Conventional antiangiogenetic inhibitors suffered from poor delivery problems that result in unsatisfactory antitumor treatment efficacy. Although the liposomes or nanomaterial-based delivery systems can improve the therapeutic efficacy of antiangiogenic molecules, the assembly process is far too complex. Herein, a nanomaterial or a new nanodrug that could work without the help of a carrier and could be easily synthesized is needed. Au nanoclusters (AuNCs) are a kind of ideal nanostructures that could spontaneously enter into the cell and could be synthesized by a relatively easy one-pot method. Here, changing the traditional ligand glutathione (GSH) into an anti-Flt1 peptide (AF) has enriched the newly synthesized AF@AuNCs with targeted antiangiogenic properties. Based on the specific binding between AF and vascular endothelial growth factor receptor 1 (VEGFR1), the interaction between VEGFR1 and its ligands could be blocked. Furthermore, the expression of VEGFR2 could be downregulated. Compared with pure AF peptide- and GSH-participated AuNCs (GSH@AuNCs), AF@AuNCs were more effective in inhibiting both tube formation and migration of the endothelial cells in vitro. Furthermore, the in vivo chick embryo chorioallantoic membrane (CAM) experiment and antitumor experiment were conducted to further verify the enhanced antiangiogenesis and tumor inhibition effect of AF@AuNCs. Our findings provide promising evidence of a carrier-free nanodrug for tumors and other vascular hyperproliferative diseases.
Poor penetrability and nonselective distribution of chemotherapeutic drugs are the main obstacles for chemotherapy for triple-negative breast cancer (TNBC). In our work, we developed a DNA-based drug delivery system to surmount these barriers. In addition, a tetrahedral framework nucleic acid (tFNA) was employed to load doxorubicin (DOX) with iRGD decoration to form a novel nanoparticle (tFNA/DOX@iRGD). The RGD sequence and the CendR motif in iRGD are used in tumor targeting and tissue penetration, respectively. Based on the sustained serum stability and pH-sensitive release behavior of DOX, tFNA/DOX@iRGD exhibited superiority for biomedical application. Moreover, tFNA/DOX@iRGD showed excellent deep penetration and drug accumulation in three-dimensional (3D) multicellular tumor spheroids compared to DOX and tFNA/DOX. Additionally, the therapeutic effect was verified in a 4T1 subcutaneous tumor model, and the complexes displayed a superior antitumor and antiangiogenic efficiency with fewer collateral damages. Therefore, these findings suggested that tFNA/DOX@iRGD might be a more effective pattern for drug delivery and TNBC therapy.
Abstract Objectives Aptamer sgc8c is a short DNA sequence that can target protein tyrosine kinase 7 ( PTK 7), which was overexpressed on many tumour cells. This study aimed to fabricate a novelty DNA nanostructure drug delivery system target on PTK 7‐positive cells— CCRF ‐ CEM (human T‐cell ALL ). Methods Aptamer‐modified tetrahedron DNA was synthesized through one‐step thermal annealing process. The sgc8c‐ TDN s (s‐ TDN s) loading DOX complexes were applied to investigate the effect to PTK 7‐negative and ‐positive cells. Results When s‐ TDN : DOX acted on PTK 7‐positive and ‐negative cells respectively, the complexes exhibited specific toxic effect on PTK 7‐positive cells but not on PTK 7‐negative Ramos cells in vitro research. Conclusions In this work, we successfully constructed a PTK 7‐targeting aptamer‐guided DNA tetrahedral nanostructure (s‐ TDN ) as a drug delivery system via a facile one‐pot synthesis method. The results showed that s‐ TDN : DOX exhibited enhanced cytotoxicity against PTK 7‐positive CCRF ‐ CEM cells, with a minor effect against PTK 7‐negative Ramos cells. Hence, this functionalized TDN s drug delivery system displayed its potential application in targeting PTK 7‐positive tumour T‐cell acute lymphoblastic leukaemia.
Abstract Neuroinflammation is a secondary response following ischemia stroke. Arginine is a non-essential amino acid that has been shown to inhibit acute inflammatory reaction. In this study we show that arginine treatment decreases neuronal death after rat cerebral ischemia/reperfusion (I/R) injury and improves functional recovery of stroke animals. We also show that arginine suppresses inflammatory response in the ischemic brain tissue and in the cultured microglia after OGD insult. We further provide evidence that the levels of HIF-1α and LDHA are increased after rat I/R injury and that arginine treatment prevents the elevation of HIF-1α and LDHA after I/R injury. Arginine inhibits inflammatory response through suppression of HIF-1α and LDHA in the rat ischemic brain tissue and in the cultured microglia following OGD insult, and protects against ischemic neuron death after rat I/R injury by attenuating HIF-1α/LDHA-mediated inflammatory response. Together, these results indicate a possibility that arginine-induced neuroprotective effect may be through the suppression of HIF-1α/LDHA-mediated inflammatory response in microglia after cerebral ischemia injury.
One of the biggest obstacles for the use of antisense oligonucleotides as antibacterial therapeutics is their limited uptake by bacterial cells without a suitable carrier, especially in multi-drug-resistant bacteria with a drug efflux mechanism. Existing vectors, such as cell-penetrating peptides, are inefficient and nontargeting, and accordingly are not ideal carriers. A noncytotoxic tetrahedral DNA nanostructure (TDN) with a controllable conformation has been developed as a delivery vehicle for antisense oligonucleotides. In this study, antisense peptide nucleic acids (asPNAs) targeting a specific gene (ftsZ) were efficiently transported into methicillin-resistant Staphylococcus aureus cells by TDNs, and the expression of ftsZ was successfully inhibited in an asPNA-concentration-dependent manner. The delivery system specifically targeted the intended gene. This novel delivery system provides a better platform for future applications of antisense antibacterial therapeutics and provides a basis for the development of a new type of antibacterial drug for multi-drug-resistant bacterial infections.
Abstract Objectives The aim of this study was to investigate the role of insulin‐like growth factor‐1 ( IGF ‐1) and crosstalk between endothelial cells ( EC s) and adipose‐derived stem cells ( ASC s) in the process of angiogenesis. Methods A three‐dimensional collagen gel used to culture mouse ASC s and mouse EC s in vitro was established. The effects of angiogenesis after exposure to IGF ‐1 were observed by confocal laser scanning microscopy. Western blotting and qPCR were performed to elucidate the underlying mechanisms. Results IGF ‐1 treatment promoted the formation of vessel‐like structures and the recruitment of ASC s in the three‐dimensional collagen gel. The angiogenic genes and proteins in EC s were up‐regulated by IGF ‐1 and in co‐culture. Similar changes in the genes and in the proteins were detected in ASC s after exposure to IGF ‐1 and co‐culture. p‐Akt expression levels were high in EC s and ASC s after exposure to IGF ‐1 and co‐culture. Conclusions IGF ‐1 and co‐culture between cells facilitate the process of angiogenesis via the PI 3‐kinase/Akt signalling pathway. In EC s, IGF ‐1 stimulates the expression of angiogenesis‐related growth factors with the activation of the PI 3‐kinase/Akt signalling pathway. Co‐cultured EC s exposed to excess VEGF‐A and other angiogenesis‐related growth factors para‐secreted from ASC s exhibit high expression of angiogenesis‐related genes and proteins. In ASC s, IGF ‐1 induces the recruitment and function of ASC s by up‐regulating the expression of PDGFB , MMP s and α ‐ SMA . Crosstalk with EC s further facilitates changes in ASC s.
Abstract Glaucoma is the world's leading irreversible cause of blindness. It is characterized by progressive retinal ganglion cells (RGCs) loss and axon damage, and there is no effective prevention or treatment so far. In this study, tetrahedral frame nucleic acids (tFNAs) with various biological functions are selected as the carrier, and microRNA‐22‐3p (miR‐22) are modified by attaching them onto tFNAs to synthesize a novel DNA nanocomplex (tFNAs‐miR22). Relevant results show that tFNAs can efficiently transfer miR‐22 into damaged retinal neurons to impose a neuroprotective effect on glaucoma. More interestingly, a certain synergism between tFNAs and miR‐22 is shown. tFNAs‐miR22 can selectively activate tyrosine kinase receptor B (TrkB) and regulate the TrkB‐brain‐derived growth factor (BDNF) signaling pathway to restore the expression of BDNF on the models of N‐methyl‐D‐aspartate (NMDA)‐induced glaucoma in vivo and in vitro, thus exerting the neuroprotective effect on retinal neurons. This study shows the successfully establishment of a simple but effective delivery system of microRNAs associated with glaucoma treatment, which may be a promising neuroprotective agent for future treatment of this optic neurodegenerative disease.
Abstract Objectives The aim of the study was to investigate the role of the JAK / STAT 3 signalling pathway in angiogenesis. Materials and methods The model established in vitro , involved a 3D collagen gel being implanted with endothelial cells ( EC s) from red fluorescent protein‐labelled mice, and adipose‐derived stromal cells ( ASC s) from green fluorescent protein‐labelled mice. Phenomena of angiogenesis, after treatment by the inhibitor and the activator of JAK / STAT 3 pathway respectively, were observed using confocal laser scanning microscopy. Transwell co‐culture of EC s and ASC s was used to elucidate mechanisms. Results Stattic, inhibitor of JAK / STAT 3 pathway, attenuated angiogenesis in the model. In contrast, angiogenesis was promoted after treatment of Olanzapine, an activator. We found that protein levels of VEGFA and cyclin D1 were regulated by the JAK / STAT 3 pathway, and flow cytometry further confirmed variations in cell cycle parameters of EC s and ASC s. Genes VEGFA /B , VEGFR 2, MMP ‐2 , MMP ‐9 , IGF ‐1 and b‐ FGF were down‐regulated by Stattic in EC s, while Olanzapine significantly up‐regulated mRNA levels of these genes. As for ASC s, genes VEGFA , MMP ‐2 , MMP ‐9 , IGF ‐1 and b‐ FGF were modulated by the JAK / STAT 3 pathway. Conclusions Angiogenesis in the 3D collagen gel was regulated by the JAK / STAT 3 pathway which involved changes in vessel length, vessel diameter and sprout number. The underlying mechanism was that the JAK / STAT 3 signalling pathway regulated angiogenesis by modulation of numbers of angiogenesis‐related growth factors and by direct regulation of cell cycle.
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