Combination of PEI-Mn0.5Zn0.5Fe2O4 nanoparticles and pHsp 70-HSV-TK/GCV with magnet-induced heating for treatment of hepatoma

Abstract

Background To explore a new combination of thermal treatment and gene therapy for hepatoma, a heat-inducible herpes simplex virus thymidine kinase /ganciclovir ( HSV - TK /GCV) gene therapy system was developed in which thermal energy generated by Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles (MZF-NPs) under an alternating magnetic field was used to activate gene expression. Methods First, a recombinant eukaryotic plasmid, pHsp 70- HSV-TK , was constructed as a target gene for therapy. This recombinant plasmid was used to transfect SMMC-7721 hepatoma cells and the gene expression was evaluated. Magnet-induced heating was then applied to cells to assess the antihepatoma effects of the polyethylenimine (PEI)-MZF-NPs/pHsp 70- HSV-TK /GCV complex, in vitro and in vivo. Results The results showed that cells were successfully transfected with pHsp 70- HSV-TK and that expression levels of HSV-TK remained stable. Both in vitro and in vivo results indicated that the combination of gene therapy and heat treatment resulted in better therapeutic effects than heating-alone group. The rates of apoptosis and necrosis in the combined treatment group were 49.0% and 7.21%, respectively. The rate of inhibition of cell proliferation in the combined treatment group was significantly higher (87.5%) than that in the heating-alone group (65.8%; P <0.01). The tumor volume and mass inhibition rates of the combined treatment group were 91.3% and 87.91%, respectively, and were significantly higher than the corresponding rates of the heating-alone group (70.41% and 57.14%; P <0.01). The expression levels of Stat3 and Bcl-xL messenger RNA and p-Stat3 and Bcl-xL protein in the combined treatment group were significantly lower than those in the other groups ( P <0.01). The expression levels of Bax messenger RNA and protein in the recombinant plasmid group were significantly higher than those in the other groups ( P <0.01). Conclusion It can therefore be concluded that the combined application of heat treatment and gene therapy has a synergistic and complementary effect and that PEI-MZF-NPs can simultaneously act both as a nonviral gene vector and a magnet-induced source of heat, thereby representing a viable approach for the treatment of cancer.

Adenovirus‑mediated herpes simplex virus thymidine kinase gene therapy combined with ganciclovir induces hepatoma cell apoptosis

“…As major members of the Bcl-2 family, Bcl-2 and Bax serve a crucial role in the inhibition of the intrinsic apoptotic signaling pathway and tumor progression triggered by mitochondrial dysfunction (35). In a previous study, the expression level of Bcl protein was significantly lower, whereas Bax protein expression level was significantly higher following 70-HSV-TK and GCV administration combined with Mn 0.5 Zn 0.5 Fe 2 O 4 nanoparticles for HCC treatment in vitro and in vivo (36). A study suggested that the balance between Bcl and Bax proteins is important in assessing the sensitivity of tumor cells to GCV (37).…”

A Combination Therapy of pHRE-Egr1-HSV-TK/Anti-CD133McAb-131I/MFH Mediated by FePt Nanoparticles for Liver Cancer Stem Cells

“…Plasmids pHRE-Egr1-HSV-TK. Eukaryotic expression plasmids pCDNA3.1-pHRE-Egr1-HSV-TK (pHRE-Egr1-HSV-TK) were designed and constructed as References [13][14][15][16][17]. pHRE-Egr1-HSV-TK were digested by BglII+XhoI and then subjected to 1% agarose gel electrophoresis.…”

“…The Investigation of the Potential of PEI-FePt-NPs Used for Gene Transfer Carrier. Using pHRE-Egrl-EGFP constructed according to References [13][14][15][16][17] as a model, the potential of PEI-FePt-NPs used for gene transfer carrier was investigated.…”

“…9 Journal of Nanomaterials comes from herpes simplex virus and encodes thymidine kinase. The product HSV-TK expressed can concentrate in the tumor area to convert prodrug GCV into cytotoxic drug to selectively kill the tumor, thus reducing side effects [13]. But it is of extreme importance to select an appropriate regulatory sequence and activating mode to generate exact and efficient expression of the therapeutic gene.…”

A combination hepatoma-targeted therapy based on nanotechnology: pHRE-Egr1-HSV-TK/131I-antiAFPMcAb-GCV/MFH

“…Particularly, except the general properties of nanoparticles, super-paramagnetic magnetic nanoparticle gene transfer vectors can produce highly efficient transfection and do directional movement in an external magnetic field, in turn which help to implement targeting gene therapy. Moreover, since magnetic nanoparticles can generate heat by magnetic induction in an external magnetic field, they also can be used for cancer thermotherapy 39 40 41 .…”