Binary Proton Therapy of Ehrlich Carcinoma Using Targeted Gold Nanoparticles.

Proton therapy can treat tumors located in radiation-sensitive tissues. This article demonstrates the possibility of enhancing the proton therapy with targeted gold nanoparticles that selectively recognize tumor cells. Au-PEG nanoparticles at concentrations above 25 mg/L and 4 Gy proton dose caused complete death of EMT6/P cells in vitro. Binary proton therapy using targeted Au-PEG-FA nanoparticles caused an 80% tumor growth inhibition effect in vivo. The use of targeted gold nanoparticles is promising for enhancing the proton irradiation effect on tumor cells and requires further research to increase the therapeutic index of the approach.

Bismuth Nanoparticles Increase Effectiveness of Proton Therapy of Ehrlich Carcinoma.

We studied the antitumor activity of the combined use of local proton irradiation in two modes (10 and 31 Gy) with preliminary intra-tumoral injection of two types of bismuth nanoparticles differing in surface coating: coated with the amphiphilic molecule Pluronic-F127 or Silane-PEG (5 kDa)-COOH polymer. Nanoparticles were used in doses of 0.75 and 1.5 mg/mouse. In two independent series on experimental tumor model (solid Ehrlich carcinoma), bismuth nanoparticles of both modifications injected directly into the tumor enhanced the antitumor effects of proton therapy. Moreover, the radiosensitizing effect of bismuth nanoparticles administered via this route increased with the increasing the doses of nanoparticles and the doses of radiation exposure. In our opinion, these promising data obtained for the first time extend the possibilities of treating malignant neoplasms.

Polymer-coated BiOCl nanosheets for safe and regioselective gastrointestinal X-ray imaging.

Bismuth-based compounds are considered to be the best candidates for computed tomography (CT) imaging of gastrointestinal (GI) tract due to high X-ray absorption. Here, we report the introduction of polymer-coated bismuth oxychloride (BiOCl) nanosheets for highly efficient CT imaging in healthy mice and animal with colitis. We demonstrate simple, low cost and fast aqueous synthesis protocol which provides gram-quantity yield of chemically stable BiOCl nanosheets. The developed contrast gives 2.55-fold better CT enhancement compared to conventional contrast with negligible in vivo toxicity. As a major finding we report a regioselective CT imaging of GI tract by using nanoparticles coated with differentially charged polymers. Coating of nanoparticles with a positively charged polymer leads to their fast accumulation in small intestine, while the coating with negatively charged polymers stimulates prolonged stomach retention. We propose that this effect may be explained by a pH-controlled aggregation of nanoparticles in stomach. This feature may become the basis for advancement in clinical diagnosis of entire GI tract.

Phage-mimicking nanoagents for rapid depolymerase specificity screening against multidrug resistant bacteria.

With the rise of drug resistance, bacteriophages and bacteriophage-derived proteins may become an efficient successor to traditional antibiotics. While the enormous natural diversity of the phages allows matching virtually any bacteria, identification of the potentially life-saving phage is currently a tedious and time-consuming challenge that often cannot be performed within a reasonable time. Here we show a rapid 1-min bacteriophage screening assay based on specially constructed phage-mimicking nanoagents and surface plasmon resonance effect. Within the assay, a panel of phage-mimicking gold nanoparticles, possessing the specificity and enzymatic activity of a particular phage, is mixed with a suspension of the bacteria of interest. The spectral behaviour of the assay mix allows measurement of two critical parameters of the nanoagents and the corresponding bacteriophages: 1) direct assessment of their specificity due to convergence of the particles on the cell walls, and more importantly, 2) real-time evaluation of their enzymatic activity for the destruction of the cell capsule via detection of nanoagent detachment from the surface of bacteria. The proposed assay overcomes the current time limitations of the phage-bacteria matching procedures and thereby can facilitate faster development and adoption of phage-based therapies as a much-needed alternative to traditional antibiotics.

Nanoparticle-based drug delivery via RBC-hitchhiking for the inhibition of lung metastases growth.

Delivery of particle-based theranostic agents via their transportation on the surfaces of red blood cells, commonly referred to as RBC-hitchhiking, has historically been developed as a promising strategy for increasing the extremely poor blood circulation lifetime, primarily, of the large-sized sub-micron agents. Here, we show for the first time that RBC-hitchhiking can be extremely efficient for nanoparticle delivery and tumor treatment even in those cases when no circulation prolongation is observed. Specifically, we demonstrate that RBC-hitchhiking of certain small 100 nm particles, unlike that of the conventional sub-micron ones, can boost the delivery of non-targeted particles to lungs up to a record high value of 120-fold (and up to 40% of the injected dose). To achieve this remarkable result, we screened sub-200 nm nanoparticles of different sizes, polymer coatings and ζ-potentials and identified particles with the optimal RBC adsorption/desorption behavior. Furthermore, we demonstrated that such RBC-mediated rerouting of particles to lungs can be used to fight pulmonary metastases of aggressive melanoma B16-F1. Our findings could change the general paradigm of drug delivery for cancer treatment with RBC-hitchhiking. It is not the blood circulation lifetime that is the key factor for nanoparticle efficiency, but rather the complexation of nanoparticles with the RBC. The demonstrated technology could become a valuable tool for development of new strategies based on small nanoparticles for the treatment of aggressive and small-cell types of cancer as well as other lung diseases.

Magnetometry based method for investigation of nanoparticle clearance from circulation in a liver perfusion model.

Nanoparticles (NPs) are among the most promising agents for advanced theranostics. However, their functioning in vivo is severely inhibited by the mononuclear phagocyte system (MPS), which rapidly removes all foreign entities from blood circulation. Little is known about the sequestration mechanisms and the ways to counteract them. New methods are highly demanded for investigation with high scrutiny of each aspect of NP clearance from blood. For example, while liver macrophages capture the majority of the administered particles, reliable investigation of this process in absence of other MPS components is hard to implement in vivo. Here, we demonstrate a novel method for real-time investigation hepatic uptake of NPs in an isolated perfused liver based on an extremely accurate magnetometric registration technique. The signal is obtained solely from the magnetic NPs without any 'background' from blood or tissues, which is a significant advantage over other techniques, e.g. optical ones. We illustrate the method capacity by investigation of behavior of different particles and show good correlation with in vivo studies. We also demonstrate notable suitability of the method for studying the NP clearance from the flow in the user-defined mediums, e.g. those containing specific serum components. Finally, the method was applied to reveal an interesting effect of short-term decrease of liver macrophage activity after the first interaction with small amounts of NPs. The developed perfusion model based on the high-performance magnetometry can be used for finding new mechanisms of NP sequestration and for development of novel 'stealth' nanoagents.

Synthesis and Characterization of Hybrid Core-Shell Fe3O4/SiO2 Nanoparticles for Biomedical Applications.

The creation of markers that provide both visual and quantitative information is of considerable importance for the mapping of tissue macrophages and other cells. We synthesized magnetic and magneto-fluorescent nanomarkers for the labeling of cells which can be detected with high sensitivity by the magnetic particle quantification (MPQ) technique. For stabilization under physiological conditions, the markers were coated with a dense silica shell. In this case, the size and zeta-potential of nanoparticles were controlled by a modified Stober reaction. Also, we developed a novel facile two-step synthesis of carboxylic acid-functionalized magnetic SiO2 nanoparticles, with a carboxyl polymer shell forming on the nanoparticles before the initiation of the Stober reaction. We extensively characterized the nanomarkers by transmission electron microscopy, electron microdiffraction, and dynamic and electrophoretic light scattering. We also studied the nanoparticle cellular uptake by various eukaryotic cell lines.

Synthesis of magnetic silica nanomarkers with controlled physicochemical properties.

Magnetic markers which can be detected with an extremely high sensitivity with the method of magnetic particle quantification (MPQ) were synthesized. Using a controlled Stober reaction, a set of magnetic silica markers of different sizes and zeta potentials was obtained. The use of a carboxymethyl dextran polymer to stabilize the magnetite particles during the synthesis made it possible to substantially reduce the detection limit of the obtained construct, which opens up new opportunities for creating effective diagnostic nanoagents.

A comprehensive study of interactions between lectins and glycoproteins for the development of effective theranostic nanoagents.

A comprehensive study of the interactions between lectins and glycoproteins possessing different glycosylation profiles in the composition of nanoparticles was carried out in order to find specifically interacting protein pairs for the creation of novel classes of multifunctional nanoagets that based on protein-assisted selfassembly. We obtained information about specific interactions of certain lectins with selected glycoproteins as well as about the ability of certain monosaccharides to competitively inhibit binding of glycoproteins with lectins. These protein-mediated interactions may be involved in the formulation of self-assembled nanoparticles for therapy and diagnostics of various diseases.