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Histopathological analysis of zebrafish after introduction of non-biodegradable polyelectrolyte microcapsules into the circulatory system.

ABSTRACT: Polyelectrolyte microcapsules are among the most promising carriers of various sensing substances for their application inside the bloodstream of vertebrates. The long-term effects of biodegradable microcapsules in mammals are relatively well studied, but this is not the case for non-biodegradable microcapsules, which may be even more generally applicable for physiological measurements. In the current study, we introduced non-biodegradable polyelectrolyte microcapsules coated with polyethylene glycol (PMs-PEG) into the circulatory system of zebrafish to assess their long-term effects on fish internal organs with histopathologic analysis. Implantation of PMs-PEG was not associated with the formation of microclots or thrombi in thin capillaries; thus, the applied microcapsules had a low aggregation capacity. The progression of the immune response to the implant depended on the time and the abundance of microparticles in the tissues. We showed that inflammation originated from recognition and internalization of PMs-PEG by phagocytes. These microcapsule-filled immune cells have been found to migrate through the intestinal wall into the lumen, demonstrating a possible mechanism for partial microparticle elimination from fish. The observed tissue immune response to PMs-PEG was local, without a systemic effect on the fish morphology. The most pronounced chronic severe inflammatory reaction was observed near the injection site in renal parenchyma and within the abdominal cavity since PMs-PEG were administered with kidney injection. Blood clots and granulomatosis were noted at the injection site but were not found in the kidneys outside the injection site. Single microcapsules brought by blood into distal organs did not have a noticeable effect on the surrounding tissues. The severity of noted pathologies of the gills was insufficient to affect respiration. No statistically significant alterations in hepatic morphology were revealed after PMs-PEG introduction into fish body. Overall, our data demonstrate that despite they are immunogenic, non-biodegradable PMs-PEG have low potential to cause systemic effects if applied in the minimal amount necessary for detection of fluorescent signal from the microcapsules.

SUBMITTER: Borvinskaya E

PROVIDER: S-EPMC8106396 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundToxicity of nanomaterials is one of the most important factors limiting their medical application. Evaluation of in vitro nanotoxicity allows for the identification and elimination of most of the toxic materials prior to animal testing. The current knowledge of the possible side effects of biodegradable nanomaterials, such as liposomes and polymeric organic nanoparticles, is limited. Previously, we developed a potential drug delivery system in the form of nanocapsules with polyelectrolyte, biodegradable shells consisting of poly-l-lysine and poly-l-glutamic acid (PGA), formed by the layer-by-layer adsorption technique.MethodsHemolysis assay, viability tests, flow cytometry analysis of vascular cell adhesion molecule-1 expression on endothelium, analysis of nitric oxide production, measurement of intracellular reactive oxygen species levels, detection of antioxidant enzyme activity, and analysis of DNA damage with comet assay were performed to study the in vitro toxicity of nanocapsules.ResultsIn this work, we present the results of an in vitro analysis of toxicity of five-layer positively charged poly-l-lysine-terminated nanocapsules (NC5), six-layer negatively charged PGA-terminated nanocapsules (NC6) and five-layer PEGylated nanocapsules (NC5-PEG). PGA and polyethylene glycol (PEG) were used as two different "stealth" polymers. Of all the polyelectrolyte nanocapsules tested for blood compatibility, only cationic NC5 showed acute toxicity toward blood cells, expressed as hemolysis and aggregation. Neither NC6 nor NC5-PEG had proinflammatory activity evaluated through changes in the expression of NF-?B-dependent genes, iNOS and vascular cell adhesion molecule-1, induced oxidative stress, or promoted DNA damage in various cells.ConclusionOur studies clearly indicate that PGA-coated (negatively charged) and PEGylated polyelectrolyte nanocapsules do not show in vitro toxicity, and their potential as a drug delivery system may be safely studied in vivo.

Project description:Rationale: The tireless research for effective drug delivery approaches is prompted by poor target tissue penetration and limited selectivity against diseased cells. To overcome these issues, various nano- and micro-carriers have been developed so far, but some of them are characterized by slow degradation time, thus hampering repeated drug administrations. The aim of this study was to pursue a selective delivery of magnetic biodegradable polyelectrolyte capsules in a mouse breast cancer model, using an external magnetic field. Methods: Four different kinds of magnetic polyelectrolyte capsules were fabricated via layer-by-layer assembly of biodegradable polymers on calcium carbonate templates. Magnetite nanoparticles were embedded either into the capsules' shell (sample S) or both into the shell and the inner volume of the capsules (samples CnS, where n is the number of nanoparticle loading cycles). Samples were first characterized in terms of their relaxometric and photosedimentometric properties. In vitro magnetic resonance imaging (MRI) experiments, carried out on RAW 264.7 cells, allowed the selection of two lead samples that proceeded for the in vivo testing on a mouse breast cancer model. In the set of in vivo experiments, an external magnet was applied for 1 hour following the intravenous injection of the capsules to improve their delivery to tumor, and MRI scans were acquired at different time points post administration. Results: All samples were considered non-cytotoxic as they provided more than 76% viability of RAW 264.7 cells upon 2 h incubation. Sample S appeared to be the most efficient in terms of T2-MRI contrast, but the less sensitive to external magnet navigation, since no difference in MRI signal with and without the magnet was observed. On the other side, sample C6S was efficiently delivered to the tumor tissue, with a three-fold T2-MRI contrast enhancement upon the external magnet application. The effective magnetic targeting of C6S capsules was also confirmed by the reduction in T2-MRI contrast in spleen if compared with the untreated with magnet mice values, and the presence of dense and clustered iron aggregates in tumor histology sections even 48 h after the magnetic targeting. Conclusion: The highlighted strategy of magnetic biodegradable polyelectrolyte capsules' design allows for the development of an efficient drug delivery system, which through an MRI-guided externally controlled navigation may lead to a significant improvement of the anticancer chemotherapy performance.

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Histopathological analysis of zebrafish after introduction of non-biodegradable polyelectrolyte microcapsules into the circulatory system.

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