Insufficient secretion of pancreatic FGF21 is the toxicological mechanism and therapeutic target of asparaginase-associated pancreatitis.

Asparaginase-associated pancreatitis (AAP) is a severe and potentially life-threatening drug-induced pancreas targeted toxicity in the combined chemotherapy of acute lymphoblastic leukemia among children and adolescents. The toxicological mechanism of AAP is not yet clear, and there are no effective preventive and treatment measures available clinically. Fibroblast growth factor 21 (FGF21) is a secretory hormone that regulates lipid, glucose, and energy metabolism balance. Acinar tissue is the main source of pancreatic FGF21 protein and plays an important role in maintaining pancreatic metabolic balance. In this study, we found that the decrease of FGF21 in pancreas is closely related to AAP. Pegaspargase (1 IU/g) induces widespread edema and inflammatory infiltration in the pancreas of rats/mice. The specific expression of FGF21 in the acinar tissue of AAP rats was significantly downregulated. Asparaginase caused dysregulation of the ATF4/ATF3/FGF21 axis in acinar tissue or cells, and thus mediated the decrease of FGF21. It greatly activated ATF3 in the acinar, which competed with ATF4 for the Fgf21 promoter, thereby inhibiting the expression of FGF21. Pharmacological replacement of FGF21 (1 mg/kg) or PERK inhibitors (GSK2656157, 25 mg/kg) can significantly mitigate the pancreatic tissue damage and reduce markers of inflammation associated with AAP, representing potential strategies for the prevention and treatment of AAP.

In vitro test methods for evaluating high molecular weight polyethylene oxide polymer induced hemolytic and thrombotic potential.

To combat opioid abuse, the U.S. Food and Drug Administration (FDA) released a comprehensive action plan to address opioid addiction, abuse, and overdose that included increasing the prevalence of abuse-deterrent formulations (ADFs) in opioid tablets. Polyethylene oxide (PEO) has been widely used as an excipient to deter abuse via nasal insufflation. However, changes in abuse patterns have led to unexpected shifts in abuse from the nasal route to intravenous injection. Case reports identify adverse effects similar to thrombotic thrombocytopenic purpura (TTP) syndrome following the intravenous (IV) abuse of opioids containing PEO excipient. Increased risk of IV opioid ADF abuse compared to clinical benefit of the drug led to the removal of one opioid product from the market in 2017. Because many generic drugs containing PEO are still in development, there is interest in assessing safety consistent with generic drug regulation and unintended uses. Currently, there are no guidelines or in vitro assessment tools to characterize the safety of PEO excipients taken via intravenous injection. To create a more robust excipient safety evaluation tool and to study the mechanistic basis of HMW PEO-induced TMA, a dynamic in vitro test system involving blood flow through a needle model has been developed.

Pharmacokinetics, biodistribution, and in vivo toxicity of 7-nitroindazole loaded in pegylated and non-pegylated nanoemulsions in rats.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. The development of sepsis is associated with excessive nitric oxide (NO) production, which plays an important role in controlling vascular homeostasis. 7-nitroindazole (7-NI) is a selective inhibitor of neuronal nitric oxide synthase (NOS-1) with potential application for treating NO imbalance conditions. However, 7-NI exhibits a low aqueous solubility and a short plasma half-life. To circumvent these biopharmaceutical limitations, pegylated (NEPEG7NI) and non-pegylated nanoemulsions (NENPEG7NI) containing 7-NI were developed. This study evaluates the pharmacokinetic profiles and toxicological properties of 7-NI loaded into the nanoemulsions. After a single intravenous administration of the free drug and the nanoemulsions at a dose of 10 mg.kg-1 in Wistar rats, 7-NI was widely distributed in the organs. The pharmacokinetic parameters of Cmax, t1/2, and AUC0-t were significantly increased after administration of the NEPEG7NI, compared to both free 7-NI and NENPEG7NI (p < 0.05). No observable adverse effects were observed after administering the free 7-NI, NEPEG7NI, or NENPEG7NI in the animals after a single dose of up to 3.0 mg.kg-1. The results indicated that 7-NI-loaded nanoemulsions are safe, constituting a promising approach to treating sepsis.

In vitro and in vivo toxicity of thiolated and PEGylated organosilica nanoparticles.

This study comprises the comprehensive toxicological assessment of thiolated organosilica nanoparticles (NPs) synthesised from 3-mercaptopropyltrimethoxysilane (MPTS). We investigated the influence of three different types of nanoparticles synthesised from 3-mercaptopropyltrimethoxysilane: the starting thiolated silica (Si-NP-SH) and their derivatives prepared by surface PEGylation with PEG 750 (Si-NP-PEG750) and 5000 Da (Si-NP-PEG5000) on biological subjects from in vitro to in vivo experiments to explore the possible applications of those nanoparticles in biomedical research. As a result of this study, we generated a comprehensive understanding of the toxicological properties of these nanoparticles, including their cytotoxicity in different cell lines, hemolytic properties, in vitro localisation, mucosal irritation properties and biodistribution in BALB/c mice. Our findings indicate that all three types of nanoparticles can be considered safe and have promising prospects for use in biomedical applications. Nanoparticles did not affect the viability of HPF, MCF7, HEK293 and A549 cell lines at low concentrations (up to 100 µg/mL); moreover, they did not cause organ damage to BALB/c mice at concentrations of 10 mg/kg. The outcomes of this study enhance our understanding of the impact of organosilica nanoparticles on health and the environment, which is vital for developing silica nanoparticle-based drug delivery systems and provides opportunities to expand the applications of organosilica nanoparticles.

Cellular uptake and cytotoxicity of PEGylated MXene nanomaterials mediated by protein corona.

A stringent analysis of the biocompatibility of MXene is a necessary condition for assessing the biological risk of MXene. Owing to high surface free energy, MXene is capable of adsorbing a large amount of blood proteins to form MXene-protein corona complexes, however, a comprehensive understanding of the relationship between MXene and cellular physiological systems remains limited. Therefore, we investigated the cellular uptake and cytotoxicity effect of MXene Ti3C2Tx and PEGylation Ti3C2Tx mediated by human serum protein corona in THP-1 cells. It was found that PEGylation can alter the interaction between Ti3C2Tx and serum proteins, inducing a significant transformation in the fingerprint of the protein corona. Following protein corona formation, both Ti3C2Tx and PEGylated Ti3C2Tx predominantly accumulated at lysosomal sites within THP-1 cells. Further analysis revealed that clathrin-mediated endocytosis was the primary mechanism of Ti3C2Tx internalization by THP-1 cells. There was no significant effect on cell viability. However, we found that Ti3C2Tx plays a dual role as both a stimulus and scavenger of ROS within THP-1 cells, influenced by its PEGylation and the formation of a protein corona. This study provides important insights for biocompatibility evaluation and rational design of nanoproducts based on Ti3C2Tx in the future.

Fabrication of Dual pH/Reduction-Responsive P(CL-co-ACL)-Based Cross-Linked Polymeric Micelles for PTX Delivery.

To enhance the stability of the polymeric micelles and optimize their drug-controlled release ability, three disulfide-linked polyethylene glycol methyl ether methacrylate-disulfide-poly(ε-caprolactone-co-γ-amine-ε-caprolactone) (PPEGMA-SS-P(CL-co-ACL)) polymers were synthesized and characterized by 1H NMR, GPC, and FT-IR successfully, and their dual pH/reduction-responsive cross-linked polymeric micelles were prepared for paclitaxel (PTX) delivery by using 2,3-dimethylmaleic anhydride (DMMA) as the cross-linking agent. The PTX loading capacity (LC) and encapsulation efficiency (EE) values of the cross-linked micelles formed by PPEGMA8-SS-P(CL47-co-ACL15) achieved were 23.96% and 71.58%, slightly higher than those of un-cross-linked micelles. Both particle sizes of blank micelles and in vitro drug release of PTX-loaded micelles confirmed that compared with those un-cross-linked micelles, the cross-linked micelles were more stable at pH 7.4 + 0 mM DTT, with a PTX cumulative release of 13% at 120 h, while the PTX cumulative release of the cross-linked micelles at pH 5.0 + 10 mM DTT were close to that of un-cross-linked micelles after 60 h, indicating the successful reversible cross-linking and smooth drug release of the cross-linked micelles. The cytotoxicity assay showed that PPEGMA8-SS-P(CL47-co-ACL15) and its cross-linked micelles had low cell cytotoxicity, and both PTX-loaded micelles revealed a certain inhibitory effect on HepG2 cells. These results revealed that the dual pH/reduction-responsive cross-linked polymeric micelles prepared from PPEGMA8-SS-P(CL47-co-DCL15) were a promising candidate for PTX delivery.

Toxicity of a Modified PEG-Asparaginase-Based SMILE Regimen Is Comparable to L-Asparaginase-Based SMILE in a Non-Asian Population.

INTRODUCTION: L-asparaginase-based chemotherapy regimens are effective for treating chemotherapy-resistant natural killer- (NK-) cell neoplasms. To treat these lymphoma subtypes in Asia, where NK/T-cell lymphomas are more prevalent, the NK-Cell Tumor Study Group developed the SMILE regimen, which includes a steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide. In the US however, the only commercially available form of asparaginase is the pegylated form (PEG-asparaginase) which has been incorporated into a modified SMILE (mSMILE). We sought to study the toxicity associated with replacing L-asparaginase with PEG-asparaginase in mSMILE. PATIENTS AND METHODS: We retrospectively identified all adult patients treated with the mSMILE chemotherapy regimen in our database at Moffitt Cancer Center (MCC) between December 1, 2009, and July 30, 2021. Patients were included if they were treated with mSMILE irrespective of their underlying diagnosis. Toxicity was assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 5. The rate of toxicity in our mSMILE treatment group was numerically compared to data published in a metanalysis of the SMILE regimen's toxicity (Pokrovsky et al., 2019). RESULTS: A total of 21 patients were treated with mSMILE at MCC during the 12-year analysis window. Compared to patients receiving the L-asparaginase-based SMILE, patients receiving mSMILE experienced grade 3 or 4 leukopenia less often, with a toxicity rate of 62% (median with SMILE, 85% [95% CI, 74%-95%]); thrombocytopenia, however, was more common, with a toxicity rate of 57% (median with SMILE, 48% [95% CI, 40%-55%]). Other hematological, hepatic and coagulation related toxicities were also reported. CONCLUSION: In a non-Asian population, the mSMILE regimen with PEG-asparaginase is a safe alternative to the L-asparaginase-based SMILE regimen. There is a comparable risk of hematological toxicity, and no treatment-related mortality was seen in our population.

Polyethyleneimine/polyethylene glycol-conjugated gold nanoparticles as nanoscale positive/negative controls in nanotoxicology: testing in frog embryo teratogenesis assay-Xenopus and mammalian tissue culture system.

Despite the great potential of using positively charged gold nanoparticles (AuNPs) in nanomedicine, no systematic studies have been reported on their synthesis optimization or colloidal stability under physiological conditions until a group at the National Institute of Standards and Technology recently succeeded in producing remarkably stable polyethyleneimine (PEI)-coated AuNPs (Au-PEI). This improved version of Au-PEI (Au-PEI25kB) has increased the demand for toxicity and teratogenicity information for applications in nanomedicine and nanotoxicology. In vitro assays for Au-PEI25kB in various cell lines showed substantial active cytotoxicity. For advanced toxicity research, the frog embryo teratogenesis assay-Xenopus (FETAX) method was employed in this study. We observed that positively-charged Au-PEI25kB exhibited significant toxicity and teratogenicity, whereas polyethylene glycol conjugated AuNPs (Au-PEG) used as comparable negative controls did not. There is a characteristic avidity of Au-PEI25kB for the jelly coat, the chorionic envelope (also known as vitelline membrane) and the cytoplasmic membrane, as well as a barrier effect of the chorionic envelope observed with Au-PEG. To circumvent these characteristics, an injection-mediated FETAX approach was utilized. Like treatment with the FETAX method, the injection of Au-PEI25kB severely impaired embryo development. Notably, the survival/concentration curve that was steep when the standard FETAX approach was employed became gradual in the injection-mediated FETAX. These results suggest that Au-PEI25kB may be a good candidate as a nanoscale positive control material for nanoparticle analysis in toxicology and teratology.

High-Strength Injectable Hydrogel into Perivascular Interstitial Space Enhances Arterial Adventitial Stress.

Injectable hydrogels with strong mechanical properties have significant potential for biomedical applications, including the development of electronic skin, intelligent medical robots, as well as tissue engineering. In this study, we report on an injectable hydrogel with notable tensile strength and adhesion properties, achieved through cross-linking thiol-terminated four-arm poly (ethylene glycol) using silver-doped nano-hydroxyapatite, modified with dopamine. Subsequently, the hydrogel was injected in vivo through the perivascular interstitial space of rats. The hydrogel wrapped around the damaged abdominal aortic adventitia, which greatly increases the stress strength of the arterial adventitia. We found that the hydrogel was characterized by excellent biocompatibility, and it induced little immune response over a span of 21 days post-implantation. This simple and minimally invasive vascular protection strategy appears promising for the treatment of vascular diseases, such as abdominal aortic aneurysm (AAA).

Impaired barrier integrity of endothelial cells induced by PEGylated black phosphorus nanosheets.

PEGylated black phosphorus nanosheets (PEG-BPNSs) have shown promising applications in biomedicine and potentially interact with the vasculature following iatrogenic exposures. Whether the exposure to PEG-BPNSs could induce toxic effects on endothelial cells that line the blood vessels remains largely unknown. Herein, we investigate the cellular response and transcriptional profiling of human umbilical vein endothelial cells (HUVECs) after the exposure to BPNSs and PEG-BPNSs. BPNSs and PEG-BPNSs induce cellular elongation and cause significant cytotoxicity to HUVECs at 0.8 µg/mL, with viabilities of 87.8% and 87.7% respectively. The transcriptome analysis indicates that BPNSs and PEG-BPNSs at 0.4 µg/mL cause marked alterations in the expression of genes associated with detection of stimulus, ion transmembrane transport and components of plasma membrane. BPNSs and PEG-BPNSs at 0.4 µg/mL decrease the transendothelial electrical resistance (TEER) across monolayers of HUVECs by 22.8% and 20.3% compared to the control, respectively. The disturbance of tight junctions (TJs) after 24 h exposure to 0.4 µg/mL BPNSs and PEG-BPNSs is indicated with the downregulated mRNA expression of zona occluden-1 (ZO-1) by respective 16.5% and 29.9%, which may be involved in the impairment of endothelial barrier integrity. Overall, the response of HUVECs to PEG-BPNSs and BPNSs has no statistical difference, suggesting that PEGylation does not attenuate the BPNSs-induced endothelial injury. This study demonstrates the detrimental effects of BPNSs and PEG-BPNSs on barrier integrity of HUVECs, contributing to our understanding on the potential toxicological mechanisms.

Normal Neurodevelopment and Fertility in Juvenile Male Rats Exposed to Polyethylene Glycol Following Dosing With PEGylated rFIX (Nonacog Beta Pegol, N9-GP): Evidence from a 10-Week Repeat-Dose Toxicity Study.

N9-GP/Rebinyn®/Refixia® is an approved PEGylated (polyethylene glycol-conjugated) recombinant human factor IX intended for prophylactic and/or on-demand treatment in adults and children with haemophilia B. A juvenile neurotoxicity study was conducted in male rats to evaluate effects on neurodevelopment, sexual maturation, and fertility following repeat-dosing of N9-GP. Male rats were dosed twice weekly from Day 21 of age with N9-GP or vehicle for 10 weeks, followed by a dosing-free recovery period for 13 weeks and terminated throughout the dosing and recovery periods. Overall, dosing N9-GP to juvenile rats did not result in any functional or pathological effects, as measured by neurobehavioural/neurocognitive tests, including motor activity, sensory function, learning and memory as well as growth, sexual maturation, and fertility. This was further supported by the extensive histopathologic evaluation of brain tissue. Exposure and distribution of polyethylene glycol was investigated in plasma, choroid plexus, cerebrospinal fluid, and brain sections. PEG did not cross the blood brain barrier and PEG exposure did not result in any effects on neurodevelopment. In conclusion, dosing of N9-GP to juvenile rats did not identify any effects on growth, sexual maturation and fertility, clinical and histological pathology, or neurodevelopment related to PEG exposure and supports the prophylactic use of N9-GP in children.

Human osteoblasts response to different dental implant abutment materials: An in-vitro study.

OBJECTIVES: This study aimed to investigate human osteoblasts (HOB) response towards different dental implant abutment materials. METHODS: Five dental implant abutment materials were investigated: (1) titanium (Ti), (2) titanium coated nitride (TiN), (3) cobalt chromium (CoCr), (4) zirconia (ZrO2), and (5) modified polyether ether ketone (m-PEEK). HOBs were cultured, expanded, and seeded according to the supplier's protocol (PromoCell, UK). Cell proliferation and cytotoxicity were evaluated at days 1, 3, 5, and 10 using Alamar Blue (alamarBlue) and lactate dehydrogenase (LDH) colorimetric assays. Data were analysed via two-way ANOVA, one-way ANOVA and Tukey's post hoc test (significance was determined as p < 0.05 for all tests). RESULTS: All the investigated materials showed high and comparable initial proliferation activities apart from ZrO2 (46.92%), with P% of 79.91%, 68.77%, 73.20%, and 65.46% for Ti, TiN, CoCr, and m-PEEK, respectively. At day 10, all materials exhibited comparable and lower P% than day 1 apart from TiN (70.90%) with P% of 30.22%, 40.64%, 37.27%, and 50.65% for Ti, CoCr, ZrO2, and m-PEEK, respectively. The cytotoxic effect of the investigated materials was generally low throughout the whole experiment. At day 10, the cytotoxicity % was 7.63%, 0.21%, 13.30%, 5.32%, 8.60% for Ti, TiN, CoCr, ZrO2, and m-PEEK. The Two-way ANOVA and Tukey's Multiple Comparison Method highlighted significant material and time effects on cell proliferation and cytotoxicity, and a significant interaction (p < 0.0001) between the tested materials. Notably, TiN and m-PEEK showed improved HOB proliferation activity and cytotoxic levels than the other investigated materials. In addition, a non-significant negative correlation between viability and cytotoxicity was found for all tested materials. Ti (p = 0.07), TiN (p = 0.28), CoCr (p = 0.15), ZrO2 (p = 0.17), and m-PEEK (p = 0.12). SIGNIFICANCE: All the investigated materials showed excellent biocompatibility properties with more promising results for the newly introduced TiN and m-PEEK as alternatives to the traditionally used dental implant and abutment materials.

A Time-Course Evaluation of DNA Damage and Neurotoxicity Induced by PEGylated Graphene Oxide Nanoparticle in Swiss Albino Mice.

PEGylated graphene oxide nanoparticle (PEG-nGO) has been commonly used as a carrier for therapeutic drugs and vaccines, because of its unique properties, such as high solubility, more stability and increased biocompatibility in physiological solutions. This study aimed to examine the DNA damage and neurotoxicity in young mice after up to 4 h of the treatment with PEG-nGO. A single dose (5 mg/kg) of intravenous injection was administered through the tail vein of adult mice. Total genomic DNA was isolated from the control and treated animals after 1 h, 2 h, and 4 h of treatments and examined for DNA damage by diphenyl assay, DNA fragmentation Assay, and FTIR (Fourier transform infrared) techniques. DNA damage studies indicated DNA fragmentation after 1 h and 2 h of treatments followed by recovery at 4 h. FTIR analysis further supported these results and showed a detailed molecular effect of the treatments that caused single and double-strand DNA breaks at 1 to 2 h after the treatments and indicated DNA damage response and recovery at 4 h. Histopathology showed neuronal apoptosis and lesions in the brain after 1 to 2 h and invasion of inflammatory response and chromatolysis after 4 h. PEG-nGO caused immediate DNA damage and cytotoxicity to the brain and its future use as a drug carrier should be considered with caution.

Pyrene-polyethylene glycol-modified multi-walled carbon nanotubes: Genotoxicity in V79-4 fibroblast cells.

The genotoxicity of pyrene-polyethylene glycol-modified multi-walled carbon nanotubes (MWCNT-PyPEG), engineered as a nanoplatform for bioapplication, was evaluated. Toxicity was assessed in hamster lung fibroblast cells (V79-4). MTT and Cell Titer Blue methods were used to evaluate cell viability. Genotoxicity was measured by the comet assay and the cytokinesis-block micronucleus cytome (CBMN-Cyt) assay, and fluorescence in situ hybridization (FISH) was used to test induction of structural chromosome aberrations (clastogenic activity) and/or numerical chromosome changes (aneuploidogenic activity). Exogenous metabolic activation enzymes were used in the CBMN-Cyt and FISH tests. Only with metabolic activation, the hybrids caused chromosomal damage, by both clastogenic and aneugenic processes.

Toxicity of high-molecular-weight polyethylene glycols in Sprague Dawley rats.

Polyethylene glycol (PEG) is present in a variety of products. Little is known regarding the accumulation of high-molecular-weight PEGs or the long-term effects resulting from PEG accumulation in certain tissues, especially the choroid plexus. We evaluated the toxicity of high-molecular-weight PEGs administered to Sprague Dawley rats. Groups of 12 rats per sex were administered subcutaneous injections of 20, 40, or 60 kDa PEG or intravenous injections of 60 kDa PEG at 100 mg PEG/kg body weight/injection once a week for 24 weeks. A significant decrease in triglycerides occurred in the 60 kDa PEG groups. PEG treatment led to a molecular-weight-related increase in PEG in plasma and a low level of PEG in cerebrospinal fluid. PEG was excreted in urine and feces, with a molecular-weight-related decrease in the urinary excretion. A higher prevalence of anti-PEG IgM was observed in PEG groups; anti-PEG IgG was not detected. PEG treatment produced a molecular-weight-related increase in vacuolation in the spleen, lymph nodes, lungs, and ovaries/testes, without an inflammatory response. Mast cell infiltration at the application site was noted in all PEG-treated groups. These data indicate that subcutaneous and intravenous exposure to high-molecular-weight PEGs produces anti-PEG IgM antibody responses and tissue vacuolation without inflammation.

Chronic intraperitoneal injection of polyethylene glycol 200 in mice induces hippocampal neuroinflammation.

In vivo treatment of hydrophobic substances requires the use of organic solvents, which are often toxic. Consequently, polyethylene glycols (PEGs), which are considered as nontoxic, have been widely used for many years in chemistry and biology. We used PEG 200, which was administrated by intraperitoneal (i.p.) injection once a week to mice. After 4 months of injections, at the dose of 1.67 mL/kg, a surprising increase in expression of GFAP (glial fibrillary acidic protein) and IBA1 (ionized calcium binding adaptor molecule 1), glial markers of astrocytes and microglia respectively, was observed in the mice's hippocampus. These results were associated with a dramatic increase in pro-inflammatory cytokine interleukin-1ß (IL-1ß) expression, all together suggesting an inflammatory process. It is important to communicate these results to the scientific community to provide awareness of this potential effect when PEG 200 is used under similar conditions as a vehicle in mice.

Influence of nanoparticle size on blood-brain barrier penetration and the accumulation of anti-seizure medicines in the brain.

Anti-seizure medicines constitute a common yet important modality to treat epilepsy. However, some of them are associated with serious side effects including hepatotoxicity and hypersensitivity. Furthermore, the blood-brain barrier (BBB) is an insurmountable obstacle for brain drug delivery. Fortunately, the introduction of the nanoparticles for drug delivery is a feasible approach to overcome these obstacles. Encapsulating drugs into nanoparticles and delivering them to specific sites shows great potential for improving the efficiency of drug delivery and reducing systemic toxicity. Several in vivo studies have investigated the effect of nanoparticle size on biodistribution in mice, but very few have investigated its effects on efficient drug delivery while crossing the BBB. Therefore, we designed a methoxy poly(lactide-co-glycolide)-b-poly(ethylene glycol) methyl ether (mPEG-PLGA) nanoparticle delivery system and explored the cell uptake efficiency of nanoparticles with different sizes and their ability to penetrate the BBB while carrying carbamazepine (CBZ). CBZ-loaded nanoparticles could significantly reduce the cytotoxicity of CBZ to L929 cells at high concentrations. Results from the endocytosis experiment involving human cerebral microvessel endothelial cell/D3 showed that the DiR-loaded mPEG5K-PLGA10K nanoparticles possessed the highest cell uptake efficiency. The endocytosis efficiency was 90% at 30 min, which far exceeded that of the other groups. Moreover, similar results were obtained from subsequent experiments where fluorescence images of the isolated organs of the mice were acquired. To summarize, our study demonstrated that drug delivery to the brain using nanocarriers is size dependent. Nanoparticles with the smallest particle size can be internalized more effectively, and easily penetrate the BBB, and accumulate in the brain.

Silver Nanoparticles Impair Cognitive Functions and Modify the Hippocampal Level of Neurotransmitters in a Coating-Dependent Manner.

Due to their potent antibacterial properties, silver nanoparticles (AgNPs) are widely used in industry and medicine. However, they can cross the brain-blood barrier, posing a risk to the brain and its functions. In our previous study, we demonstrated that oral administration of bovine serum albumin (BSA)-coated AgNPs caused an impairment in spatial memory in a dose-independent manner. In this study, we evaluated the effects of AgNPs coating material on cognition, spatial memory functioning, and neurotransmitter levels in rat hippocampus. AgNPs coated with BSA (AgNPs(BSA)), polyethylene glycol (AgNPs(PEG)), or citrate (AgNPs(Cit)) or silver ions (Ag+) were orally administered at a dose of 0.5 mg/kg b.w. to male Wistar rats for a period of 28 days, while the control (Ctrl) rats received 0.2 mL of water. The acquisition and maintenance of spatial memory related to place avoidance were assessed using the active allothetic place avoidance task, in which rats from AgNPs(BSA), AgNPs(PEG), and Ag+ groups performed worse than the Ctrl rats. In the retrieval test assessing long-term memory, only rats from AgNPs(Cit) and Ctrl groups showed memory maintenance. The analysis of neurotransmitter levels indicated that the ratio between serotonin and dopamine concentration was disturbed in the AgNPs(BSA) rats. Furthermore, treatment with AgNPs or Ag+ resulted in the induction of peripheral inflammation, which was reflected by the alterations in the levels of serum inflammatory mediators. In conclusion, depending on the coating material used for their stabilization, AgNPs induced changes in memory functioning and concentration of neurotransmitters.

In Vitro Evaluation of DSPE-PEG (5000) Amine SWCNT Toxicity and Efficacy as a Novel Nanovector Candidate in Photothermal Therapy by Response Surface Methodology (RSM).

Nowadays, finding a novel, effective, biocompatible, and minimally invasive cancer treatment is of great importance. One of the most promising research fields is the development of biocompatible photothermal nanocarriers. PTT (photothermal therapy) with an NIR (near-infrared) wavelength range (700-2000 nm) would cause cell death by increasing intercellular and intracellular temperature. PTT could also be helpful to overcome drug resistance during cancer treatments. In this study, an amine derivative of phospholipid poly ethylene glycol (DSPE-PEG (5000) amine) was conjugated with SWCNTs (single-walled carbon nanotubes) to reduce their intrinsic toxicity. Toxicity studies were performed on lung, liver, and ovarian cancer cell lines that were reported to show some degree of drug resistance to cisplatin. Toxicity results suggested that DSPE-PEG (5000) amine SWCNTs might be biocompatible photothermal nanocarriers in PTT. Therefore, our next step was to investigate the effect of DSPE-PEG (5000) amine SWCNT concentration, cell treatment time, and laser fluence on the apoptosis/necrosis of SKOV3 cells post-NIR exposure by RSM and experimental design software. It was concluded that photothermal efficacy and total apoptosis would be dose-dependent in terms of DSPE-PEG (5000) amine SWCNT concentration and fluence. Optimal solutions which showed the highest apoptosis and lowest necrosis were then achieved.

The toxicity analysis of PVP, PVA and PEG surface functionalized ZnO nanoparticles on embryonic as well as adult Danio rerio.

Globally, the production of zinc oxide nanoparticles (ZnO NPs) increased due to its wide applications including cosmetics, paints etc., and gets accumulated in the environment during their production, use or end-of-life. The toxic effects of the NPs vary with the presence of various surface modification agents. In the current report, toxic effect of bare and capped ZnO NPs with polymeric surface modifying agent including polyvinyl alcohol (PVA), polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) is studied against adult as well as embryonic zebra fish. The surface capped NPs showed great variation in toxicity levels. It was observed that ZnO-PVA showed highly reduced toxic effects relative to ZnO-PEG and ZnO-PVP. Further, various environmental agents including humic acid can also have an impact on NPs toxicity. ZnO particles showed increased toxic effect in humic acid presence. The uptake of ZnO particles by D. rerio was high in the order of PVP-, PEG- and PVA- followed by bare-ZnO. The current investigation found that ZnO NPs dissolution and uptake are the major factors which cause the toxicity against adult as well as embryonic zebra fishes respectively.