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Humans are potentially exposed to multiple nanoparticles kinds through nanotechnology-based consumer products. There is insufficient data on the in vivo toxicity of nanotechnology products, as well as no data on the possible toxicity, including genotoxicity and reproductive toxicity of co-exposure to different kind of nanoparticles. In this work, solid lipid nanoparticles (SLNs) and superparamagnetic iron oxide nanoparticles (SPIONs) were selected for evaluation of a hypothetical condition of in vivo co-exposure. Genotoxicity of SPIONs and SLNs was performed separately and in 1:1 mixture in mice. Bone marrow micronucleus assay, sperm morphology test, and sperm count were carried out. Also, the serum ALT and AST activities; and hematological parameters of the treated mice were analyzed. The results showed a significant increase (p

Background The use of RNA interference (iRNA) therapy has proved to be an interesting target therapy for the cancer treatment; however, siRNAs are unstable and quickly eliminated from the bloodstream. To face these barriers, the use of biocompatible and efficient nanocarriers emerges as an alternative to improve the success application of iRNA to the cancer, including breast cancer. Results A hybrid nanocarrier composed of calcium phosphate as the inorganic phase and a block copolymer containing polyanions as organic phase, named HNPs, was developed to deliver VEGF siRNA into metastatic breast cancer in mice. The particles presented a rounded shape by TEM images with average size measured by DLS suitable and biocompatible for biomedical applications. The XPS and EDS spectra confirmed the hybrid composition of the nanoparticles. Moreover, after intravenous administration, the particles accumulated mainly in the tumor site and kidneys, which demonstrates the tumor targeting accumulation through the Enhanced Permeability and Retention Effect (EPR). A significant decrease in size of the tumors treated with the nanoparticles containing siVEGF (HNPs-siVEGF) was observed and the reduction was related to enhanced tumor accumulation of siRNA as well as in vivo VEGF silencing at gene and protein levels. Conclusion The hybrid system prepared was successful in promoting the RNAi effect in vivo with very low toxicity. General significance This study shows the valuable development of a hybrid nanoparticle carrying VEGF siRNA, as well as their tumor targeting, accumulation and reduction in mice triple-negative breast cancer.

Metastasis is the main cause of cancer-related death and requires the development of effective treatments with reduced toxicity and effective anticancer activity. Gallic acid derivatives have shown significant biological properties including antitumoral activity as shown in a previous study with octyl gallate (G8) in vitro. Thus, the aim of this work was to evaluate the antimetastatic effect of free and solid lipid nanoparticle-loaded G8 in mice in a lung metastasis model. Animals inoculated with melanoma cells presented metastasis in lungs, which was significantly inhibited by treatment with G8 and solid lipid nanoparticle-loaded G8, named G8-NVM. However, G8-treated mice showed an increase in several toxicological parameters, which were almost completely circumvented by G8-NVM treatment. This study supports the need for pharmacological studies on new potential medicinal plants to treat cancer and can provide new perspectives on using nanotechnology to improve biological activities while decreasing the chemotherapy toxicological effects of anticancer drugs.

Titanium dioxide nanoparticles (TiO2 NP) are present in several daily use products, and the risks associated with their bioaccumulation must be stablished. Thus, an evaluation of several toxicological-related effects was conducted after intraperitoneal injection of TiO2 NPs in mice. Mice were divided into two groups, which received 2 mg kg−1 day−1 of TiO2 NPs or vehicle saline. Assessments of body and organ weight as well as biochemical, hematological, and histopathological analyses were performed in order to evaluate adverse effects. The results showed that treatment resulted in an increased visceral and abdominal fat deposition, as well as a mononuclear inflammatory infiltrates in the abdominal fat tissue. The TiO2 NPs induced significant decrease in the weight gain and splenomegaly. Additionally, TiO2 NP-treated mice showed altered hematological parameters and significant liver injuries, which were characterized by histopathological and biochemical changes. Our results also indicated that TiO2 NPs were absorbed and significantly accumulated in the spleen, liver, and kidney. These results showed the ability of TiO2 NPs to infiltrate different organs and to induce inflammation and liver and spleen damage with visceral fat accumulation. The data obtained are useful for the governmental authorities to legislate and implement regulations concerning the use and the production of this kind of material that might be hazardous to the living beings, as well as to the environment.

Superparamagnetic iron oxide nanoparticles (SPIONS) were synthesized by thermal decomposition of an organometallic precursor at high temperature and coated with a bi-layer composed of oleic acid and methoxy-polyethylene glycol-phospholipid. The formulations were named SPION-PEG350 and SPION-PEG2000. Transmission electron microscopy, X-ray diffraction and magnetic measurements show that the SPIONs are near-spherical, well-crystalline, and have high saturation magnetization and susceptibility. FTIR spectroscopy identifies the presence of oleic acid and of the conjugates mPEG for each sample. In vitro biocompatibility of SPIONS was investigated using three cell lines; up to 100μg/ml SPION-PEG350 showed non-toxicity, while SPION-PEG2000 showed no signal of toxicity even up to 200μg/ml. The uptake of SPIONS was detected using magnetization measurement, confocal and atomic force microscopy. SPION-PEG2000 presented the highest internalization capacity, which should be correlated with the mPEG chain size. The in vivo results suggested that SPION-PEG2000 administration in mice triggered liver and kidney injury. From the Clinical Editor The potential use of superparamagnetic iron oxide nanoparticles (SPIONS) in the clinical setting have been studied by many researchers. The authors synthesized two types of SPIONS here and investigated the physical properties and biological compatibility. The findings should provide more data on the design of SPIONS for clinical application in the future.

In this work in vivo experiments were conducted in order to characterize the biocompatibility of polyurethane nanoparticles (PU-NPs) after intraperitoneal (i.p.) and oral administration. Additionally, ex vivo assays were performed to assess human blood compatibility as well as in vitro assays to assess protein binding. Our results indicated that administration of three different concentrations of PU-NPs induced a significant increase in visceral fat accumulation after oral dosing. In addition, fat tissue of mice intraperitoneally treated with the highest concentration of nanoparticles showed diffuse mononuclear inflammatory infiltrate in the fat tissue. Histopathological assessment showed inflammatory infiltrate and hepatocyte vacuolization in the liver, inflammatory infiltration and vascular congestion in the lung and glomerular necrosis in the kidney. Hepatic enzymes related with liver function were significantly increased in both groups of mice treated with PU-NPs. The PU-NPs did not affect the human blood cells number as well as coagulation time but showed a susceptibility to bind in proteins commonly found in the blood stream. In addition, increased amounts of pro inflammatory cytokines in vivo, as well as ex vivo in human cells were observed. Further studies to establish the consequences of long-term exposure to PU-NPs are warranted.

Breast cancer is a major cause of death among women worldwide. Resistance to conventional therapies has been observed in HER2-positive breast cancer patients, indicating the need for more effective treatments. Small interfering RNA (siRNA) therapy is an attractive strategy against HER2-positive tumors, but its success depends largely on the efficient delivery of agents to target tissues. In this study, we prepared a magnetic hybrid nanostructure composed of iron oxide nanoparticles coated with caffeic acid and stabilized by layers of calcium phosphate and PEG-polyanion block copolymer for incorporation of siRNA. Transmission electron microscopy images showed monodisperse, neutrally charged compact spheres sized100 nm. Dynamic light scattering and nanoparticle tracking analysis revealed that the nanostructure had an average hydrodynamic diameter of 130 nm. Nanoparticle suspensions remained stable over 42 days of storage at 4 and 25 °C. Unloaded caffeic acid-magnetic calcium phosphate (Caf-MCaP) nanoparticles were not cytotoxic, and loaded nanoparticles were successfully taken up by the HER2-positive breast cancer cell line HCC1954, even more so under magnetic guidance. Nanoparticles escaped endosomal degradation and delivered siRNA into the cytoplasm, inducing HER2 gene silencing.

Nine types of solid lipid nanoparticle (SLN) formulations were produced using tripalmitin (TPM), glyceryl monostearate (GM) or stearic acid (SA), stabilized with lecithin S75 and polysorbate 80. Formulations were prepared presenting PI values within 0.25 to 0.30, and the physicochemical properties, stability upon storage and biocompatibility were evaluated. The average particle size ranged from 116 to 306 nm, with a negative surface charge around −11 mV. SLN presented good stability up to 60 days. The SLN manufactured using SA could not be measured by DLS due to the reflective feature of this formulation. However, TEM images revealed that SA nanoparticles presented square/rod shapes with an approximate size of 100 nm. Regarding biocompatibility aspects, SA nanoparticles showed toxicity in fibroblasts, causing cell death, and produced high hemolytic rates, indicating toxicity to red blood cells. This finding might be related to lipid type, as well as, the shape of the nanoparticles. No morphological alterations and hemolytic effects were observed in cells incubated with SLN containing TPM and GM. The SLN containing TPM and GM showed long-term stability, suggesting good shelf-life. The results indicate high toxicity of SLN prepared with SA, and strongly suggest that the components of the formulation should be analyzed in combination rather than separately to avoid misinterpretation of the results.

Acute lymphoblastic leukemia (ALL) is a malignant disorder caused by the proliferation of lymphoid progenitor cells and is the most common cancer in children. Cytotoxic nucleoside analogues are important chemotherapeutic agents, which are used in many cancers, including leukemias. In this study, we investigated the effects of the synthetic nucleoside analogue 1-(5,5,5-trichloro-2-methoxy-4-oxopenten-2-yl)-4-trichloromethyl-pyrimidin-2(1H)-one, named compound 3 or C3, on leukemia cell lines. The compound stimulated cell death by apoptosis, evidenced by DNA fragmentation, phosphatidylserine externalization, and caspase-3 activation. Compound 3 seemed to trigger several cell death pathways. The mitochondrial pathway was evidenced through a disturbance of mitochondrial membrane potential, strong cytochrome c liberation, decrease of antiapoptotic Bcl-2 protein expression, and caspase-9 activation. The C3 also induced caspase-8 and -12 activation, an increase in the intracellular calcium level, and an overproduction of reactive oxygen species. Increased caspase 8 activity suggests that the extrinsic pathway was activated and that the ROS production and enzyme activity alteration (glutathione S-transferase, glutathione peroxidase, catalase, and glutathione reductase) might be related to oxidative stress. Finally, the increase in calcium release, CHOP expression, and caspase-12 activity might characterize endoplasmic reticulum stress. Compound 3 was likewise cytotoxic to leukemic and melanoma human cell lines. Taken together, the results contribute to further understanding the new pyrimidine analogue as a potential chemotherapeutic drug or lead molecule.

Solid lipid nanoparticles (SLNs) are an alternative drug delivery system compared to emulsions, liposomes and polymeric nanoparticles. Due to their unique sizes and properties, SLNs offer possibility to develop new therapeutic approaches. The ability to incorporate drugs into nanocarriers offers a new prototype in drug delivery that could be used for drug targeting. However, toxicity of these new formulations has not been investigated thus far. In this study, we carried out an in vivo toxicity study. For that mice were divided into three groups and treated intraperitoneally with triestearin-based SLNs (TN), natural wax-based SLNs (VN) or vehicle for 10 days. After that, necropsies, histopathological and hematological analysis, as well as hepatic and renal functions were performed. Our results indicated that both TN and VN were absorbed post-exposure and induced an inflammatory response in adipose tissue. However, histopathological analysis demonstrated the absence of toxicity in both treated groups. In addition, the body weights were similar among the groups and low toxicity was also indicated by the unchanged serum biochemical parameters. This study provides a preliminary data for toxicological studies of two different SLNs in long-term in vivo exposure. However, further studies should be conducted in order to investigate the inflammatory response in order to establish the safety of these SLNs.

Several obstacles are encountered in conventional chemotherapy, such as drug toxicity and poor stability. Nanotechnology is envisioned as a strategy to overcome these effects and to improve anticancer therapy. Nanoemulsions comprise submicron emulsions composed of biocompatible lipids, and present a large surface area revealing interesting physical properties. Chalcones are flavonoid precursors, and have been studied as cytotoxic drugs for leukemia cells that induce cell death by different apoptosis pathways. In this study, we encapsulated chalcones in a nanoemulsion and compared their effect with the respective free compounds in leukemia and in non-tumoral cell lines, as well as in an in vivo model. Free and loaded-nanoemulsion chalcones induced a similar anti-leukemic effect. Free chalcones induced higher toxicity in VERO cells than chalcones-loaded nanoemulsions. Similar results were observed in vivo. Free chalcones induced a reduction in weight gain and liver injuries, evidenced by oxidative stress, as well as an inflammatory response. Considering the high toxicity and the side effects induced generally by all cancer chemotherapies, nanotechnology provides some options for improving patients’ life quality and/or increasing survival rates.

Chalcones, naturally occurring open-chain flavonoids abundant in plants, have demonstrated anticancer activity in multiple tumor cells. In a previous work, the potential anticancer activity of three naphthylchalcones named R7, R13 and R15 was shown. In this study, the mechanism of actions of these chalcones was originally shown. The chalcones presented concentration and time-dependent cytotoxicity. To determine the type of cell death induced by chalcones, we assessed a series of assays including measurements of the caspase-8, -9 and -12 activities, expression of important apoptosis-related genes and proteins, changes in the cell calcium concentration and cytochrome c release. The activities of caspase-8, -9 and -12 increased after the treatment of L1210 cells with the three compounds. Chalcones R7 and R13 induced an increase of pro-apoptotic proteins Bax, Bid and Bak (only chalcone R13), as well as a decrease in anti-apoptotic Bcl-2 expression. These chalcones also induced an increase in Fas and a decrease in p21 and p53 expression. Chalcone R15 seems to act by a different mechanism to promote cell death, as it did not change the mitochondrion-related proteins, nor did it induce the cytochrome c release. All compounds induced an increase in cell calcium concentration and an increase in CHOP expression, which together with an increase in caspase-12 activity, suggest that chalcones could induce an endoplasmic reticulum (ER) stress. Taken together, these results suggest that chalcones induce apoptosis by different pathways, being an interesting strategy to suggest for cancer therapy.