Although anti-PD-1 immunotherapy is widely used to treat melanoma, its efficacy still has to be improved. In this work, we present a therapeutic method that combines immunotherapy and starvation therapy to achieve better antitumor efficacy. We designed the CMSN-GOx method, in which mesoporous silica nanoparticles (MSN) are loaded with glucose oxidase (GOx) and then encapsulate the surfaces of cancer cell membranes to realize starvation therapy. By functionalizing the MSN’s biomimetic surfaces, we can synthesize nanoparticles that can escape the host immune system and homologous target. These attributes enable the nanoparticles to have improved cancer targeting ability and enrichment in tumor tissues. Our synthetic CMSN-GOx complex can ablate tumors and induce dendritic cell maturity to stimulate an antitumor immune response. We performed an in vivo analysis of these nanoparticles and determined that our combined therapy CMSN-GOx plus PD-1 exhibits a better antitumor therapeutic effect than therapies using CMSN-GOx or PD-1 alone. Additionally, we used the positron emission tomography imaging to measuring the level of glucose metabolism in tumor tissues, for which we investigate the effect with the cancer therapy in vivo.
We describe a strategy of fabricating CO-triggered oil-in-water Pickering emulsion based on silica nanoparticles functionalized in situ by a trace amount of conventional CO-switchable surfactant, N-(3-(dimethylamino)propyl)alkyl amide (CPMA). By alternately bubbling CO and N at a moderate conditions (30 °C, 80 mL min), silica nanoparticles reversibly switch between amphipathic and hydrophilic as a result of the adsorption of ammonium (CO) and the desorption of tertiary amine (N). The emulsion can then be smart switched "on (stable)" and "off (unstable)", along with homogenization, without needing cooling and heating. The switching of the current tertiary-based system is simple, moderate, and environmentally friendly, without contamination and the restriction of rigorous conditions. The surfactant concentration window of the Pickering emulsion is closely related to the length of hydrophobic tail, and the upper limit is no more than 0.20 cmc of that of the corresponding ammonium surfactant. Such a strategy is also suitable for commercial alkyl tertiary amines, without needing complicated organic synthesis.
Recently, RBC membrane coated nanoparticles have attracted much attention because of their excellent immune escape ability; meanwhile, Au nanocages (AuNs) have been extensively used for cancer therapy due to its photothermal effect and drug delivery capability. The combination of RBC membrane coating and Au nanocages may provide an effective approach for targeted cancer therapy. However, few reports have shown the utilization of combining these two technologies. Here, we present the development of Erythrocyte membrane-coated Gold nanocages for targeted cancer photothermal and chemical therapy. First, anti-EpCam antibodies are used to modify RBC membranes to target 4T1 cancer cells. Second, the antitumor drug paclitaxel is encapsulated into AuNs. Then, the AuNs are coated with the modified RBC membranes. This new nanoparticles are termed EpCam-RPAuNs. We characterize the capability of EpCam-RPAuNs for selective tumor targeting via exposure to the near-infrared irradiation. Experimental results demonstrate that EpCam-RPAuNs can effectively generate hyperthermia and precisely deliver the antitumor drug PTX to targeted cells. We also validate the biocompatibility of our EpCam-RPAuNs in vitro. By combining the targeting moleculars modified RBC membrane and AuNs, our approach provides a new way to design biomimetic nanoparticles to enhance the surface functionality of nanoparticles. We believe that EpCam-RPAuNs can be potentially applied for cancer diagnoses and therapies.
Vascular endothelial cells (ECs) are natively exposed to dynamic cyclic stretch and respond to it by the production of vasoactive molecules. Among them, reactive oxygen species (ROS) are closely implicated to the endothelial function and vascular homeostasis. However, the dynamic monitoring of ROS release during endothelial mechanotransduction remains a steep challenge. Herein, we developed a stretchable electrochemical sensor by decoration of uniform and ultrasmall platinum nanoparticles (Pt NPs) on gold nanotube (Au NT) networks (denoted as Au@Pt NTs). The orchestrated structure exhibited prominent electrocatalytic property toward the oxidation of hydrogen peroxide (H 2 O 2 ) (as the most stable ROS) while maintaining excellent mechanical compliance of Au NT networks. Moreover, the favorable biocompatibility of Au NTs and Pt NPs promoted the adhesion and proliferation of ECs cultured thereon. These allowed in situ inducing ECs mechanotransduction and synchronously real-time monitoring of H 2 O 2 release. Further investigation revealed that the production of H 2 O 2 was positively correlated with the applied mechanical strains and could be boosted by other coexisting pathogenic factors. This indicates the great prospect of our proposed sensor in exploring ROS-related signaling for the deep understanding of cell mechanotransduction and vascular disorder.
Background and ObjectiveTetrandrine (TET) is a bisbenzylisoquinoline alkaloid extracted from Stephania tetrandra Moore. Recent studies have suggested that TET can reduce the inflammatory response in microglia, but the mechanisms remain unclear. The aim of this study is to investigate whether TET can inhibit lipopolysaccharide (LPS)-induced microglial activation and clarify its possible mechanisms.Study Design/Materials and MethodsCell viability assays and cell apoptosis assays were used to determine the working concentrations of TET. Then, BV2 cells were seeded and pretreated with TET for 2 h. LPS was then added and incubated for an additional 24 hours. qRT-PCR and ELISA were used to measure the mRNA or protein levels of IL1β and TNFα. Western blotting was utilized to quantify the expression of CD11b and cell signaling proteins.ResultsTET at optimal concentrations (0.1 µM, 0.5 µM or 1 µM) did not affect the cell viability. After TET pretreatment, the levels of IL1β and TNFα (both in transcription and translation) were significantly inhibited in a dose-dependent manner. Further studies indicated that phospho-p65, phospho-IKK, and phospho-ERK 1/2 expression were also suppressed by TET.ConclusionsOur results indicate that TET can effectively suppress microglial activation and inhibit the production of IL1β and TNFα by regulating the NF-kB and ERK signaling pathways. Together with our previous studies, we suggest that TET would be a promising candidate to effectively suppress overactivated microglia and alleviate neurodegeneration in glaucoma.
Mitochondria are believed to be the major source of intracellular reactive oxygen species (ROS). However, in situ, real‐time and quantitative monitoring of ROS release from mitochondria that are present in their cytosolic environment remains a great challenge. In this work, a platinized SiC@C nanowire electrode is placed into a single cell for in situ detection of ROS signals from intracellular mitochondria, and antineoplastic agent (paclitaxel) induced ROS production is successfully recorded. Further investigations indicate that complex IV (cytochrome c oxidase, COX) is the principal site for ROS generation, and significantly more ROS are generated from mitochondria in cancer cells than that from normal cells. This work provides an effective approach to directly monitor intracellular mitochondria by nanowire electrodes, and consequently obtains important physiological evidence on antineoplastic agent‐induced ROS generation, which will be of great benefit for better understanding of chemotherapy at subcellular levels.
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