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Graphene, known as “black gold”, has important applications in various fields. In previous studies, it has been proved that graphene oxide (GO) which is a derivative of graphene has low toxicity. However, the immunotoxicity of GO has not been fully elucidated. In this work, we used DC2.4 cell line to investigate the in vitro immunotoxicity of two types of GO, mono-layer GO (mono-GO) and multi-layer GO (multi- GO). We found that mono-GO had less effect on cell viability than multi-GO, but both mono-GO and multi-GO significantly induced the generation of ROS in DC2.4 cells. Interestingly, mono-GO caused DC2.4 cells to aggregate, thus changed the cell morphology significantly. However, no similar influence occurred for multi-GO. In addition, the results showed that these two GOs obviously enhance the release of TNF-α by DC2.4 cells with and without LPS stimulation. GO did not affect the level of IL-6 released from DC2.4 cells, but multi-GO promoted the release of IL-6 while mono-GO inhibited the production of IL-6 when cells were in response to LPS stimulation. Whole-transcriptome sequencing analysis found some immune-related differentially expressed genes including H2-DMb1, Ncbp3, Oas2, Men1, Fas, Cd320, Cd244, and Tinagl1 which are engaged in the immune system process. These results suggested that both mono-GO and multi-GO are immunotoxic to DC2.4 cells, which provides important basis for subsequent biological and clinical medical applications.

Nanomaterials with localized surface plasmon resonance (LSPR) have exquisite optical properties, which allow a wide range of applications. Non-stoichiometric copper sulfides with active LSPR have drawn great attention, because its LSPR peak falls in the NIR region that is suitable for deep bioimaging and photothermal therapy (PTT). Despite numerous biomedical applications, the biocompatibility and toxicity of copper sulfides have not been studied systematically. In this contribution, we synthesized the ultrasmall biocompatible copper sulfide nanoparticle encapsulated within bovine serum albumin (BSA), CuS@BSA. The physical features of CuS@BSA were characterized. The MTT and flow cytometry assays were performed. The PTT was also investigated. The results indicated that such CuS@BSA nanoparticle had an average TEM size of 8 nm, and an average DLS size of 15 nm. A lower concentration of CuS@BSA was not toxic to HeLa cells, but the critical apoptotic events occurred in HeLa cells after co-incubation with 45 μg/mL CuS@BSA for 48 h. The photothermal effect of the CuS@BSA in aqueous medium were concentration-dependent and time-dependent, which were also verified by flow cytometry and microscopy, while the CuS@BSA were co-cultured with HeLa cells and treated with laser. This work designed an ultrasmall potential biocompatible nanoparticle, CuS@BSA, for cancer photothermal therapy, and provided the toxic information to safely guide its biomedical applications.

Although InP/ZnS quantum dots (QDs) have emerged as a presumably less hazardous alternative to cadmium-based QDs, their toxicity has not been fully understood. In this work, we report the cytotoxicity of InP/ZnS QDs with different surface groups (NH , COOH, OH) toward two lung-derived cell lines. The diameter and the spectra of InP/ZnS QDs were characterized and the hydrodynamic size of QDs in aqueous solution was compared. The confocal laser scanning microscopy was applied to visualize the labeling of QDs for human lung cancer cell HCC-15 and Alveolar type II epithelial cell RLE-6TN. The flow cytometry was used to confirm qualitatively the uptake efficiency of QDs, the cell apoptosis and ROS generation, respectively. The results showed that in deionized water, InP/ZnS-OH QDs were easier to aggregate, and the hydrodynamic size was much greater than the other InP/ZnS QDs. All these InP/ZnS QDs were able to enter the cells, with higher uptake efficiency for InP/ZnS-COOH and InP/ZnS-NH at low concentration. High doses of InP/ZnS QDs caused the cell viability to decrease, and InP/ZnS-COOH QDs and InP/ZnS-NH QDs appeared to be more toxic than InP/ZnS-OH QDs. In addition, all these InP/ZnS QDs promoted cell apoptosis and intracellular ROS generation after co-cultured with cells. These results suggested that appropriate concentration and surface functional groups should be optimized when InP/ZnS QDs are utilized for biological imaging and therapeutic purpose in the future.

Indium phosphide (InP) quantum dots (QDs) have shown a broad application prospect in the fields of biophotonics and nanomedicine. However, the potential toxicity of InP QDs has not been systematically evaluated. In particular, the effects of different surface modifications on the biodistribution and toxicity of InP QDs are still unknown, which hinders their further developments. The present study aims to investigate the biodistribution and in vivo toxicity of InP/ZnS QDs. Three kinds of InP/ZnS QDs with different surface modifications, hQDs (QDs-OH), aQDs (QDs-NH ), and cQDs (QDs-COOH) were intravenously injected into BALB/c mice at the dosage of 2.5 mg/kg BW or 25 mg/kg BW, respectively. Biodistribution of three QDs was determined through cryosection fluorescence microscopy and ICP-MS analysis. The subsequent effects of InP/ZnS QDs on histopathology, hematology and blood biochemistry were evaluated at 1, 3, 7, 14 and 28 days post-injection. These types of InP/ZnS QDs were rapidly distributed in the major organs of mice, mainly in the liver and spleen, and lasted for 28 days. No abnormal behavior, weight change or organ index were observed during the whole observation period, except that 2 mice died on Day 1 after 25 mg/kg BW hQDs treatment. The results of H&E staining showed that no obvious histopathological abnormalities were observed in the main organs (including heart, liver, spleen, lung, kidney, and brain) of all mice injected with different surface-functionalized QDs. Low concentration exposure of three QDs hardly caused obvious toxicity, while high concentration exposure of the three QDs could cause some changes in hematological parameters or biochemical parameters related to liver function or cardiac function. More attention needs to be paid on cQDs as high-dose exposure of cQDs induced death, acute inflammatory reaction and slight changes in liver function in mice. The surface modification and exposure dose can influence the biological behavior and in vivo toxicity of QDs. The surface chemistry should be fully considered in the design of InP-based QDs for their biomedical applications.

Ribonucleic acid (RNA) interference (RNAi) therapies are promising cancer treatment modalities that can specifically target abnormal proto-oncogenes, thus improving the therapeutic effect. For the treatment of pancreatic cancer, targeting one mutant proto-oncogene by RNAi usually does not yield the desired therapeutic efficiency. Both K-ras gene mutations and Notch1 overexpression are common symptoms in pancreatic cancer patients, and play a crucial role in pancreatic cancer cell drug resistance. In this study, biodegradable charged polyester-based vectors (BCPVs) were synthesized for the co-delivery of K-ras and Notch1 small interfering ribonucleic acid (siRNA) into MiaPaCa-2 cells (pancreatic cancer cell line) to overcome drug resistance to gemcitabine (GEM), a first-line chemotherapeutic drug used in the clinic. BCPVs could effectively absorb negative siRNA to form a capsule-like structure, prevent siRNA from nuclease digestion in the serum, and promote effective siRNA cell internalization and endosomal escape. Through K-ras and Notch1 gene silencing in MiaPaCa-2 cells, BCPV-siRNA K-ras -siRNA Notch1 nanocomplexes effectively reversed the epithelia-mesenchymal transition (EMT) in MiaPaCa-2 cells, thereby greatly enhancing the sensitivity of MiaPaCa-2 cells to GEM. MiaPaCa-2 cell proliferation, migration, and invasion were effectively inhibited, and cell apoptosis was also significantly enhanced by the synergistic antitumor effect of BCPV-siRNA K-ras -siRNA Notch1 nanocomplexes and GEM. These results suggest that this combination RNAi therapy can be used to improve cancer cell sensitivity to chemotherapeutic drugs. Specifically, this newly developed strategy has a great potential for treating pancreatic cancer.

Background The toxicity of CdSe/ZnS quantum dots (QDs) in the environment and biological systems has become a major concern for the nanoparticle community. However, the potential toxicity of QDs on immune cells and its corresponding immune functions remains poorly understood. In this study, we investigated the immunotoxicity of CdSe/ZnS QDs using the in vitro in macrophages and lymphocytes and in vivo in BALB/c mice. Results Our results indicated that macrophages treated with 1.25 or 2.5 nM QDs exhibited decreased cell viability, increased levels of reactive oxygen species (ROS), elevated apoptotic events, altered phagocytic ability, and decreased release of TNF-α and IL-6 by upon subsequent stimulation with Lipopolysaccharide (LPS). In contrast, lymphocytes exposed to QDs exhibited enhanced cell viability, increased release of TNF-α and IL-6 following exposure with CpG-ODN, and decreased transformation ability treatment in response to LPS. To study the in vivo effects in mice, we showed that QDs injection did not cause significant changes to body weight, hematology, organ histology, and phagocytic function of peritoneal macrophages in QDs-treated mice. In addition, the QDs formulation accumulated in major immune organs for more than 42 days. Lymphocytes from QDs-treated mice showed reduced cell viability, changed subtype proportions, increased TNF-α and IL-6 release, and reduced transformation ability in response to LPS. Conclusions Taken together, these results suggested that exposures to CdSe/ZnS QDs could suppress immune-defense against foreign stimuli, which in turn could result in increased susceptibility of hosts to diseases.

In recent years, quantum dots (QDs) have emerged as a potential contrast agent for bioimaging due to their bright luminescence and excellent photostability. However, the wide use of QDs in vivo has been limited due to underlying toxicity caused by leakage of heavy metals. Although non-cadmium QDs have been developed to resolve this issue, a comprehensive understanding of the toxicity of these newly developed QDs remains elusive. In this study, we administered PEGylated copper indium sulfide/zinc sulfide (CuInS2/ZnS), which are typical non-cadmium QDs, and analyzed the long-term effects of these nanoparticles in BALB/c mice. Body weight, hematology, blood biochemistry, organ histology, and biodistribution were examined at different time points. We found no significant difference in body weight after injection of CuInS2/ZnS QDs. These CuInS2/ZnS QDs entered and were accumulated in major organs for 90 days post-injection. The majority of biochemical indicators were not significantly different between the QDs-treated group and the control group. In addition, no significant histopathological abnormalities were observed in the treated mice compared with the control mice. CuInS2/ZnS QDs did not lead to observable toxicity in vivo following either the administration of a high or low dose. Our research not only provides direct evidence of the bio-safety of CuInS2/ZnS QDs, but also a feasible method for evaluating nanoparticle toxicity.

Since CdSe quantum dots (QDs) are increasingly used in electronics, medical, and pharmaceutical science due to their excellent optical properties, it is necessary to carry out thorough and systematic studies on their biosafety. Numerous studies have reported the toxicity of QDs on liver, kidney, immune system, and reproductive system. However, few studies have been done on the cardiotoxicity of QDs. In this study, we administered carboxylated CdSe/ZnS QDs in BALB/c mice via the tail vein and analyzed the in vivo cardiotoxicity of CdSe/ZnS QDs. The body weight, hematology, serum biochemistry, histology, heart elements concentration, echocardiography, and heart oxidative stress markers were carried out at different time. There were no significant differences in body weight and heart organ index between QDs group and the control group. Hematology results showed the platelet (PLT) counts on Day 1 and Day 42 in both high dose QDs group and low dose QDs group, and the PLT counts on Day1 in the high dose group were significantly higher than that in control group. Serum biochemistry results showed that lactate dehydrogenase (LDH), creatine kinase (CK), and creatine kinase isoenzyme (CK-MB) of mice exposed to CdSe/ZnS QDs were significantly higher than that of the control group on Day 1, and CK-MB levels still remained high on Day 7. A higher concentration of Cd was observed in the heart of CdSe/ZnS QDs exposed mice on Day 42, whereas no Cd was detected in the control group, which suggested that QDs can accumulate in heart. No significant histopathological changes and cardiac function were observed in all mice at different time after treatment. Increased level of glutathione peroxidase (GPx) and malondialdehyde (MDA) was observed in mice administered with high dose QDs on Day 1, and increased level of total antioxidant capacity (T-AOC) and MDA activities was observed on Day 42. These results indicated that CdSe/ZnS QDs could accumulate in heart, cause some biochemical indicators change, induce oxidative damage, and have cardiotoxicity. Our findings might provide valuable information on the biological safety evaluation of the cardiovascular system of QDs.

Recently, RNA interfering (RNAi) has become a promising approach for cancer therapy. However, the application of RNAi for clinics is still hindered due to the lack of safe and efficient carriers. In this study, a pH-responsive micelle based on polycaprolactone-block–poly 2-(dimethylamino)ethyl methacrylate (PCL-PDEM) cationic copolymer was developed to carry short interfering RNA (siRNA) for silencing interleukin 8 (IL-8) gene in hepatoma cancer cells. The transfection efficiency of the PCL-PDEM-siRNA/quantum dots (QDs) nanoplex has reached about 70%, and the expression level of IL-8 decreased about 63%. Furthermore, the codelivery of QDs and siRNA has been realized, which is beneficial to visualize the process of siRNA delivery. No considerable cytotoxicity from the nanoparticles has been observed, indicating that our responsive cationic micelle is potential in clinical trial for hepatoma cancer therapy.