RESUMO
Insufficient drug accumulation in tumors is still a major concern for using cancer nanotherapeutics. Here, the neutrophil-based delivery of three nanoparticle types-liposomes, PLGA, and magnetite nanoparticles-was assessed both in vitro and in vivo. Confocal microscopy and a flow cytometry analysis demonstrated that all the studied nanoparticles interacted with neutrophils from the peripheral blood of mice with 4T1 mammary adenocarcinoma without a significant impact on neutrophil viability or activation state. Intravital microscopy of the tumor microenvironment showed that the neutrophils did not engulf the liposomes after intravenous administration, but facilitated nanoparticle extravasation in tumors through micro- and macroleakages. PLGA accumulated along the vessel walls in the form of local clusters. Later, PLGA nanoparticle-loaded neutrophils were found to cross the vascular barrier and migrate towards the tumor core. The magnetite nanoparticles extravasated in tumors both via spontaneous macroleakages and on neutrophils. Overall, the specific type of nanoparticles largely determined their behavior in blood vessels and their neutrophil-mediated delivery to the tumor. Since neutrophils are the first to migrate to the site of inflammation, they can increase nanodrug delivery effectiveness for nanomedicine application.
RESUMO
Human glioblastoma multiforme (GBM) is a primary malignant brain tumor, a radically incurable disease characterized by rapid growth resistance to classical therapies, with a median patient survival of about 15 months. For decades, a plethora of approaches have been developed to make GBM therapy more precise and improve the diagnosis of this pathology. Targeted delivery mediated by the use of various molecules (monoclonal antibodies, ligands to overexpressed tumor receptors) is one of the promising methods to achieve this goal. Here we present a novel genetically encoded nanoscale dual-labeled system based on Quasibacillus thermotolerans (Qt) encapsulins exploiting biologically inspired designs with iron-containing nanoparticles as a cargo, conjugated with human fluorescent labeled transferrin (Tf) acting as a vector. It is known that the expression of transferrin receptors (TfR) in glioma cells is significantly higher compared to non-tumor cells, which enables the targeting of the resulting nanocarrier. The selectivity of binding of the obtained nanosystem to glioma cells was studied by qualitative and quantitative assessment of the accumulation of intracellular iron, as well as by magnetic particle quantification method and laser scanning confocal microscopy. Used approaches unambiguously demonstrated that transferrin-conjugated encapsulins were captured by glioma cells much more efficiently than by benign cells. The resulting bioinspired nanoplatform can be supplemented with a chemotherapeutic drug or genotherapeutic agent and used for targeted delivery of a therapeutic agent to malignant glioma cells. Additionally, the observed cell-assisted biosynthesis of magnetic nanoparticles could be an attractive way to achieve a narrow size distribution of particles for various applications.
RESUMO
We examined standard clinical and laboratory biochemical parameters, as well as the levels of aminothiols in the blood and urine (homocysteine (Hcy), cysteine (Cys), S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH)) via capillary electrophoresis in patients with CKD at stages II-V. Patient outcomes were assessed after five years. To complete forecasting, correlation and ROC analysis were performed. It was found that the levels of Cys and Hcy in blood plasma were earlier markers of CKD starting from stage II, while the levels of SAM and SAM/SAH in urine made it possible to differentiate between CKD at stages II and III. Blood plasma Hcy and urinary SAM and SAM/SAH correlated with mortality, but plasma Hcy concentrations were more significant. Thus, plasma Hcy, urine SAM, and SAM/SAH can be considered to be potential diagnostic and prognostic markers in patients with CKD.
RESUMO
Magnetic nanoparticles based on iron oxide attract researchers' attention due to a wide range of possible applications in biomedicine. As synthesized, most of the magnetic nanoparticles do not form the stable colloidal solutions that are required for the evaluation of their interactions with cells or their efficacy on animal models. For further application in biomedicine, magnetic nanoparticles must be further modified with biocompatible coating. Both the size and shape of magnetic nanoparticles and the chemical composition of the coating have an effect on magnetic nanoparticles' interactions with living objects. Thus, a universal method for magnetic nanoparticles' stabilization in water solutions is needed, regardless of how magnetic nanoparticles were initially synthesized. In this paper, we propose the versatile and highly reproducible ligand exchange technique of coating with 3,4-dihydroxiphenylacetic acid (DOPAC), based on the formation of Fe-O bonds with hydroxyl groups of DOPAC leading to the hydrophilization of the magnetic nanoparticles' surfaces following phase transfer from organic solutions to water. The proposed technique allows for obtaining stable water-colloidal solutions of magnetic nanoparticles with sizes from 21 to 307 nm synthesized by thermal decomposition or coprecipitation techniques. Those stabilized by DOPAC nanoparticles were shown to be efficient in the magnetomechanical actuation of DNA duplexes, drug delivery of doxorubicin to cancer cells, and targeted delivery by conjugation with antibodies. Moreover, the diversity of possible biomedical applications of the resulting nanoparticles was presented. This finding is important in terms of nanoparticle design for various biomedical applications and will reduce nanomedicines manufacturing time, along with difficulties related to comparative studies of magnetic nanoparticles with different magnetic core characteristics.
RESUMO
The magneto-mechanical approach is a powerful technique used in many different applications in biomedicine, including remote control enzyme activity, cell receptors, cancer-selective treatments, mechanically-activated drug releases, etc. This approach is based on the use of a combination of magnetic nanoparticles and external magnetic fields that have led to the movement of such nanoparticles with torques and forces (enough to change the conformation of biomolecules or even break weak chemical bonds). However, despite many theoretical and experimental works on this topic, it is difficult to predict the magneto-mechanical effects in each particular case, while the important results are scattered and often cannot be translated to other experiments. The main reason is that the magneto-mechanical effect is extremely sensitive to changes in any parameter of magnetic nanoparticles and the environment and changes in the parameters of the applied magnetic field. Thus, in this review, we (1) summarize and propose a simplified theoretical explanation of the main factors affecting the efficiency of the magneto-mechanical approach; (2) discuss the nature of the MNP-mediated mechanical forces and their order of magnitude; (3) show some of the main applications of the magneto-mechanical approach in the control over the properties of biological systems.
