Penetration of the blood-brain barrier and anti-tumor effect of a novel PLGA-lysoGM1/DOX micelles drug delivery system

Effective treatment of glioma and other central nervous system (CNS) diseases is hindered by the presence of the blood-brain barrier (BBB). A novel nano-delivery vehicle system comprised of PLGA-lysoGM1/DOX micelles was developed to across the BBB for CNS administration. We have shown that Doxorubicin (DOX) as a model drug encapsulated in PLGA-lysoGM1 micelles, can achieve up to 3.8% loading efficiency and 61.6% encapsulation efficiency by the orthogonal test design. Our in vitro experiments demonstrate that PLGA-lysoGM1/DOX micelles have a slow and sustainable drug release under physiological conditions and exhibit a high cellular uptake through the macropinocytosis and the autophagy/lysosomal pathways. In vivo experimental studies in zebrafish and mice confirmed that PLGA-lysoGM1/DOX micelles could across the BBB and specifically accumulated in the brain. Moreover, an excellent anti-glioma effect presented in intracranial glioma‐bearing rat. Therefore, PLGA-lysoGM1/DOX micelles not only effectively acrossed the BBB, but our results suggest it has a great potential for anti-glioma therapy and other central nervous system diseases

Biomimetic nanotherapies: red blood cell based core-shell structured nanocomplexes for atherosclerosis management

Cardiovascular disease is the leading cause of mortality worldwide. Atherosclerosis, one of the most common forms of the disease, is characterized by a gradual formation of atherosclerotic plaque, hardening, and narrowing of the arteries. Nanomaterials can serve as powerful delivery platforms for atherosclerosis treatment. However, their therapeutic efficacy is substantially limited in vivo due to nonspecific clearance by the mononuclear phagocytic system. In order to address this limitation, rapamycin (RAP)‐loaded poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles are cloaked with the cell membrane of red blood cells (RBCs), creating superior nanocomplexes with a highly complex functionalized bio‐interface. The resulting biomimetic nanocomplexes exhibit a well‐defined “core–shell” structure with favorable hydrodynamic size and negative surface charge. More importantly, the biomimetic nature of the RBC interface results in less macrophage‐mediated phagocytosis in the blood and enhanced accumulation of nanoparticles in the established atherosclerotic plaques, thereby achieving targeted drug release. The biomimetic nanocomplexes significantly attenuate the progression of atherosclerosis. Additionally, the biomimetic nanotherapy approach also displays favorable safety properties. Overall, this study demonstrates the therapeutic advantages of biomimetic nanotherapy for atherosclerosis treatment, which holds considerable promise as a new generation of drug delivery system for safe and efficient management of atherosclerosis

Chemical ordering suppresses large-scale electronic phase separation in doped manganites

For strongly correlated oxides, it has been a long-standing issue regarding the role of the chemical ordering of the dopants on the physical properties. Here, using unit cell by unit cell superlattice growth technique, we determine the role of chemical ordering of the Pr dopant in a colossal magnetoresistant (La1-yPry)1-xCaxMnO3 (LPCMO) system, which has been well known for its large length-scale electronic phase separation phenomena. Our experimental results show that the chemical ordering of Pr leads to marked reduction of the length scale of electronic phase separations. Moreover, compared with the conventional Pr-disordered LPCMO system, the Pr-ordered LPCMO system has a metal–insulator transition that is ~100 K higher because the ferromagnetic metallic phase is more dominant at all temperatures below the Curie temperature

Analytical Study on Reinforced Concrete Columns and Composite Columns under Lateral Impact

This study investigates the lateral impact responses of reinforced concrete (RC) and composite columns through dynamic nonlinear analysis using LS-DYNA. The simulation results were first validated against experimental results performed earlier on four different cross sections. The finite element analysis results show that the simulation results of LS-DYNA can predict the experimental results well and can be used for further parametric analysis. The overall impact resistance of the four new composite columns is significantly better than that of RC columns. Among the composite columns, the solid concrete-filled double steel tube (S-DS) column has the best impact resistance with higher impact plateau force and smaller mid-span deflection under the same test conditions. It was found that the impact response process of all types of composite columns was similar. Finally, parametric analysis of the composite columns is performed to study the influence of load, material and other related parameters on the impact response of the composite columns. The results provide new information on the impact response of composite columns and the influence of materials and load parameters. The study provides a basis for the design and analysis of composite columns under lateral impact loading

Sappan Lignum Extract Inhibits Restenosis in the Injured Artery through the Deactivation of Nuclear Factor-κB

The aim of the study was to explore whether Sappan Lignum Extract (SLE) would inhibit vascular restenosis in injured artery and its inhibitory mechanism by using a balloon-injured rat carotid artery restenosis model. Different doses of SLE were administered to the rats by tube feeding, starting from four days before surgery and continuing twice per day for two weeks after carotid injury. Injured carotid arteries isolated from rats were embedded in paraffin block and tissue sections were stained with H&E to assess restenosis. The Effects of SLE on vascular restenosis, which are involved in smooth muscle cell cycle, NF-κB p65 expression, and Superoxide (O2-) production, was assessed by RT-PCR, western blot assay, and immunohistochemistry. The results showed that in a rat carotid model of balloon dilatation injury, SLE significantly reduced the intimal-to-medial area ratio and vascular restenosis after 14 days of the injury. Immunohistochemistry study revealed no inhibited PCNA expression caused by SLE. Rat serum containing Sappan Lignum (RSC) was found neither anti-proliferative effect in cultured vascular smooth muscle cells (VSMCs) and nor arrest cell cycle progress detected by flow cytometry. RSC remarkably decreased the expression of TNF-α mRNA and protein in cultured VSMCs. Electrophoretic mobility shift assay proved that RSC inhibited the binding of NF-κB to specific DNA sequences in TNF-α treated VSMCs. Western blot pronounced that RSC and N-acetyl-L-cysteine (NAC) reduced expression of NF-κB p65 in nuclear extracts in TNF-α treated VSMCs. RSC and NAC also attenuated superoxide anion generation in TNF-α treated VSMCs. In summary, the inhibitory effects of SLE on vascular restenosis may not be mediated through inhibiting vascular cell proliferation, but through inhibiting vascular inflammation instead, which may be attributed to the inhibition of TNF-α and subsequent deactivation of NF-κB, which was in part mediated through inhibiting superoxide anion generation

Recent advancements in the use of exosomes as drug delivery systems

Abstract Extracellular vesicles (EVs) are the substances that are released by most types of cells and have an important role in cell to cell communication. Among the most highly researched EVs are exosome. Recent studies show that exosomes derived from cells have different roles and targets. Many studies show that exosome can efficiently deliver many different kinds of cargo to the target cell. Therefore, they are often used to deliver therapeutic cargo for treatment. The exosomes that have been used include both natural ones and those that have been modified with other substances to increase the delivery ability. This article provides a review of both exosomes derived from various cells and modified exosome and their ability in delivering the many kinds of cargo to the target cell

Recent advancements in the use of exosomes as drug delivery systems

Abstract Extracellular vesicles (EVs) are the substances that are released by most types of cells and have an important role in cell to cell communication. Among the most highly researched EVs are exosome. Recent studies show that exosomes derived from cells have different roles and targets. Many studies show that exosome can efficiently deliver many different kinds of cargo to the target cell. Therefore, they are often used to deliver therapeutic cargo for treatment. The exosomes that have been used include both natural ones and those that have been modified with other substances to increase the delivery ability. This article provides a review of both exosomes derived from various cells and modified exosome and their ability in delivering the many kinds of cargo to the target cell

Effect of Caspase Inhibitor Ac-DEVD-CHO on Apoptosis of Vascular Smooth Muscle Cells Induced by Artesunate

Numerous studies have shown that the proliferation and apoptosis of vascular smooth muscle cells play a key role in restenosis. Artesunate is a triterpenoid with a peroxide structure and its antimalarial, antitumor, and antiangiogenetic activities can inhibit the proliferation and apoptosis of multifarious cells. Apoptosis is caused by the activation of a series of intracellular proteolytic enzymes, among which caspase-dependent apoptosis was the earliest to be recognized. The purpose of this article is to study the effects of caspase-3 inhibitor Ac-DEVD-CHO on proliferation and apoptosis of vascular smooth muscle cells induced by Artesunate and to explore the mechanism of Artesunate-induced apoptosis of vascular smooth muscle cells. By using the method based on methyl thiazolyl tetrazolium to observe the effects of Artesunate on the growth and proliferation of vascular smooth muscle cells; observing the change in cell shape before and after Artesunate administration by transmission electron microscopy; detecting the changes in cell cycle and apoptosis rates before and after drug administration by flow cytometry; detecting the activity of caspase-3 in the caspase apoptosis pathway by the Western Blot method, we found that Artesunate inhibits the growth and proliferation of vascular smooth muscle cells in a dose- and time-dependent manner within the concentration range of 7.5–120 μg/mL, and the inhibition rate of Artesunate can be as high as 89.49 % at a concentration of 120 μg/mL after acting for 72 hours; vascular smooth muscle cells show a typical apoptosis peak due to the effects of higher concentration of Artesunate. Compared with the control group, the higher-concentration group shows major variability, Ac-DEVD-CHO, however, can significantly decrease this induction; it has been detected by Western Blot that Artesunate can induce caspase-3 activity dramatically in vascular smooth muscle cells, but this activation may be remarkably inhibited by Ac-DEVD-CHO