The use of small interfering RNAs (siRNAs) has been under investigation for the treatment of several unmet medical needs, including acute lung injury/acute respiratory distress syndrome (ALI/ARDS) wherein siRNA may be implemented to modify the expression of pro-inflammatory cytokines and chemokines at the mRNA level. The clear anatomy, accessibility, and relatively low enzyme activity make the lung a good target for local siRNA therapy. However, the clinical translation of siRNA is hampered by the inefficient delivery of siRNA therapeutics to the target cells due to the properties of naked siRNA. Thus, this review will focus on the various delivery systems that can be used and the different barriers that need to be surmounted for the development of stable inhalable siRNA formulations for human use before siRNA therapeutics for ALI/ARDS become available in the clinic.

No abstract

No abstract

Atherosclerosis is a chronic disease comprising intima malfunction and arterial inflammation. Recent studies have demonstrated that autophagy could inhibit inflammatory response in atherosclerosis and exert subsequent atheroprotective effects. Our previous study also demonstrated the role of autophagy in the inhibition of inflammation by atorvastatin in vitro. Therefore, in the present study, we aimed to determine whether atorvastatin could upregulate autophagy to inhibit inflammatory cytokines secretion, lipid accumulation, and improve vulnerable plaque stability, both in vitro and in vivo. First, we established a vulnerable atherosclerotic plaque mouse model through partial ligation of left common carotid artery and left renal artery to explore the effect of atorvastatin on vulnerable plaques. The results showed that atorvastatin could enhance the stability of vulnerable atherosclerotic plaques and reduce the lesion area in the aorta. Atorvastatin could also inhibit NLRP3 inflammasome activation and inflammatory cytokines, such as IL-1β, TNF-α, and IL-18 secretion in vivo. Atorvastatin treatment upregulated the expression of autophagy-related protein microtubule-associated protein light chain (LC3B) and downregulated the expression of SQSTM1/p62, which suggested that autophagy was activated in vulnerable plaques. Transmission electron microscopy further demonstrated the atorvastatin-induced increase in autophagy activity in vulnerable atherosclerotic plaques. We employed oxidized low-density lipoprotein (ox-LDL) to stimulate RAW264.7 cells with atorvastatin, which showed that atorvastatin could attenuate lipid deposition, ameliorate inflammation, inhibit NLRP3 inflammasome activation, and enhance autophagy in vitro. All these beneficial effects were abolished by 3-methyladenine treatment, an autophagy inhibitor. Atorvastatin also significantly inhibited the phosphorylation of mTOR, which strongly suggested the involvement of the mTOR pathway. Our study proposed a new role for atorvastatin as an autophagy inducer to exert anti-inflammatory and atheroprotective effects, to stabilize vulnerable atherosclerotic plaques.

Treatment for metastatic cancer is a great challenge throughout the world. Commonly, directed inhibition of extracellular matrix metalloproteinases (MMPs) secreted by cancer cells can reduce metastasis. Here, a novel nanoplatform (HPMC NPs) assembled from hyaluronic acid (HA)-paclitaxel (PTX) prodrug and marimastat (MATT)/β-casein (CN) complexes was established to cure a 4T1 metastatic cancer model via targeting CD44 and intracellular, rather than extracellular, MMPs.Methods: HPMC NPs were prepared by assembling the complexes and prodrug under ultrasonic treatment, which the interaction between them was evaluated by förster resonance energy transfer, circular dichroism and fluorescence spectra. The developed nanoplatform was characterized via dynamic light scattering and transmission electron microscopy, and was evaluated in terms of MMP-sensitive release and stability. Subsequently, the cellular uptake, trafficking, and in vitro invasion were studied by flow cytometry, confocal laser microscopy and transwell assay. MMP expression and activity was determined by western blotting and gelatin zymography. Finally, the studies of biodistribution and antitumor efficacy in vivo were performed in a mouse 4T1 tumor breast model, followed by in vivo safety study in normal mouse.Results: The interaction between the prodrug and complexes is strong with a high affinity, resulting in the assembly of these two components into hybrid nanoparticles (250 nm). Compared with extracellular incubation with MATT, HPMC NP treatment markedly reduced the expression (100%) and activity (50%) of MMPs in 4T1 cells and in the tumor. HPMC NPs exhibited 1.4-fold tumor accumulation, inhibited tumor-growth by >8-fold in volume with efficient apoptosis and proliferation, and suppressed metastasis (>5-fold) and angiogenesis (>3-fold). Overall, HPMC NPs were efficient in metastatic cancer therapy. Conclusions: According to the assembly of polymer prodrug and protein-drug complexes, this study offers a new strategy for constructing nanoparticles for targeted drug delivery, biomedical imaging, and combinatorial treatment. Importantly, via inhibition of intracellular MMPs, metastasis and angiogenesis can be potently blocked, benefiting the rational design of nanomedicine for cancer treatment.

Metastasis is a major cause of chemotherapeutic failure and death. Degradation of a specific component of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) affects the physical barrier of the tumor microenvironment (TME) and induces metastasis. Here, lysolipid-containing thermosensitive liposomes (LTSLs) were prepared to deliver an MMP inhibitor, marimastat (MATT), to the TME to inhibit MMP activity and expression. LTSLs rapidly released their payloads at 42 °C. Compared with the saline control, MATT-LTSLs exhibited enhanced accumulation in the tumor and a 20-fold decrease in tumor growth in 4T1 tumor-bearing mice; moreover, MATT-LTSLs reduced MMP-2 and MMP-9 activity by 50% and 43%, respectively, and downregulated MMP-2 and MMP-9 expression in vivo by 30% and 43%, respectively. Most importantly, MATT-LTSL treatment caused a 7-fold decrease in metastatic lung nodules and a 6-fold reduction in microvessels inside the tumor. We believe this study provides an effective approach for the suppression of metastasis, and the use of a cytotoxic agent in combination with MATT is a potential strategy for metastatic cancer treatment.

Macrophages play crucial roles in immune response and atherosclerosis-related cardiovascular disease. Recent evidence of macrophage autophagy has demonstrated a novel pathway through which contributes to vascular inflammation. The aim of this study was to elucidate the role of autophagy in the inhibition of inflammatory response in macrophages by atorvastatin. We found that atorvastatin promoted autophagy flow determined by up-regulating the expression of autophagy-related protein microtubule-associated protein light chain (LC3B), inducing the formation of autophagosomes and down-regulating the expression of SQSTM1/P62, which is consumed during autophagy. Atorvastatin also inhibited the expression of inflammatory factors IL-1β and TNFα induced by LPS in RAW264.7 cells. Furthermore, pretreatment with an autophagy inhibitor 3MA or LY294002 attenuated the suppressive effect of atorvastatin on LPS-induced IL-1β and TNFα expression. Additionally, knockdown autophagy-related gene 5(Atg5) with a special siRNA also prevented the role of atorvastatin in decreasing IL-1β and TNFα release induced by LPS. Finally, we detected that AKT/mTOR/P70S6K signaling pathway was involved in atorvastatin-induced autophagy in macrophages. These data suggest that atorvastatin attenuates LPS-induced inflammatory factors secretion, at least in part, through enhancing autophagy by AKT/mTOR signaling pathway. Our findings provide a novel evidence that statins exert anti-inflammatory effect in atherosclerosis by autophagy activation.

A cobalt­(II) coordination polymer with an unusual 4,4,4-connected network was hydrothermally synthesized and observed with high thermal, solvent, and pH stabilities. This polymer can serve as the first dual-responsive fluorescent chemosensor for the selective detection of acetylacetone and Cr2O7 2– ion (pH 3.0) in aqueous systems.