Engineering properties optimization of dispersive soil by calcium silicate waste-The role of steel-making slag.

Steel slag (SS) is a byproduct that comes from the production of crude steel in alkaline oxidation furnaces. Resource utilization of steel slag, a calcium-silicon solid waste, is an urgent problem. This paper investigates a solid waste disposal method that applies different steel slag contents to modify dispersive soil. The engineering properties and modification mechanisms of dispersive soil specimens are studied and revealed by performing microstructure, mineral evolution, unconfined compressive strength (UCS), and tensile strength analysis. The pinhole test, mud ball crumb test (BCT), and mud cube crumb test (CCT) were carried out to determine the dispersivity of the soil specimens. Results show that when the steel slag content increases from 1% to 10%, the unconfined compressive strength and tensile strength increase by 176.05% and 75.40%, respectively. For soil specimens without curing time under 50 mm water head, the weight loss of the specimen with 10% steel slag content decreases by 72.03% compared to specimens with 1% steel slag content. Microstructural and mineralogical analyses indicate that the hydration reaction of steel slag changes the ionic composition of the soil and generates reaction products with effects such as filling and connection. To sum up, steel slag effectively improves water stability and mechanical properties of dispersive soil.

Red blood cell-hitchhiking mediated pulmonary delivery of ivermectin: Effects of nanoparticle properties.

Recent studies have demonstrated that ivermectin (IVM) exhibits antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus of coronavirus disease 2019 (COVID-19). However, the repurposing of IVM for the treatment of COVID-19 has presented challenges primarily due to the low IVM plasma concentration after oral administration, which was well below IC50. Here, a red blood cell (RBC)-hitchhiking strategy was used for the targeted delivery of IVM-loaded nanoparticles (NPs) to the lung. IVM-loaded poly (lactic-co-glycolic acid) (PLGA) NPs (IVM-PNPs) and chitosan-coating IVM-PNPs (IVM-CSPNPs) were prepared and adsorbed onto RBCs. Both RBC-hitchhiked IVM-PNPs and IVM-CSPNPs could significantly enhance IVM delivery to lungs, improve IVM accumulation in lung tissue, inhibit the inflammatory responses and finally significantly alleviate the progression of acute lung injury. Specifically, the redistribution and circulation effects were related to the properties of NPs. RBC-hitchhiked cationic IVM-CSPNPs showed a longer circulation time, slower accumulation and elimination rates, and higher anti-inflammatory activities than RBC-hitchhiked anionic IVM-PNPs. Therefore, RBC-hitchhiking provides an alternative strategy to improve IVM pharmacokinetics and bioavailability for repurposing of IVM to treat COVID-19. Furthermore, according to different redistribution effects of different NPs, RBC-hitchhiked NPs may achieve various accumulation rates and circulation times for different requirements of drug delivery.

Targeted delivery of PARP inhibitors to neuronal mitochondria via biomimetic engineered nanosystems in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) is known to activate poly (ADP-ribose) polymerase (PARP-1), which leads to pronounced negative effects on mitochondrial DNA (mt-DNA) repair and function. Notably, PARP inhibitors are reported to be beneficial in experimental models of TBI. A targeting strategy for the delivery of neuronal mitochondria-specific PARP inhibitors could result in a greater neuroprotective effect and be a safer approach for TBI treatment. In the present study, we developed the PARP inhibitor olaparib (Ola) as a model drug and devised red blood cell (RBC)-coated nanostructured lipid carriers (RBCNLCs) co-modified with C3 and SS31 peptide (C3/SS31-RBCNLCs) for brain neuronal mitochondria-targeting. Our results indicated that biomimetic nanosystems have the physical and chemical properties of the NLCs, as well as the biological properties of RBC. A high concentration of Ola delivered into brain mitochondria by C3/SS31-RBCNLCs-Ola effectively improved mitochondrial function and prevented neuronal cell death caused by excessive activation of injury-induced mitochondrial PARP (mt-PARP) in vitro and in vivo. Taken together, the results of this study support the preclinical feasibility of developing highly effective nano-drugs as part of precision medicine for TBI. STATEMENT OF SIGNIFICANCE: TBI-induced neuronal mitochondria DNA damage activates Poly(ADP-ribose) Polymerase (PARP1) which leads to a pronounced negative effect on mitochondrial DNA repair and mitochondrial function. In recent years, PARP inhibitors showed strong benefits in experimental models of TBI, more importantly PARP inhibitors specially target neuronal mitochondria may play a greater neuroprotective role and may be a safer approach for TBI treatment. Herein, we designed red blood cell (RBC) membrane-coated nanostructure lipid carriers dual-modified with C3 and SS31 (C3/SS31-RBCNLCs) to accomplish these objectives. After encapsulating Olaparib (Ola) as the model PARP inhibitor, the data demonstrated that C3/SS31-RBCNLCs, with brain neuronal mitochondria targeting, can reduce neuronal cell death and improve mitochondrial dysfunction triggered by mitochondrial PARP activation in vitro and in vivo.

RBC-hitchhiking chitosan nanoparticles loading methylprednisolone for lung-targeting delivery.

Hyper-inflammation associated with cytokine storm syndrome causes high mortality in patients with COVID-19. Glucocorticoids, such as methylprednisolone sodium succinate (MPSS), effectively inhibit this inflammatory response. However, frequent and chronic administration of glucocorticoids at high doses leads to hormone dependence and serious side effects. The aim of the present study was to combine nanoparticles with erythrocytes for the targeted delivery of MPSS to the lungs. Chitosan nanoparticles loading MPSS (MPSS-CSNPs) were prepared and adsorbed on the surface of red blood cells (RBC-MPSS-CSNPs) by non-covalent interaction. In vivo pharmacokinetic study indicated that RBC-hitchhiking could significantly reduce the plasma concentration of the drug and prolong the circulation time. The mean residence time (MRT) and area under the curve (AUC) of the RBC-MPSS-CSNPs group were significantly higher than those of the MPSS-CSNPs group and the MPSS injection group. Moreover, in vivo imaging and tissue distribution indicated that RBC-hitchhiking facilitated the accumulation of nanoparticles loading fluorescein in the lung, preventing uptake of these nanoparticles by the liver. Furthermore, compared with the MPSS-CSNPs and MPSS treatment groups, treatment with RBC-MPSS-CSNPs considerably inhibited the production of inflammatory cytokines such as TNF-α and IL-6, and consequently attenuated lung injury induced by lipopolysaccharide in rats. Therefore, RBC-hitchhiking is a potentially effective strategy for the delivery of nanoparticles to the lungs for the treatment of acute lung injury and acute respiratory distress syndrome.

Cepharanthine loaded nanoparticles coated with macrophage membranes for lung inflammation therapy.

Acute lung injury (ALI) is a disease associated with suffering and high lethality, but to date without any effective pharmacological management in the clinic. In the pathological mechanisms of ALI, a strong inflammatory response plays an important role. Herein, based on macrophage 'homing' into inflammation sites and cell membrane coating nanotechnology, we developed a biomimetic anti-inflammation nanosystem (MM-CEP/NLCs) for the treatment of ALI. MM-CEP/NLCs were made with nanostructured lipid carriers (NLCs) coated with natural macrophage membranes (MMs) to achieve effective accumulation of cepharanthine (CEP) in lung inflammation to achieve the effect of treating ALI. With the advantage of suitable physicochemical properties of NLCs and unique biological functions of the macrophage membrane, MM-CEP/NLCs were stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. In vivo, the macrophage membranes enabled NLCs to be targeted and accumulated in the inflammation sites. Further, MM-CEP/NLCs significantly attenuated the severity of ALI, including lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammation cytokines. Our results provide a bionic strategy via the biological properties of macrophages, which may have greater value and application prospects in the treatment of inflammation.

Red blood cell-hitchhiking chitosan nanoparticles for prolonged blood circulation time of vitamin K1.

Nanocarriers have been extensively applied for intravascular drug delivery. However, rapid clearance from circulation by mononuclear phagocyte system has limited their applications. Erythrocytes carriers are potential solutions to overcome the limitations of nanocarriers and considered to be ideal natural carriers for drug delivery because of their unique properties. The purpose of this work is to combine nanocarriers with erythrocytes carriers for sustained release and prolonged circulation time of vitamin K1. Chitosan nanoparticles loading VK1 (VK-CSNPs) were prepared using ionotropic gelation method, which was optimized using box-behnken design and response surface methodology. VK-CSNPs adsorbed onto red blood cells (RBC-VK-CSNPs) rapidly via electrostatic interactions. The exposure of phosphatidylserine, osmotic fragility and turbulence fragility of RBC loading nanoparticles were investigated to study the toxicity of nanoparticles to erythrocytes. In vivo pharmacokinetic study indicated that Cmax, AUC and MRT of RBC-VK-CSNPs group were remarkably higher than that of VK-CSNPs group. Flow cytometry showed VK-CSNPs steadily retained on the surface of RBC for a long time without affecting the circulation profiles of RBC themselves. The nanoparticles carried on RBC released drug, desorbed and were eliminated in vivo. Therefore, the circulation time of RBC-hitchhiking chitosan nanoparticles was greatly prolonged compared with nanoparticles alone. RBC-hitchhiking could be a valuable hybrid strategy for prolonging the in vivo life of nanocarriers.