Necrotic cell death is a hallmark feature of ischemic stroke and it may facilitate inflammation by releasing intracellular components after cell-membrane rupture. Previous studies reported that β-caryophyllene (BCP) mitigates cerebral ischemia-reperfusion (I/R) injury, but the underlying mechanism remains unclear. We explored whether BCP exerts a neuroprotective effect in cerebral I/R injury through inhibiting necroptotic cell death and inflammation. Primary neurons with and without BCP (0.2, 1, 5, 25 μM) treatment were exposed to oxygen-glucose deprivation and re-oxygenation (OGD/R). Neuron damage, neuronal death type and mixed lineage kinase domain-like (MLKL) protein expression were assessed 48 h after OGD/R. Furthermore, mice underwent I/R procedures with or without BCP (8, 24, 72 mg/kg, ip.). Neurologic dysfunction, cerebral infarct volumes, cell death, cytokine levels, necroptosis core molecules, and HMGB1-TLR4 signaling were determined at 48 h after I/R. BCP (5 μM) significantly reduced necroptotic neurons and MLKL protein expression following OGD/R. BCP (24, 72 mg/kg, ip.) reduced infarct volumes, neuronal necrosis, receptor-interaction protein kinase-1 (RIPK1), receptor-interaction protein kinase-3 (RIPK3) expression, and MLKL phosphorylation after I/R injury. BCP also decreased high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) levels. Thus, BCP alleviates ischemic brain damage potentially by inhibiting necroptotic neuronal death and inflammatory response. This study suggests a novel application for BCP as a neuroprotective agent.
A multifunctional drug delivery vehicle, which combines the active targeted mesoporous silica nanoparticle (MSN) and microbubble (MB) drug delivery system, is proposed and fabricated. The resulting delivery vehicle integrates the merits of high drug loading capacity, multitargeting, and ultrasound-guided releasing. Folate (FA), which serves as an active ligand, is modified to the surface of MSN (MSN-FA) to enhance cell membrane translocation. MSN-FA is loaded with tanshinone IIA (TAN), then encapsulated in a microbubble (denoted as MSN-FA-TAN-MB) for more precise tumor targeting. The conjunction between FA and MSN is confirmed by fourier transform infrared spectroscopy (FTIR). The characteristics and morphology of MSN-FA-TAN-MB are investigated by confocal microscopy and transmission electron microscopy. In vitro cytotoxicity and cellular uptake studies of MSN-FA-TAN-MB are conducted on A549 and HeLa tumor cells. FA-facilitated MSN-FA-TAN uptake is shown by HeLa cells that overexpress FA receptors via a FA-receptor-mediated endocytosis mechanism. The ultrasound response property of MSN-FA-TAN-MB is also verified. MSN-FA-TAN-MB shows significant antitumor efficacy in vivo with the assistance of FA, MB, and an external ultrasound irradiation. Thus, this multifunctional vehicle may provide a novel strategy for tumor targeting and imaging in tumor therapy.
This study fabricated novel multifunctional pH-sensitive nanoparticles loaded into microbubbles (PNP-MB) with the combined advantages of two excellent drug delivery vehicles, namely, pH-sensitive nanoparticles and microbubbles. As an antitumor drug, resveratrol (RES) was loaded into acetylated β-cyclodextrin nanoparticles (RES-PNP). The drug-loaded nanoparticles were then encapsulated into the internal space of the microbubbles. The characterization and morphology of this vehicle were investigated through dynamic light scattering and confocal laser scanning microscopy, respectively. In vitro drug release was performed to investigate the pH sensitivity of RES-PNP. The antitumor property of RES-loaded PNP-MB (RES-PNP-MB) was also analyzed in vivo to evaluate the antitumor effect of RES-PNP-MB. Results suggested that PNP exhibited pH sensitivity, and was successfully encapsulated into the microbubbles. RES-PNP-MB exhibit effective tumor growth suppressing in vivo. Therefore, such drug delivery vehicle should be of great attention in tumor therapy.
The limited information on biological fate impedes the development of more efficient polymeric nanoparticles for oral delivery of bio‐macromolecules. In this study, the in vivo fate as well as the trans‐epithelia transport of polycaprolactone (PCL) nanoparticles is explored by labeling with aggregation‐caused quenching probes, which is capable of identifying intact nanoparticles. Live imaging and confocal laser scan microscopy confirm size‐dependent absorption of PCL nanoparticles. In general, reducing particle size favors a faster and more oral absorption. Nanoparticles larger than 200 nm, such as 600 and 2000 nm, cannot be efficiently transported across the intestinal membrane. The absorbed nanoparticles (50 and 200 nm) mainly accumulate in the liver. Lymph may be the main absorption route for PCL nanoparticles, transporting 2.39 ± 1.81% and 0.98 ± 0.58% of administered 50 and 200 nm nanoparticles, respectively. Cellular uptake and transportation of PCL nanoparticles are also size dependent. Both enterocytes and M cells mediated transcytosis are involved in the transport of 50 nm PCL nanoparticles, while the M cell pathway is dominative for other nanoparticles. In conclusion, the study provides a valuable tool for bioimaging of intact polymeric nanoparticles as well as solid evidence supporting size‐dependent translocation of the nanoparticles via oral delivery.
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