The chemical composition, size, shape and surface characteristics of nanoparticles affect the way proteins bind to these particles, and this in turn influences the way in which nanoparticles interact with cells and tissues. Nanomaterials bound with proteins can result in physiological and pathological changes, including macrophage uptake, blood coagulation, protein aggregation and complement activation, but the mechanisms that lead to these changes remain poorly understood. Here, we show that negatively charged poly(acrylic acid)-conjugated gold nanoparticles bind to and induce unfolding of fibrinogen, which promotes interaction with the integrin receptor, Mac-1. Activation of this receptor increases the NF-κB signalling pathway, resulting in the release of inflammatory cytokines. However, not all nanoparticles that bind to fibrinogen demonstrated this effect. Our results show that the binding of certain nanoparticles to fibrinogen in plasma offers an alternative mechanism to the more commonly described role of oxidative stress in the inflammatory response to nanomaterials.
The binding of fibrinogen to various nanoparticles can result in protein unfolding and exposure of cryptic epitopes that subsequently interact with cell surface receptors. This response is dependent on the size, charge, and concentration of the nanoparticle. Here we examine the binding kinetics of human fibrinogen to negatively charged poly(acrylic acid)-coated gold nanoparticles ranging in size from 7 to 22 nm. These particles have previously been shown to elicit an inflammatory response in human cells. The larger nanoparticles bound fibrinogen with increasing affinity and a slower dissociation rate. Each fibrinogen molecule could accommodate two 7 nm nanoparticles but only one when the diameter increased to 10 nm. Nanoparticles larger than 12 nm bound multiple fibrinogen molecules in a positively cooperative manner. However, in the presence of excess nanoparticle, fibrinogen induced aggregation of the larger particles that could bind more than one protein molecule. This is consistent with interparticle bridging by the fibrinogen. Taken together, these results demonstrate that subtle changes in nanoparticle size can influence protein binding both with the surface of the nanoparticle and within the protein corona.
A variety of functional polymer chains prepared by RAFT were directly grafted onto 5, 10, and 20 nm gold nanoparticles (AuNPs). The polymer shell coating the AuNPs was densely packed because of the strong binding between the trithioester groups on the polymer chain-ends and gold. It was found that due to the densely packed nature of the shell the polymer chains were significantly stretched compared to their usual Gaussian coil conformation in water. This was even evident for polymer chains where ionic repulsion between neighboring chains should be significant. Therefore, with such high grafting densities the surface properties and size of the hybrid nanoparticles should be the only contributing factors in cellular uptake in epithelial Caco-2 cells. This study has provided valuable insight into the effects of charge and size of NPs for the application of NPs in the delivery of therapeutic agents across the intestine. Our results showed that the negatively charged AuNPs were taken up by the cells with greater efficiency than the neutral AuNPs, most probably due to binding with membrane proteins. The positively charged AuNPs as expected gave the greatest uptake efficiency. Interestingly, the uptake for PNIPAM-AuNPs (hydrophobic coating at 37 degrees C) increased from approximately 2% efficiency after a 30 min incubation to 8% after 2 h, and was much greater than the negative or neutral AuNPs. We believe that this was due to the interplay between the hydrophobic nature of the NPs and their increased size.
This paper describes a simple method of formulating PEGylated siRNA-loaded lipid particles. Given the ease of preparation, long term stability and favourable characteristics for in vivo delivery, our work represents an advance in lipid formulation of siRNA for in vivo use.
The binding of proteins to nanoparticles is an important event that can determine the biological effect of nanoparticles in the body. We examined plasma protein binding to gold nanoparticles (5-20 nm) with different surface charge. Positively and negatively charged nanoparticles bound a range of proteins whereas neutral nanoparticle bound very little. As little as 25% neutral polymer on the surface of the charged nanoparticles inhibited protein binding, with only slight change in surface charge. Fibrinogen bound with high affinity to both of the charged nanoparticles. However, binding kinetics and protease digestion suggested that the binding orientation for each nanoparticle was different. Only the negatively charged nanoparticles induced cytokine release from THP-1 cells. While common proteins can bind to different nanoparticles, the biological outcome may not be the same. Consequently, knowledge about the composition of the protein corona is not sufficient to predict biological effects of nanoparticles.
We synthesized a library of polymer-coated gold nanoparticles (AuNPs) with well-defined sizes (5, 10, and 20 nm) and surface properties, and investigated their efficiency to cross the Caco-2 epithelial barrier and disrupt tight junctions connecting the cellular barrier. The positively charged and hydrophobic polymer-coated AuNPs showed little or no translocation across the model Caco-2 monolayer. Most of these positive and hydrophobic nanoparticles were either bound to the surface or internalized within the cell. The neutral and negatively charged polymer-coated AuNPs with a size of 5 nm showed a significantly higher translocation. All polymer-coated AuNPs induced the translocation of small molecules across the cellular monolayer, suggesting the loosening of the paracellular tight junction joining individual cells. The decrease in the TEER values of the monolayers supported the opening of the tight junctions. These tight junctions fully recovered for most polymer-coated AuNPs 12 h after removal of the nanoparticles. The exception was the cationic polymer-coated AuNPs in which the barrier function only recovered up to 62%. The library of polymer-coated AuNPs showed no apparent signs of hemolysis to erythrocytes at physiological pH. Our investigation has provided insight on the influence of polymer coatings on the epithelial barrier.
The most common feature for antigen-delivery systems is their particulate nature. Together with a certain depot effect, it is the particulate nature that primarily dictates whether the antigen-delivery system will be successful in inducing a certain type and strength of immune response. In this article, we will summarize recent data on particulate delivery systems for peptide and protein antigens with a main focus on lipid or polymer-based particles, all of which possess high potential as both preventive and therapeutic vaccines for parenteral, nasal, and possibly oral administration.
BackgroundThe poor prognosis of patients with drug resistant ovarian cancer and the lack of targeted therapy have raised the need for alternative treatments. Albendazole (ABZ) is an anti-parasite compound capable of impairing microtubule formation. We hypothesized that ABZ could be repurposed as a potential anti-angiogenic drug due to its potent inhibition of vascular endothelial growth factor (VEGF) in ovarian cancer with ascites. However, the poor aqueous solubility of ABZ limits its potential for cancer therapy. In this study, we have assembled ABZ with bovine serum albumin into nanoparticles with a size range of 7–10 nm (BSA-ABZ) and 200–250 nm (Nab-ABZ). We further examined the anticancer effects of ABZ carrying nanoparticles in ovarian cancer cells, in both in vitro and in vivo models.ResultsDrug release studies demonstrated that about 93% of ABZ was released from BSA-ABZ 10 nm in comparison to 83% from Nab-ABZ 200 nm at pH 7.4 in 8 days. In vitro cell proliferation studies showed that the BSA-ABZ 10 nm exhibited the highest killing efficacy of ovarian cancer cells with surprisingly least toxicity to healthy ovarian epithelial cells. Confocal microscopy and fluorescence activated cell sorting analysis (FACS) revealed more efficient internalization of the BSA-ABZ 10 nm by cancer cells. For in vivo studies, we examined the tumor growth, ascites formation and the expression of VEGF and secreted protein acidic and rich in cysteine (SPARC) in tumor samples and only VEGF in plasma samples. The BSA-ABZ 10 nm reduced the tumor burden significantly (p < 0.02) at a much lower drug dose (10 μg/ml) compare to free drug. Both formulations were capable of suppressing the ascites volume significantly (p < 0.05) and reducing the number of ascites cells. The expression of VEGF and SPARC was also reduced, which indicates the underlying therapeutic mechanism of the ABZ.ConclusionOur data suggest that the BSA-ABZ may hold promise for the treatment and control of progression of ovarian cancer with ascites. However further studies are required to examine the efficacy of both the formulations in aggressive models of recurrent ovarian cancer with respect to particle size and dosing parameters.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-015-0082-8) contains supplementary material, which is available to authorized users.
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