Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector

Peruta, Marco Della; Badar, Adam; Rosales, Cecilia; Chokshi, Shilpa; Kia, Azadeh; Nathwani, Devhrut; Galante, Eva; Yan, Ran; Årstad, Erik; Davidoff, Andrew M.; Lythgoe, Mark F.; Nathwani, Amit C.

doi:10.1089/hum.2014.052

Cited by 27 publications

(25 citation statements)

References 47 publications

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“…GBM8401/ luc2 cells (1 × 10 7 ) in 150 μL mixture containing serum-free RPMI and Matrigel (2:1) were subcutaneously inoculated into the right hind legs of the 30 mice [ 32 ]. We measured the tumor volume of each animal with a digital caliper and calculated with the equation: tumor volume = 0.523 × length × width 2 [ 33 ]. After the tumor volume reached 100–120 mm 3 , mice were randomized into three different treatment groups (n = 10 for each group), including vehicle, PEITC-10 group, and PEITC-20.…”

Section: Methodsmentioning

confidence: 99%

Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells

et al. 2018

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Phenethyl isothiocyanate (PEITC) from cruciferous vegetables can inhibit the growth of various human cancer cells. In previous studies, we determined that PEITC inhibited the in vitro growth of human glioblastoma GBM 8401 cells by inducing apoptosis, inhibiting migration and invasion, and altering gene expression. Nevertheless, there are no further in vivo reports disclosing whether PEITC can suppress the growth of glioblastoma. Therefore, in this study we investigate the anti-tumor effects of PEITC in a xenograft model of glioblastoma in nude mice. Thirty nude mice were inoculated subcutaneously with GBM 8401 cells. Mice with one palpable tumor were divided randomly into three groups: control, PEITC-10, and PEITC-20 groups treated with 0.1% dimethyl sulfoxide (DMSO), and 10 and 20 μmole PEITC/100 μL PBS daily by oral gavage, respectively. PEITC significantly decreased tumor weights and volumes of GBM 8401 cells in mice, but did not affect the total body weights of mice. PEITC diminished the levels of anti-apoptotic proteins MCL-1 (myeloid cell leukemia 1) and XIAP (X-linked inhibitor of apoptosis protein) in GBM 8401 cells. PEITC enhanced the levels of caspase-3 and Bax in GBM 8401 cells. The growth of glioblastoma can be suppressed by the biological properties of PEITC in vivo. These effects might support further investigations into the potential use of PEITC as an anticancer drug for glioblastoma.

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Section: Methodsmentioning

confidence: 99%

Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells

et al. 2018

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“…Viral vectors with high transfection efficiency are commonly applied for gene delivery. Nevertheless, viral vectors have side effects including immunogenicity, complicated synthesis procedure, and carcinogenicity [ 9 ]. In recent years, nonviral gene vectors with low immunogenicity, simplicity of synthesis, and ease of large-scale production have overcome problems occurring with viral vectors and attracted more attention [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of miR-146a/bFGF/PEG-PEI Nanoparticles on Inflammation Response and Tissue Regeneration of Human Dental Pulp Cells

Liu

Shan

Cheung

et al. 2016

BioMed Research International

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Introduction. Inflammation in dental pulp cells (DPCs) initiated by Lipopolysaccharide (LPS) results in dental pulp necrosis. So far, whether there is a common system regulating inflammation response and tissue regeneration remains unknown. miR-146a is closely related to inflammation. Basic fibroblast growth factor (bFGF) is an important regulator for differentiation. Methods. To explore the effect of miR-146a/bFGF on inflammation and tissue regeneration, polyethylene glycol-polyethyleneimine (PEG-PEI) was synthesized, and physical characteristics were analyzed by dynamic light scattering and gel retardation analysis. Cell absorption, transfection efficiency, and cytotoxicity were assessed. Alginate gel was combined with miR-146a/PEG-PEI nanoparticles and bFGF. Drug release ratio was measured by ultraviolet spectrophotography. Proliferation and odontogenic differentiation of DPCs with 1 μg/mL LPS treatment were determined. Results. PEG-PEI prepared at N/P 2 showed complete gel retardation and smallest particle size and zeta potential. Transfection efficiency of PEG-PEI was higher than lipo2000. Cell viability decreased as N/P ratio increased. Drug release rate amounted to 70% at the first 12 h and then maintained slow release afterwards. Proliferation and differentiation decreased in DPCs with LPS treatment, whereas they increased in miR-146a/bFGF gel group. Conclusions. PEG-PEI is a promising vector for gene therapy. miR-146a and bFGF play critical roles in inflammation response and tissue regeneration of DPCs.

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“…Similar to reports by Peruta et al., who utilized the liver-specific nature of AAV8 to construct miRNA122a-based post-transcriptionally liver detargeted gene delivery system, we observed that transduction of Hepa1-6 with scAAV8-GLuc-miR199a*3 leads to a significant reduction of reporter expression when compared to scAAV8-GLuc. 36 This observation was further corroborated by post-transcriptionally detargeted suicide gene therapy with scAAV8-CD-miR199a*3 in Hepa1-6. Given the ability of AAV8 to transduce liver and tissues of liver origin, our system could provide an option to target disseminated tumors.…”

Section: Discussionmentioning

confidence: 72%

MicroRNA199a-Based Post-transcriptional Detargeting of Gene Vectors for Hepatocellular Carcinoma

Dhungel¹,

Ramlogan‐Steel²,

Layton³

et al. 2018

Molecular Therapy - Nucleic Acids

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A gene therapeutic platform needs to be both efficient and safe. The criterion of safety is particularly important for diseases like hepatocellular carcinoma (HCC), which develop in a background of an already compromised liver. Gene vectors can be constructed either by targeting HCC or by detargeting liver and/or other major organs. miRNA-based negative detargeting has gained considerable attention in recent times due to its effectiveness and the ease with which it can be adapted into current gene delivery vectors. In this study, we provide a proof-of-concept using miRNA199a as a negative targeting agent. We introduced vectors harboring reporters with miRNA199a binding sites in cells expressing high endogenous levels of miRNA199a and compared the reporter expression in HCC cells with low endogenous miRNA199a. We observed that the expression of reporters with miRNA199a binding sites is significantly inhibited in miRNA199a-positive cells, whereas minimal effect was observed in miRNA199a-negative HCC cells. In addition, we created a post-transcriptionally regulated suicide gene therapeutic system based on cytosine deaminase (CD)/5-fluorocytosine (5-FC) exploiting miRNA199a binding sites and observed significantly lower cell death for miRNA199a-positive cells. Furthermore, we observed a decrease in the levels of miRNA199 in 3D tumorspheres of miRNA199a-positive Hepa1-6 cells and a reduction in the inhibition of reporter expression after transfection in these 3D models when compared with 2D Hepa1-6 cells. In summary, we provide evidence of miRNA199a-based post-transcriptional detargeting with relevance to HCC gene therapy.

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Preferential Targeting of Disseminated Liver Tumors Using a Recombinant Adeno-Associated Viral Vector

Cited by 27 publications

References 47 publications

Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells

Phenethyl Isothiocyanate Inhibits In Vivo Growth of Xenograft Tumors of Human Glioblastoma Cells

Effect of miR-146a/bFGF/PEG-PEI Nanoparticles on Inflammation Response and Tissue Regeneration of Human Dental Pulp Cells

MicroRNA199a-Based Post-transcriptional Detargeting of Gene Vectors for Hepatocellular Carcinoma

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