Polyamidoamine Dendrimers with a Modified Pentaerythritol Core Having High Efficiency and Low Cytotoxicity as Gene Carriers

Wang, Yanming; Kong, Weiling; Song, Yu; Duan, Yajun; Wang, Lianyong; Steinhoff, Gustav; Kong, Deling; Yu, Yaoting

doi:10.1021/bm801333s

Cited by 54 publications

(39 citation statements)

References 26 publications

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“…To prepare the PAMAM dendriplex, an appropriate amount of stock polymer solution was mixed with a diluted solution of pDNA by pipetting thoroughly at charge ratios of 0.5, 1, 2, 4, 6, and 8 for the PAMAM dendriplex and left for 30 min at room temperature. For pharmaceutical modification, CS was added to PAMAM dendiplex 4 at charge ratios of 4,6,8,10,12,14,16, and 18; and left for another 30 min at room temperature. The theoretical charge ratio of anionic polymer to pDNA was calculated as the molar ratio of CS to pDNA phosphate.…”

Section: Preparation Of Complexesmentioning

confidence: 99%

“…11,13) On the other hand, cationic non-viral gene vectors show cytotoxicity by binding non-specifically to negatively charged proteoglycans on cell membranes. 14) Cationic non-viral gene vectors also agglutinate with negatively charged blood components, such as erythrocytes and serum albumin. These agglutinations often cause adverse events, such as rapid elimination, embolization, and inflammatory reactions.…”

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confidence: 99%

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Ternary Complex of Plasmid DNA Electrostatically Assembled with Polyamidoamine Dendrimer and Chondroitin Sulfate for Effective and Secure Gene Delivery

Imamura

Kodama

Higuchi

et al. 2014

Biological & Pharmaceutical Bulletin

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The purpose of this study was to develop a ternary complex of plasmid DNA (pDNA) electrostatically assembled with polyamidoamine (PAMAM) dendrimer and chondroitin sulfate (CS) for effective and secure gene delivery. PAMAM dendrimers are new cationic polymers that are expected to be used as gene delivery vectors. However, cationic non-viral gene vectors showed cytotoxicity by binding to negative cellular membranes. We therefore prepared a ternary complex by adding CS, an anionic polymer, and examined its usefulness. The pDNA/PAMAM dendrimer complex (PAMAM dendriplex) and the PAMAM dendriplex coated by CS (CS complex) showed nanoparticles with positive ζ-potential and negative ζ-potential, respectively. The CS complex had no cytotoxicity against B16-F10 cells and no agglutination activity, although severe cytotoxicity and high agglutination were observed in the PAMAM dendriplex. As a result of an in vitro gene expression study of B16-F10 cells, not only the PAMAM dendriplex but also the CS complex showed high transfection efficiency. The transfection efficiency of the CS complex was significantly inhibited by clathrinmediated endocytosis inhibitor (chlorpromazine), caveolae-mediated endocytosis inhibitor (genistein), and hypothermia. Tail-vein injection of the CS complex into mice led to significantly higher gene expression in the spleen than the PAMAM dendriplex. Thus, the ternary complex of pDNA electrostatically assembled with PAMAM denriplex and CS showed safe high gene expression in the spleen. This vector is expected to be useful for useful gene delivery.Key words ternary complex; chondroitin sulfate; polyamidoamine dendrimer; gene delivery Gene therapy is expected to be an effective method to treat cancer, infection, innate immunodeficiency and cardiovascular diseases.1-4) The success of gene therapy is largely dependent on the development of vectors capable of effectively delivering foreign genes into targeted cells. One major approach in gene therapy is based on cationic polymers, such as polyethylenimine (PEI), polylysine, polyarginine, and chitosan.5-8) When cationic polymer-encapsulated plasmid DNA (pDNA) makes association with the cell surface, it enters the cells by endocytosis.Polyamidoamine (PAMAM) dendrimers are new cationic polymers, which are highly branched radial polymers that have specific and systematically variable size, shape and chemical structure. Their radical structure contains a 2-carbon ethylenediamine core and primary amino groups on the surface. Successive generations (G) have increasing diameter and double the surface functional amino groups of the preceding generation.9,10) PAMAM dendrimers can be used as carriers for pDNA and show high transfection efficiency. 11,12)The pDNA/PAMAM dendrimer complexes (PAMAM dendriplex) are formed by electrostatic interactions and initiate cell entry through binding to anionic phospholipids on the cell membrane. With increasing generations of dendrimers, the PAMAM dendriplex showed higher transfection efficiency, which depended on the charge rati...

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Section: Preparation Of Complexesmentioning

confidence: 99%

mentioning

confidence: 99%

Ternary Complex of Plasmid DNA Electrostatically Assembled with Polyamidoamine Dendrimer and Chondroitin Sulfate for Effective and Secure Gene Delivery

Imamura

Kodama

Higuchi

et al. 2014

Biological & Pharmaceutical Bulletin

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show abstract

“…47 The selection of pentaerythritol cores was based on literature findings which revealed that PAMAM dendrimers around pentaerythritol cores showed less cytotoxicity compared to the parent ones. 48,49 The syntheses of G0 dendrimers 1 and 2 were achieved using the literature procedure previously reported by our group. 44,47 found that the microwave irradiation promoted the reaction rate and helped in the completion of reaction within 6 h, while the same reaction, when performed under similar conditions without microwave treatments, took overnight to be completed.…”

Section: Resultsmentioning

confidence: 99%

Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

et al. 2016

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Low G1 generation polyamine dendrimers built around programmable, flexible, and short tetraethyleneglycol branches were readily prepared in a divergent manner using a combination of orthogonal AB 3 or AB 5 units and highly efficient chemical transformations based on Cu(I) catalyzed alkyne-azide cycloaddition (CUAAC) and thiol-ene click reactions. The constructs showed that the G1 polyamines with only twelve and eighteen amine surface groups can successfully deliver siRNA in human cells, with transfection efficiency comparable to that of Lipofectamine 2000®. Measurements of cell viability following transfection of plasmid DNA and siRNA showed that the dendritic polyamines are less cytotoxic than Lipofectamine 2000® and are thus preferable for biological applications.

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“…A new family of PAMAM dendrimers that uses a pentaerythritol derivative (PD) as a core possessing 12 branches was synthesized by Wang et al (45). The synthesized PD dendrimers of generations 3-5 efficiently condensed DNA into nanoscale complexes with slightly positive charges, and showed a higher transfection efficiency with a much lower cytotoxicity than the commercial non-viral gene carriers PEI, polylysine (PLL) and PAMAM dendrimers with an ethylenediamine core (generations 5 and 7).…”

Section: Heat Treatment Tang Et Almentioning

confidence: 99%

Polyamidoamine dendrimers as gene delivery carriers in the inner ear: How to improve transfection efficiency

Wang

Shi

Yin

2011

Experimental and Therapeutic Medicine

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Abstract. Hair cells in the cochlea can be damaged by various insults, including noise, drugs, infections and presbycusis, which may cause sensorineural hearing loss. Gene therapy is a novel therapeutic technology that, recently, has led to the idea of treating inner ear diseases on a genetic level. Depending on their characteristics, such as a high efficiency in delivery, the capability of specific targeting, multifunctionality, biodegradability, non-toxicity, non-immunogenicity and the capability of limiting DNA degradation, nanovectors, such as polyamidoamine (PAMAM) dendrimers for cellular gene delivery, provide a promising approach to eradicate genetic diseases. They are a new class of highly branched spherical polymers that are highly soluble in aqueous solution. Their unique surface is composed of positively charged primary amine groups which allow them to form stable complexes with plasmid DNA, oligonucleotides, antibodies and drugs. This review provides an overview of the characteristics of PAMAMs which may be used in gene transfer into the cochlea as well as the efforts to improve their transfection efficiency as gene-delivery carriers.

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Polyamidoamine Dendrimers with a Modified Pentaerythritol Core Having High Efficiency and Low Cytotoxicity as Gene Carriers

Cited by 54 publications

References 26 publications

Ternary Complex of Plasmid DNA Electrostatically Assembled with Polyamidoamine Dendrimer and Chondroitin Sulfate for Effective and Secure Gene Delivery

Ternary Complex of Plasmid DNA Electrostatically Assembled with Polyamidoamine Dendrimer and Chondroitin Sulfate for Effective and Secure Gene Delivery

Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

Polyamidoamine dendrimers as gene delivery carriers in the inner ear: How to improve transfection efficiency

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