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Extracellular vesicles (EVs) have recently received much attention about the application of drug carriers due to their desirable properties such as nano-size, biocompatibility, and high stability. Herein, we demonstrate orange-derived extracellular vesicles (OEV) nanodrugs (DN@OEV) by modifying cRGD-targeted doxorubicin (DOX) nanoparticles (DN) onto the surface of OEV, enabling significantly enhancing tumor accumulation and penetration, thereby efficiently inhibiting the growth of ovarian cancer. The obtained DN@OEV enabled to inducement of greater transcytosis capability in ovarian cancer cells, which presented the average above 10-fold transcytosis effect compared with individual DN. It was found that DN@OEV could trigger receptor-mediated endocytosis to promote early endosome/recycling endosomes pathway for exocytosis and simultaneously reduce degradation in the early endosomes-late endosomes-lysosome pathway, thereby inducing the enhanced transcytosis. In particular, the zombie mouse model bearing orthotopic ovarian cancer further validated DN@OEV presented high accumulation and penetration in tumor tissue by the transcytosis process. Our study indicated the strategy in enhancing transcytosis has significant implications for improving the therapeutic efficacy of the drug delivery system.
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There is a broad and urgent need for the clinical application of anticancer nanomedicine in tumor therapy, but the complex biological barrier in solid tumors has always been the main obstacle to infiltrating nanomedicine into the tumor. The traditional design of nanomedicine based on enhanced permeability and retention (EPR) effect still has some limitations in tumor permeability, it is urgent to find other design theories. Therefore, this review summarizes two novel strategies, active transcytosis and immune cell-mediated tumor penetration, for promoting tumor penetration of anticancer nanomedicine.
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Insurmountable blood‒brain barrier (BBB) and complex pathological features are the key factors affecting the treatment of Alzheimer's disease (AD). Poor accumulation of drugs in lesion sites and undesired effectiveness of simply reducing A
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Tumor vasculature is characterized by aberrant structure and function, resulting in immune suppressive profiles of tumor microenvironment through limiting immune cell infiltration into tumors, endogenous immune surveillance and immune cell function. Vascular normalization as a novel therapeutic strategy tends to prune some of the immature blood vessels and fortify the structure and function of the remaining vessels, thus improving immune stimulation and the efficacy of immunotherapy. Interestingly, the presence of "immune‒vascular crosstalk" enables the formation of a positive feedback loop between vascular normalization and immune reprogramming, providing the possibility to develop new cancer therapeutic strategies. The applications of nanomedicine in vascular-targeting therapy in cancer have gained increasing attention due to its specific physical and chemical properties. Here, we reviewed the recent advances of effective routes, especially nanomedicine, for normalizing tumor vasculature. We also summarized the development of enhancing nanoparticle-based anticancer drug delivery
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The integrity of poly(ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) micelles transcellular transported across madin-darby canine kidney (MDCK) epithelial cells was investigated. Fluorescein isothiocyanate isomer I (FITC) was conjugated to PEG-PCL and the product PEG-PCL-FITC was identified by fluorescence spectra. Two micelles were prepared using the thin-film hydration method:3,3'-dioctadecyloxacarbocyanine perchlorate (DiO) and 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) co-loaded PEG-PCL micelles (DiO-DiI-M), DiI loaded and PEG-PCL-FITC contained micelles (FITC-DiI-M). The size of the micelles was characterized by dynamic light scattering analysis using a Malvern Zetasizer Nano ZS and it turned out that the particle sizes of both micelles were about 30 nm with identical polydispersity index (PDI). The stability of the micelles in phosphate buffer saline (PBS) was monitored using fluorescence spectra and both micelles were stable within 4 h in PBS. The integrity of PEG-PCL micelles in the transcellular process across MDCK epithelial cell monolayer at 1 and 4 h was investigated using laser confocal scanning microscope and Förster resonance energy transfer (FRET) technology. The Person's coefficient and FRET efficiency of both Transwell layer and Receive layer were recorded. The results show that the FRET efficiency and Person's coefficient of the Receive layer was consistent with that of Transwell layer for both the micelles at 1 h, but decreased at 4 h and FITC-DiI-M decreased more significantly than DiO-DiI-M. The results indicated that the micelles could transport across the MDCK monolayer intactly at 1 h but some of them were disassembled during the 4 h transportation process.
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Aim To investigate the transcytosis mechanism of chlorogenic acid(CGA)by using Caco-2 and MDCK(Madin Darby canine kidney) monolayers models.Method ① Caco-2 and MDCK cell models:Caco-2 cell(105 cells/cm2) and MDCK cell(5?104 cells/cm2) were inoculated in Millicell-CM culture plate inserts,and the TEER of cell monolayer were detected to make sure the models are available for experiments.② Permeating experiments: to measure the value of OD of CGA and calculate the cumulative amount.Result CGA could be Absorbed and secreted on two monolayer models.Verapamil could inhibit the secretion at lower concentration of CGA on MDCK monolayer model.P-pg could partly act on the secretion of CGA on Caco-2 and MDCK cell models.Conclusion CGA can secrete and Absorb at the same time across Caco-2 and MDCK cell monolayers,P-pg partly involving in the secretion of CGA.