Lipid-coated ruthenium dendrimer conjugated with doxorubicin in anti-cancer drug delivery: Introducing protocols

One of the major limitations for the treatment of many diseases is an inability of drugs to cross the cell membrane barrier. Different kinds of carriers are being investigated to improve drug bioavailability. Among them, lipid or polymer-based systems are of special interest due to their biocompatibility. In our study, we combined dendritic and liposomal carriers and analysed the biochemical and biophysical properties of these formulations. Two preparation methods of Liposomal Locked-in Dendrimers (LLDs) systems have been established and compared. Carbosilane ruthenium metallodendrimer was complexed with an anti-cancer drug (doxorubicin) and locked in a liposomal structure, using both techniques. The LLDs systems formed by hydrophilic locking had more efficient transfection profiles and interacted with the erythrocyte membrane better than systems using the hydrophobic method. The results indicate these systems have improved transfection properties when compared to noncomplexed components. The coating of dendrimers with lipids significantly reduced their hemotoxicity and cytotoxicity. The nanometric size, low polydispersity index and reduced positive zeta potential of such complexes made them attractive for future application in drug delivery. The formulations prepared by the hydrophobic locking protocol were not effective and will not be considered furthermore as prospective drug delivery systems. In contrast, the formulations formed by the hydrophilic loading method have shown promising results where the cytotoxicity of LLD systems with doxorubicin was more effective against cancer than normal cells

Effect of Blue Light Filtering Intraocular Lenses on Visual Perception

Background and Objectives: This retrospective consecutive case control study compares best-corrected visual acuity (BCVA), mesopic contrast sensitivity (CS), color vision, and glare between a group of eyes with blue-light-filtering intraocular lenses and another with UV-light-filtering intraocular lenses. Materials and Methods: We used Early Treatment Diabetic Retinopathy Study charts to compare BCVA, Rabin charts for mesopic CS testing, Oculus HMC Anomaloscope MR to test for chromatic discrimination, and Oculus Mesotest II to measure scotopic CS with glare. For analysis, we used descriptive statistics and compared means with parametric and non-parametric tests. The level of significance was set as α = 0.05. Results: For the group with the blue-light-filtering intraocular lens, the average results were BCVA = 0.96 (SD ± 0.09), CS = 1.78 log (SD ± 0.12), chromatic discrimination results M = 63.91 (SD ± 11.88), R = 60.07 (SD ± 7.89). For mesopic CS with glare, the group achieved on average 2.54 (SD ± 1.50) points out of 4. For the group with the UV-light-filtering intraocular lens, the average results were BCVA = 0.93 (SD ± 0.14), CS = 1.79 log (SD ± 0.13), chromatic discrimination results M = 65.38 (SD ± 17.14), R = 60.79 (SD ± 10.39). For mesopic CS with glare, this group achieved an average of 2.79 (SD ± 1.53) points out of 4. Conclusion: No significant differences (p > 0.05) were found in any of the tested parameters between the analyzed groups. Slight shift in color vision was observed, although not statistically significant

Sleep Problems and 6-Sulfatoxymelatonin as Possible Predictors of Symptom Severity, Adaptive and Maladaptive Behavior in Children with Autism Spectrum Disorder

In children with autism spectrum disorder (ASD), sleep disturbances are a frequent comorbidity with an adverse effect on their behavior and functioning. It was suggested that melatonin deficit is at least partly responsible for the sleep problems. The study aimed to investigate, in a sample of 56 children with ASD aged 2.8–13.3 years, if the sleep problems and melatonin secretion can serve as predictors of adaptive functioning and severity of the ASD core symptoms. We demonstrated that, after adjustment for age, the Sleep score assessed by the Children’s Sleep Habits Questionnaire predicts the Adaptive behavior composite score only in children younger than 6 years, and the preferred predictive model is for the domain Socialization. The age-adjusted Sleep score predicted Externalizing and Internalizing maladaptive behavior, with a near-zero contribution of age to the relationship between the Internalizing maladaptive behavior and Sleep score. After adjustment for age, the reduced night-time melatonin secretion predicted a higher severity of ASD symptoms in the domain Social affect and the Calibrated Severity Score, but not the sleep problems. Our results emphasize the importance of assessing sleep problems as a modifiable predictor of behavior in children with ASD and support the hypothesis about the role of melatonin in pathophysiology of ASD

The Phthalic Selenoanhydride Decreases Rat Blood Pressure and Tension of Isolated Mesenteric, Femoral and Renal Arteries

Phthalic selenoanhydride (R-Se) solved in physiological buffer releases various reactive selenium species including H2Se. It is a potential compound for Se supplementation which exerts several biological effects, but its effect on the cardiovascular system is still unknown. Therefore, herein we aimed to study how R-Se affects rat hemodynamic parameters and vasoactive properties in isolated arteries. The right jugular vein of anesthetized Wistar male rats was cannulated for IV administration of R-Se. The arterial pulse waveform (APW) was detected by cannulation of the left carotid artery, enabling the evaluation of 35 parameters. R-Se (1–2 µmol kg−1), but not phthalic anhydride or phthalic thioanhydride, transiently modulated most of the APW parameters including a decrease in systolic and diastolic blood pressure, heart rate, dP/dtmax relative level, or anacrotic/dicrotic notches, whereas systolic area, dP/dtmin delay, dP/dtd delay, anacrotic notch relative level or its delay increased. R-Se (~10–100 µmol L−1) significantly decreased the tension of precontracted mesenteric, femoral, and renal arteries, whereas it showed a moderate vasorelaxation effect on thoracic aorta isolated from normotensive Wistar rats. The results imply that R-Se acts on vascular smooth muscle cells, which might underlie the effects of R-Se on the rat hemodynamic parameters

Self-Reported Exposure to ETS (Environmental Tobacco Smoke), Urinary Cotinine, and Oxidative Stress Parameters in Pregnant Women—The Pilot Study

Background: Exposure to ETS (environmental tobacco smoke) is one of the most toxic environmental exposures. Objective: To investigate the association of ETS with physiological, biochemical, and psychological indicators, as well as with urine antioxidant capacity (AC) and oxidative damage to lipids in a pilot sample of healthy pregnant women. Methods: Exposure to ETS was investigated via a validated questionnaire, and urine cotinine and the marker of oxidative damage to lipids via 8-isoprostane concentrations using an ELISA kit. Urine AC was determined by the spectrophotometric Trolox-equivalent antioxidant capacity (TEAC) method. From a sample of pregnant women (n = 319, average age 30.84 ± 5.09 years) in 80, the levels of cotinine and oxidative stress markers were analyzed. Results: Among the 80 pregnant women, 5% (7.4% confirmed by cotinine) reported being current smokers and 25% reported passive smoking in the household (18.8% confirmed by cotinine). The Kappa was 0.78 for smokers and 0.22 for ETS-exposed nonsmokers. Pregnant women in the ETS-exposed group had significantly reduced AC compared to both the nonsmoker (ETS−) and the smoker groups (p < 0.05). Nonsmokers had significantly lower levels of 8-isoprostane than smokers (p < 0.01) and ETS-exposed nonsmokers (p < 0.05). Correlations between urine levels of cotinine and AC were positive in ETS-exposed nonsmokers. Conclusion: A harmful association of active and passive smoking and oxidative stress parameters among pregnant women has been indicated

Dendrimeric HIV-peptide delivery nanosystem affects lipid membranes structure

International audienceThe aim of this study was to evaluate the nature and mechanisms of interaction between HIV peptide/dendrimer complexes (dendriplex) and artificial lipid membranes, such as large unilayered vesicles (LUV) and lipid monolayers in the air–water interface. Dendriplexes were combined as one of three HIV-derived peptides (Gp160, P24 and Nef) and one of two cationic phosphorus dendrimers (CPD-G3 and CPD-G4). LUVs were formed of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC) or of a mixture of DMPC and dipalmitoyl-phosphatidylglycerol (DPPG). Interactions between dendriplexes and vesicles were characterized by dynamic light scattering (DLS), fluorescence anisotropy, differential scanning calorimetry (DSC) and Langmuir–Blodgett methods. The morphology of formed systems was examined by transmission electron microscopy (TEM). The results suggest that dendriplexes interact with both hydrophobic and hydrophilic regions of lipid bilayers. The interactions between dendriplexes and negatively charged lipids (DMPC–DPPG) were stronger than those between dendriplexes and liposomes composed of zwitterionic lipids (DMPC). The former were primarily of electrostatic nature due to the positive charge of dendriplexes and the negative charge of the membrane, whereas the latter can be attributed to disturbances in the hydrophobic domain of the membrane. Obtained results provide new information about mechanisms of interaction between lipid membranes and nanocomplexes formed with HIV-derived peptides and phosphorus dendrimers. These data could be important for the choosing the appropriate antigen delivery vehicle in the new vaccines against HIV infection

In Vitro Interactions of Amphiphilic Phosphorous Dendrons with Liposomes and Exosomes—Implications for Blood Viscosity Changes

Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/pharmaceutics14081596/s1. Table S1: Three-way ANOVA results on viscosities of amphiphilic phosphorous dendrons of the first (D1) and second (D2) generation: matching by factors: concentration & dendron generation; Table S2: Three-way ANOVA results on viscosities of amphiphilic phosphorous dendrons of the first (D1) and second (D2) generation: matching by factors: concentration & dendron generationInternational audienceDrug delivery by dendron-based nanoparticles is widely studied due to their ability to encapsulate or bind different ligands. For medical purposes, it is necessary (even if not sufficient) for these nanostructures to be compatible with blood. We studied the interaction of amphiphilic dendrons with blood samples from healthy volunteers using standard laboratory methods and rheological measurements. We did not observe clinically relevant abnormalities, but we found a concentration-dependent increase in whole blood viscosity, higher in males, presumably due to the formation of aggregates. To characterize the nature of the interactions among blood components and dendrons, we performed experiments on the liposomes and exosomes as models of biological membranes. Based on results obtained using diverse biophysical methods, we conclude that the interactions were of electrostatic nature. Overall, we have confirmed a concentration-dependent effect of dendrons on membrane systems, while the effect of generation was ambiguous. At higher dendron concentrations, the structure of membranes became disturbed, and membranes were prone to forming bigger aggregates, as visualized by SEM. This might have implications for blood flow disturbances when used in vivo. We propose to introduce blood viscosity measurements in early stages of investigation as they can help to optimize drug-like properties of potential drug carriers

Blood Compatibility of Amphiphilic Phosphorous Dendrons—Prospective Drug Nanocarriers

International audienceDendrons are branched synthetic polymers suitable for preparation of nanosized drug delivery systems. Their interactions with biological systems are mainly predetermined by their chemical structure, terminal groups, surface charge, and the number of branched layers (generation). Any new compound intended to be used, alone or in combination, for medical purposes in humans must be compatible with blood. This study combined results from in vitro experiments on human blood and from laboratory experiments designed to assess the effect of amphiphilic phosphorous dendrons on blood components and model membranes, and to examine the presence and nature of interactions leading to a potential safety concern. The changes in hematological and coagulation parameters upon the addition of dendrons in the concentration range of 2–10 µM were monitored. We found that only the combination of higher concentration and higher generation of the dendron affected the selected clinically relevant parameters: it significantly decreased platelet count and plateletcrit, shortened thrombin time, and increased activated partial thromboplastin time. At the same time, occasional small-sized platelet clumps in blood films under the light microscope were observed. We further investigated aggregation propensity of the positively charged dendrons in model conditions using zwitterionic and negatively charged liposomes. The observed changes in size and zeta potential indicated the electrostatic nature of the interaction. Overall, we proved that the low-generation amphiphilic phosphorous dendrons were compatible with blood within the studied concentration range. However, interactions between high-generation dendrons at bulk concentrations above 10 µM and platelets and/or clotting factors cannot be excluded