitize cancer cells to the effects of chemotherapeutic drugs. Novel anti-neoplastic agents such as antibody-drug conjugates and mesenchymal stem cells are also effective tools used to improve the therapeutic response in breast cancer. Similarly, combination of photo/thermal ablation with chemotherapy can act to overcome breast cancer resistance. In this review, we focus on the mechanism of breast cancer resistance and the nanoparticle-based strategies used to combat resistance in breast cancer.
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•Overview of resistance mechanisms in breast cancer.•Summary of recent strategies in overcoming resistance in breast cancer.•Nanotechnology-based strategies to overcome breast cancer resistance
Neutrophil extracellular traps (NETs) are large DNA reticular structures secreted by neutrophils and decorated with histones and antimicrobial proteins. As a key mechanism for neutrophils to resist ...microbial invasion, NETs play an important role in the killing of microorganisms (bacteria, fungi, and viruses). Although NETs are mostly known for mediating microbial killing, increasing evidence suggests that excessive NETs induced by stimulation of physical and chemical components, microorganisms, and pathological factors can exacerbate inflammation and organ damage. This review summarizes the induction and role of NETs in inflammation and focuses on the strategies of inhibiting NETosis and the mechanisms involved in pathogen evasion of NETs. Furthermore, herbal medicine inhibitors and nanodelivery strategies improve the efficiency of inhibition of excessive levels of NETs.
Combination therapy has gained a lot of attention thanks to its superior activity against cancer. In the present study, we report a cRGD-targeted liposomal preparation for co-delivery of programmed ...cell death ligand 1 (PD-L1) small interfering RNA (siRNA) and anemoside B4 (AB4)AB4/siP-c-Land evaluate its anticancer efficiency in mouse models of LLC and 4T1 tumors. AB4/siP-c-L showed a particle size of (180.7 ± 7.3) nm and a ζ-potential of (32.8 ± 1.5) mV, with high drug encapsulation, pH-sensitive release properties, and good stability in serum. AB4/siP-c-L demonstrated prolonged blood circulation and increased tumor accumulation. Elevated cellular uptake was dependent on the targeting ligand cRGD. This combination induced significant tumor inhibition in LLC xenograft tumor-bearing mice by downregulating PD-L1 protein expression and modulating the immunosuppressive microenvironment. Liposomes favored the antitumor T-cell response with long-term memory, without obvious toxicity. A similar tumor growth inhibition was also demonstrated in the 4T1 tumor model. In summary, our results indicate that cRGD-modified and AB4- and PD-L1 siRNA-coloaded liposomes have potential as an antitumor preparation, and this approach may lay a foundation for the development of a new targeted drug delivery system.
Chemotherapy is much less effective in tumors where multidrug resistance (MDR) has been found. To reduce resistance in tumors, small interfering RNA (siRNA) can be used to downregulate efflux ...proteins like P-glycoprotein (P-gp). In this investigation, generation 4 (G4) polyamidoamine (PAMAM)-PEG2k-DOPE and PEG5k-DOPE and monoclonal antibody 2C5 (mAb 2C5)-PEG7k-DOPE conjugates were post-inserted into the mixed dendrimer micelles. The copolymers self-assemble to create a micelle, which can contain hydrophobic chemotherapeutic medicines in its center because DOPE conjugates are inherently amphiphilic. The cationic charges on the G4 PAMAM dendrimer interact electrostatically with the siRNA to form a bond. These nano-preparations' functionalized with tumor-specific mAb 2C5 enabled better tumor targeting. The off-target effects can be reduced by increasing the drug and siRNA accumulation at the tumor site because of active targeting to tumors. In vitro tests revealed that the micelles were more effective and had stronger cellular association with the 2C5 modification. MDR cancer cell lines from the ovary (SKOV-3TR) and breast (MDA-MB-231) were used to test the immunomicelle preparation for cytotoxicity.Further, in this study, siRNA, and doxorubicin (DOX) were co-delivered to the tumor site in both male and female xenograft mice models using monoclonal antibody 2C5-modified dendrimer-based micelles. The 2C5 antibody that targets nucleosomes identifies cancer cells by binding to their nucleosomes on the cell surface. Using a wound healing assay, the 2C5-modified formulation's capacity to prevent the metastasis of extremely aggressive triple-negative breast cancer (MDA-MB-231) was evaluated. Additionally, the advancement of the tumor volume was measured to evaluate the formulation's therapeutic effectiveness. Body weight measurements, ex vivo tumor and liver weights, as well as the Aspartate Aminotransferase (AST) assay were utilized to evaluate the toxicities brought on by DOX treatment. Using ex vivo imaging of DOX in the tumors and livers of both males and females, the capability of 2C5 antibody-functionalized nanoparticles in targeting cargo to the tumor location in vivo was assessed. At the current dose of DOX and siRNA, the treatment group using 2C5-mdofiled micelles has proven to be secure. We also draw the conclusion that additional optimization of the dose of DOX and siRNA is necessary for improved efficacy in a metastatic tumor model, which will be the focus of our upcoming research.Overall, this study highlighted the ability of dendrimer-based nanopreparation as a promising platform for tumor-specific co-delivery of both hydrophobic chemotherapeutics and siRNA in multidrug resistant cancers.
Thermoresponsive drug delivery systems have been used previously to deliver chemotherapeutic agents to tumors in a hyperthermic microenvironment. The objective of the present study was to fabricate ...and characterize Cisplatin-loaded thermoresponsive liposomes (CDDP@TSLs) for enhanced anticancer efficacy. CDDP@TSLs were prepared by a thin-film hydration method with varied ratios of dipalmitoyl phosphatidylcholine and hydrogenated soy phosphatidylcholine, and fixed amounts of distearyl phosphoethanolamine polyethylene glycol2000 and Cisplatin. The prepared CDDP@TSLs had a particle size of up to 201.8 nm, surface a charge of −6.31 mV, high entrapment efficiency of Cisplatin, and thermoresponsive release behavior. The CDDP@TSLs were tested in vitro for cytotoxicity against A549 cells (lung carcinoma), SKOV-3 cells (ovarian cancer) and MDA-MB-231 cells (breast adenocarcinoma) at 37 °C and 39 °C since the temperature at tumorous sites can be higher than at normal sites. The results with CDDP@TSLs showed greater cytotoxicity at 39 °C. Cellular uptake studies displayed a many-fold uptake of the particles by the various cell types and their enhanced internalization at tumor sites. In lung carcinomas induced in albino mice by diethylnitrosamine, healing by CDDP@TSL treatment indicated the efficacy of the thermoresponsive liposomal formulation. The developed CDDP@TSLs may provide an enhanced anticancer efficacy that may maximize the therapeutic effect and minimize the systemic off-site toxicities.
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