Hepatocyte-targeting gene transfer mediated by galactosylated poly(ethylene glycol)- graft-polyethylenimine derivative

Wang, Yuqiang; Su, Jing; Cai, Wenwei; Yuan, Lifen; Jin, Tuo; Chen, Shuyan; Sheng, Jiping

doi:10.2147/dddt.s42582

Cited by 18 publications

(14 citation statements)

References 37 publications

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“…2A). Peaks at 3.5 and 4.5 ppm represented 180 H of PEG (-C H 2 C H 2 O-) and 1H of Gal, respectively [23, 24]. Integration ratios between both peaks at 3.5 and 4.5 ppm were 180.09:1 which confirmed that the molar ratio of PEG:Gal in the PEG-Gal conjugate was (180/180.09):(1/1) ≅ 1:1.…”

Section: Resultsmentioning

confidence: 99%

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

et al. 2015

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Hepatocellular carcinoma (HCC) is a fatal cancer with no effective therapy. Astrocyte elevated gene-1 (AEG-1) plays a pivotal role in hepatocarcinogenesis and inhibits retinoic acid-induced gene expression and cell death. Combination of a lentivirus expressing AEG-1 shRNA and all-trans retinoic acid (ATRA) profoundly and synergistically inhibited subcutaneous human HCC xenografts in nude mice. We now have developed liver-targeted nanoplexes by conjugating poly(amidoamine) (PAMAM) dendrimers with polyethylene glycol (PEG) and lactobionic acid (Gal) (PAMAM-PEG-Gal) which were complexed with AEG-1 siRNA (PAMAM-AEG-1si). The polymer conjugate was characterized by 1H-NMR, MALDI and mass spectrometry, and optimal nanoplex formulations were characterized for surface charge, size and morphology. Orthotopic xenografts of human HCC cell QGY-7703 expressing luciferase (QGY-luc) were established in the livers of athymic nude mice and tumor development was monitored by bioluminescence imaging (BLI). Tumor-bearing mice were treated with PAMAM-siCon, PAMAM-siCon+ATRA, PAMAM-AEG-1si and PAMAM-AEG-1si+ATRA. In the control group the tumor developed aggressively. ATRA showed little effect due to high AEG-1 levels in QGY-luc cells. PAMAM-AEG-1si showed significant reduction in tumor growth and the combination of PAMAM-AEG-1si+ATRA showed profound and synergistic inhibition so that the tumors were almost undetectable by BLI. A marked decrease in AEG-1 level was observed in tumor samples treated with PAMAM-AEG-1si. The group treated with PAMAM-AEG-1si+ATRA nanoplexes showed increased necrosis, inhibition of proliferation and increased apoptosis when compared to other groups. Liver is an ideal organ for RNAi therapy and ATRA is an approved anti-cancer agent. Our exciting observations suggest that the combinatorial approach might be an effective way to combat HCC.

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Section: Resultsmentioning

confidence: 99%

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

et al. 2015

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“…The particle size reached to 65 nm at w/w 3, and then kept relatively constant between 65 nm and 88 nm with polydispersity ranging 0.170–0.338. This size was appropriate for cellular uptake, especially for in vivo hepatocyte transfer, because the majority of fenestrate of the liver sinusoid was smaller than 200 nm in diameter [16]. As for the zeta potential, it was negative when the w/w was 1.…”

Section: Resultsmentioning

confidence: 99%

Delivery of Therapeutic AGT shRNA by PEG-Bu for Hypertension Therapy

Wang

Deng

et al. 2013

PLoS ONE

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Gene silencing by RNA interference (RNAi) is a promising approach for gene therapy. However, up to today, it is still a major challenge to find safe and efficient non-viral vectors. Previously, we reported PEI-Bu, a small molecular weight PEI derivative, as an efficient non-viral carrier. However, like many PEI-based polymers, PEI-Bu was too toxic. In order to reduce cytotoxicity while maintain or even enhance transfecion efficiency, we modified PEI-Bu with poly(ethylene glycol) (PEG) to obtain PEG-Bu, and used it to delivery a theraputic short hairpin RNA (shRNA) targeting angiotensinogen (AGT) to normal rat liver cells (BRL-3A), which was a key target for the treatment of hypertension. The structure of PEG-Bu was confirmed by proton nuclear magnetic resonance (1H-NMR). Gel permeation chromatography (GPC) showed that the weight average molecular weight (Mw) of PEG-Bu was 5880 Da, with a polydispersity of 1.58. PEG-Bu could condense gene cargo into spherical and uniform nanoparticles with particle size (65–88 nm) and zeta potential (7.3–9.6 mV). Interestingly and importantly, PEG-Bu displayed lower cytotoxicity and enhanced tranfection efficiency than PEI-Bu after PEGylation in both normal cells BRL-3A and tumor cells HeLa. Moreover, PEG-Bu could efficiently delivery AGT shRNA to knockdown the AGT expression. To sum up, PEG-Bu would be a promising non-viral vector for delivering AGT shRNA to BRL-3A cells for hypertension therapy.

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“…Moreover, an in vitro system that takes advantage of ASGPR-mediated endocytosis to transfect hepatocytes with an exogenous DNA using a soluble DNA carrier was developed [56]. Various ASGPR-mediated gene-delivery systems using different polymers have also been described, including galactose-polyethylene glycol (PEG)-poly(L-lysine) [57], galactosylated PEG-graft-polyethylenimine (PEI) [58,59], and galactosylated chitosan-grafted-PEI [60]. In order to attain hepatocyte-specificity and/or improve the efficacy of α-CDE as a genedelivery carrier, Arima et al attached a galactose residue to form Gal-α-CDE (G2) as a novel non-viral carrier [61].…”

Section: Galactosylated α-Cde As a Hepatocyte-selective Pdna Carriermentioning

confidence: 99%

Promising Use of Cyclodextrin-Based Non-Viral Vectors for Gene and Oligonucleotide Drugs

Mohammed¹,

Motoyama²,

Higashi³

et al. 2018

Cyclodextrin - A Versatile Ingredient

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Genes, short-hairpin RNA (shRNA), small-interfering RNA (siRNA), and decoy DNA can be principally used as tools for the treatment and prevention of many disorders, including but not limited to cancers, genetic disorders, and inherited diseases. This is accomplished by introducing exogenous nucleic acids into mammalian cells to modulate gene expression. However, direct use of such oligonucleotide drugs is hampered by several barriers, including their degradation by nucleases present in the blood and extracellular fluid, cell-membrane impermeability, and their retention in endosomes. To address this issue, the development of safe and effective delivery vectors has emerged as the main fundamental challenge for successful gene and oligonucleotide therapy. Due to the intrinsic risks associated with viral vectors, non-viral vectors have attracted increasing attention as gene and oligonucleotide carriers. We originally developed various cyclodextrin (CyD) conjugates with polyamidoamine (PAMAM) dendrimers as novel CyD-based polymers for the delivery of plasmid DNA, siRNA, shRNA, and decoy DNA. In this review, we describe the recent findings on PAMAM dendrimer conjugates using CyDs as carriers for gene, shRNA, siRNA, and decoy DNA delivery.

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Hepatocyte-targeting gene transfer mediated by galactosylated poly(ethylene glycol)- graft-polyethylenimine derivative

Cited by 18 publications

References 37 publications

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

Combination of Nanoparticle-Delivered siRNA for Astrocyte Elevated Gene-1 (AEG-1) and All-trans Retinoic Acid (ATRA): An Effective Therapeutic Strategy for Hepatocellular Carcinoma (HCC)

Delivery of Therapeutic AGT shRNA by PEG-Bu for Hypertension Therapy

Promising Use of Cyclodextrin-Based Non-Viral Vectors for Gene and Oligonucleotide Drugs

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