Bone marrow stromal cells (BMSC) modified with therapeutic genes are being actively pursued for gene therapy protocols. To develop safe and effective nonviral methods for BMSC modification, the cationic polymer polyethyleneimine (PEI) has been utilized to condense plasmid DNA for intracellular delivery. This study was conducted to explore the feasibility of increasing the PEI's effectiveness by coupling integrin-binding arginine-glycine-aspartic acid (RGD) peptides to the polymer. BMSC from rats were isolated and expanded in culture for gene transfer studies. In contrast to our expectations, RGD-conjugated PEI did not exhibit an enhanced binding to BMSC. This was the case where the peptides were conjugated to PEI by short, disulfide linkages or long poly(ethylene glycol) linkages. Using a reporter gene for the enhanced green fluorescent protein, the transfection efficiency of RGD-conjugated PEI was also lower than the delivery by the native PEI, which exhibited equivalent transfection efficiency to that of an adenovirus. We conclude that native PEI was sufficient for the transformation of BMSC and that coupling of the integrin-binding RGD-peptides did not improve the effectiveness of this polymer for BMSC transfection.
Highly efficient targeted delivery is crucial for successful anticancer chemotherapy. In this study, we developed a drug delivery system ANS-TAT-AuNP that loads anticancer molecule 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) via conjugation with cell-penetrating peptide TAT modified AuNPs. The in vitro study showed that the IC value of ANS-TAT-AuNPs reduced by 11.28- (24 h) and 12.64-fold (48 h) after incubation with liver hepatocellular carcinoma HepG cells compared to that of free ANS, suggesting that TAT modified AuNPs could enhance the antiproliferative activity of ANS. Also, ANS-TAT-AuNPs showed a size effect on overcoming multidrug resistance (MDR). The potential of ANS-TAT-AuNPs in overcoming MDR was assessed with MCF-7/ADR drug-resistant cell line, the drug resistance index (DRI) of which was extremely high (>190). The DRI of ANS-TAT-AuNPs decreased dramatically to 1.48 (24 h) and 2.20 (48 h), while that of ANS-TAT-AuNPs decreased to 7.64 (24 h) and 7.77 (48 h), indicating that ANS-TAT-AuNPs could treat extremely resistant MCF-7/ADR cancer cells as drug sensitive ones. The data suggest that the larger AuNPs had more profound effect on overcoming MDR, which could effectively prevent drug efflux due to their size being much larger than that of the p-glycoprotein channel (9-25 Å).
The Epstein-Barr virus latent membrane protein 1 (EBV‑LMP1) is an oncoviral protein that plays an important role in oncogenic transformation in EBV‑associated nasopharyngeal carcinoma (NPC). Our previous studies demonstrated that LMP1 increased VEGFA expression and upregulated angiogenesis in NPC. Vasculogenic mimicry (VM) is a mechanism by which tumor cells can obtain nutrients to survive, and VM has been observed in numerous types of tumors. However, the occurrence and significance of VM in NPC and the relationship between LMP1 and VM have not yet been evaluated. In the present study, we observed that it was almost impossible for LMP1-negative NPC cells to form tubular structures, whereas LMP1-positive NPC cells were able to form tubular structures. Moreover, VEGFA was found to be involved in VM formation in LMP1-positive NPC cells. Knockdown of LMP1 or VEGFR1 distinctly disrupted tubular structures, whereas inhibition of VEGFR2 did not affect the process, indicating that VEGFR1 not VEGFR2 signaling was involved in LMP1-mediated VM formation. Furthermore, the data of immunohistochemistry (IHC) and CD34/PAS double staining in a tumor tissue array showed that LMP1 was positively correlated with VEGFR1 and VM. Meanwhile, after analyzing the clinicopathological features, we found that VM formation was associated with a poor prognosis in NPC patients. These results suggest that VM formation is increased by EBV‑LMP1 via VEGF/VEGFR1 signaling and provide additional information to clarify the role of EBV‑LMP1 in NPC pathophysiology.
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