Nanoparticles for the delivery of genes and drugs to human hepatocytes

Yamada, Tesshi; Iwasaki, Yasushi; Tada, Hayato; Iwabuki, Hidehiko; Chuah, Marinee; VandenDriessche, Thierry; Fukuda, Hideki; Kondo, Akihiko; Ueda, Mitsuharu; Seno, Masaharu; Tanizawa, Katsuyuki; Kuroda, Shinya

doi:10.1038/nbt843

Cited by 240 publications

(180 citation statements)

References 33 publications

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“…In a previous publication, we reported that tissue specificity can be switched from hepatocytes (HepG2) to squamous cells (A431) by changing the ligand from preS1 to epidermal growth factor (EGF). 30 Hence, the precise opposite result would be expected if EGF was conjugated to PMBN, instead of preS1.…”

Section: Discussionmentioning

confidence: 92%

Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

Miyata

Ueda

Jinno

et al. 2009

Intl Journal of Cancer

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Using dithioester-capped 2-methacryloyloxyethyl phosphorylcholine (MPC) as a macro chain transfer agent, a diblock copolymer was synthesized with n-butyl methacrylate (BMA) as hydrophobic core-forming blocks. The MPC-BMA unit was copolymerized with an immobilizable unit, p-nitrophenylcarbonyloxyethyl methacrylate (NPMA). The NPMA moiety then was modified by the addition of preS1 domain of hepatitis B surface antigen (HBsAg). This micelle-forming nanoparticle, the poly (MPC-co-BMA-co-NPMA) (PMBN) conjugated with preS1 enables solubilization of paclitaxel (PTX) with increased hepatotropism. The 50% inhibitory concentration (IC 50 ) values of PTX and PTX/PMBN-preS1 against the human hepatocellular carcinoma cell line, HepG2, were 1,008 and 131 nM, respectively (p < 0.05). Conjugation of preS1 to PMBN enhanced strongly the synergistic inhibitory effect of paclitaxel on HepG2 cells in vitro, whereas such a change in IC 50 was not detected against the human squamous cell carcinoma cell line, A431. Tumor growth rates of a HepG2 xenograft in Balb/ c nude mice after intraperitoneal injection of PTX, PTX/PMBN and PTX/PMBN-preS1 were 197.9%, 274.3% and 296.2%*, respectively (*p < 0.05 versus PTX). The local paclitaxel levels after administration of the PMBN-preS1 conjugate were determined in the xenografts by high-performance liquid chromatography and were 8 times higher than that after administration of paclitaxel alone. No side effects attributable to PMBN-preS1 were observed histologically in vital organs, and body weight loss was significantly less in the PTX/PMBN-preS1 group. These studies demonstrate that PMBN-preS1 may be used as a human hepatocyte-specific drug delivery carrier without serious adverse effects.

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Section: Discussionmentioning

confidence: 92%

Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

Miyata

Ueda

Jinno

et al. 2009

Intl Journal of Cancer

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“…[1][2][3][4][5][6][7][8][9][10][11][12] A gene-transferring system mediated by a particulate DNA-calcium phosphate composite [1][2][3] is safer than viral [4][5][6] and lipid-based [7][8][9] systems, but its transferring efficiency is comparatively low. To enhance the gene-transferring efficiency, a surface-mediated genetransferring system derived from a DNA-apatite composite (D-Ap) layer has been developed.…”

mentioning

confidence: 99%

Novel gene-transferring scaffolds having a cell adhesion molecule–DNA–apatite nanocomposite surface

2007

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A low efficiency has long been the most critical problem of conventional gene-transferring systems using calcium phosphates, and this was successfully improved on by using a laminin-DNA-apatite composite (LD-Ap) layer. The genetransferring efficiency of the LD-Ap surface was 1-2 orders of magnitude higher than that of a DNA-calcium phosphate composite surface. This is because laminin enhances cell adhesion and spreading, and this provides regions of high DNA concentration between a cell and the LD-Ap surface. The efficiency of gene transfer of the LD-Ap surface was equivalent to, or even higher than that mediated using a commercial lipid-based transfection reagent applied using the manufacture's recommended optimum conditions. In addition, the gene-transferring efficiency of our system could be controlled by changing the laminin and DNA content in the LD-Ap layer. Moreover, our system is composed of highly safe reagents: apatite, DNA and laminin, all of which are present in the human body. Hence, the LD-Ap surface, which enhances cell attachment on its surface, and mediates a safe, highly efficient and controllable gene transfer, is highly applicable to tissue engineering and gene therapy applications. Gene Therapy (2007) An efficient and safe gene-transferring system is a key technology in tissue engineering and gene therapy applications. 1-12 A gene-transferring system mediated by a particulate DNA-calcium phosphate composite 1-3 is safer than viral 4-6 and lipid-based 7-9 systems, but its transferring efficiency is comparatively low. To enhance the gene-transferring efficiency, a surface-mediated genetransferring system derived from a DNA-apatite composite (D-Ap) layer has been developed. 12 In this system, regions of high DNA concentration are produced locally around cells, and this enhances the gene-transferring efficiency. In this work, the cell adhesion molecule, laminin, 13,14 was immobilized on a D-Ap layer to enhance further the gene-transferring efficiency by strengthening a cell's attachment and facilitating its spreading on a coating's surface. The gene-transferring efficiency was 1-2 orders of magnitude higher on the resulting laminin-DNA-apatite composite (LD-Ap) layer than the gene-transferring efficiency on a D-Ap layer. In this paper, we present an advanced gene-transferring system that has a high efficiency, is safe and has a great potential for use in tissue engineering and gene therapy applications.An LD-Ap layer was coated on a polymer surface in a metastable supersaturated calcium phosphate solution at neutral pH, and ambient pressure and temperature. [15][16][17][18] As controls, an apatite (Ap) layer, a D-Ap layer and a laminin-apatite composite (L-Ap) layer were also coated on the polymer surface. The coating layers were formed by immersing the polymer sample, that had an amorphous calcium phosphate (ACP) layer deposited on its surface, in four different coating solutions: a calcium phosphate solution (CP solution) [15][16][17][18] (for the Ap layer), a CP solution supplemented with DN...

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“…23,24 It is not known whether nanoparticles could be used successfully for targeted delivery of therapeutic genes with anti-tumor activity into human liver tumors. As a proofof-concept and as a logical extension of our prior work, 19 we have therefore investigated the distribution of L nanoparticles in a human liver tumor xenograft rat model, using a green fluorescent protein (GFP) expression plasmid as a reporter, and analyzed their potential for treatment of liver tumors using the HSV-tk/GCV system.…”

Section: Introductionmentioning

confidence: 99%

“…These nanoparticles possess high gene transfer efficiency and show high specificity to human liver cells. 19,21 We have succeeded in loading several different genes into the particles, and then transferring these genes into human liver cells in vitro and in vivo. In addition, L nanoparticles are easily produced by recombinant yeast cells and large-scale production of the particles has already been established, 20,22 whereas large-scale manufacturing of clinical-grade viral vectors remains a significant obstacle that hampers its clinical implementation.…”

Section: Introductionmentioning

confidence: 99%

“…19 These nanoparticles are engineered to display the hepatitis B virus surface L antigen (HBsAg) on their surface and are devoid of viral genomes, 20 which obviates potential safety concerns related to the emergence of replication-competent viruses. These nanoparticles possess high gene transfer efficiency and show high specificity to human liver cells.…”

Section: Introductionmentioning

confidence: 99%

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Gene therapy of liver tumors with human liver-specific nanoparticles

et al. 2006

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The development of safe and efficient liver-specific gene delivery approaches offers new perspectives for the treatment of liver disease, in particular, liver cancer. We evaluated the therapeutic potential of hepatotropic nanoparticles for gene therapy of liver tumor. These nanoparticles do not contain a viral genome and display the hepatitis B virus L antigen, which is essential to confer hepatic specificity. It has not been shown whether a therapeutic effect could be obtained using L nanoparticles in a human liver tumor xenograft model. Rats bearing human hepatic (NuE) and non-hepatic tumors were injected with L nanoparticles containing a green fluorescent protein (GFP) expression plasmid. GFP expression was observed only in NuE-derived tumors but not in the nonhepatic tumor. The potential for treatment of liver tumors was analyzed using L nanoparticles containing the herpes simplex virus thymidine kinase gene, in conjunction with ganciclovir pro-drug administration. The growth of NuE-derived tumors in L particleinjected rats was significantly suppressed, but not of the non-hepatic tumor control. In summary, this is the first demonstration that nanoparticles could be used for delivery of therapeutic genes with anti-tumor activity into human liver tumors. This intravenous delivery system may be one of the major advantages as compared to many other viral vector systems.

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Nanoparticles for the delivery of genes and drugs to human hepatocytes

Cited by 240 publications

References 33 publications

Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine‐based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel

Novel gene-transferring scaffolds having a cell adhesion molecule–DNA–apatite nanocomposite surface

Gene therapy of liver tumors with human liver-specific nanoparticles

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