Uronic acids functionalized polyethyleneimine (PEI)–polyethyleneglycol (PEG)-graft-copolymers as novel synthetic gene carriers

Weiß, Sabine; Sieverling, Nathalie; Niclasen, Maren; Maucksch, Christof; Thünemann, Andreas F.; Möhwald, Helmuth; Reinhardt, D.; Rosenecker, Joseph; Rudolph, Carsten

doi:10.1016/j.biomaterials.2005.11.011

Cited by 42 publications

(29 citation statements)

References 30 publications

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“…As reported, PEG can prevent cationic complexes from interaction with other proteins, thus stabilizing the complex and reducing cytotoxicity. 58,59 For example, it was demonstrated that PLL (24 kd) showed cytotoxicity to KB cells from 1 µg/mL, but PLL (24 kd) with a PEG grafting ratio of 8.4% (PLL-g-PEG) showed little cytotoxicity over the range of 1 µg/mL to 10 µg/mL. 59 The low cytotoxity of APC in our study warrants further investigation of the complex.…”

Section: Discussionmentioning

confidence: 99%

Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus

Zeng¹,

Han²,

Zhao³

et al. 2012

IJN

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Background:The generation of anti-adenovirus neutralizing antibody (NAb) in humans severely restricts the utilization of recombinant adenovirus serotype 5 (Ad5) vectors in gene therapy for a wide range of clinical trials. To overcome this limitation, we ionically complexed Ad5 with a newly synthesized copolymer, which we called APC, making an adenovirus shielded from NAb. Methods: APC, a cationic polyethylene glycol derivative, was synthesized via two steps of ring-opening copolymerization of ethylene oxide and allyl glycidyl ether, followed by the addition of 2-mercaptoethylamine. The copolymer or the control PEI-2k was ionically complexed to anionic Ad5 in 5% glucose, and in vitro transduction assays were carried out in coxsackievirus and adenovirus receptor-positive cells (A549) and coxsackievirus and adenovirus receptornegative cells (B16 and SKOV3). The physical properties and morphology of adenovirus alone or the complexes were investigated respectively by zeta potential, size distribution, and transmission electron microscopy image. Then cytotoxicity of APC was examined using 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide assays. Finally, the ability of APC to protect adenovirus from NAb was evaluated by transfection assays after a neutralizing effect. Results: APC was successfully synthesized and showed a low cytotoxicity. Positively charged Ad5/APC exhibited slightly increased diameter (130.2 ± 0.60 nm) than naked Ad5 (115.6 ± 5.46 nm) while Ad5/PEI-2k showed severe aggregation (1382 ± 79.9 nm). Ad5/APC achieved a gene transfection level as high as Ad5/PEI-2k in A549 or B16 cells, and significantly higher than Ad5/PEI-2k in SKOV3 cells. Most importantly, after the exposure to the neutralizing antibody, naked Ad5 and Ad5/PEI-2k exhibited poor gene expression while Ad5/APC still showed significantly efficient gene expression. Conclusion: Our results demonstrated that Ad5/APC complex offered good protection for Ad5 against NAb in vitro and suggested a potential strategy of resistance to NAb in vivo.

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Section: Discussionmentioning

confidence: 99%

Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus

Zeng¹,

Han²,

Zhao³

et al. 2012

IJN

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“…Polyethylenimine (PEI) and its derivatives are the most extensively investigated because of their "proton sponge" effect. 9,10 PEI, with abundant positive charges, condenses DNA by electrostatic interaction to compact complexes, which enables breaking through the various barriers to the nucleus of target cells. 11 DNA is condensed as nanoparticles so that it is not easily degraded by nuclease, or gathered as precipitate, which results in high transfection efficiency.…”

Section: Introductionmentioning

confidence: 99%

Degradable copolymer based on amphiphilic N-octyl-N-quatenary chitosan and low-molecular weight polyethylenimine for gene delivery

Liu¹,

Zhu²,

Wu³

et al. 2012

IJN

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Background: Chitosan shows particularly high biocompatibility and fairly low cytotoxicity. However, chitosan is insoluble at physiological pH. Moreover, it lacks charge, so shows poor transfection. In order to develop a new type of gene vector with high transfection efficiency and low cytotoxicity, amphiphilic chitosan was synthesized and linked with low-molecular weight polyethylenimine (PEI). Methods: We first synthesized amphiphilic chitosan -N-octyl-N-quatenary chitosan (OTMCS), then prepared degradable PEI derivates by cross-linking low-molecular weight PEI with amphiphilic chitosan to produce a new polymeric gene vector (OTMCS-PEI). The new gene vector was characterized by various physicochemical methods. We also determined its cytotoxicity and gene transfecton efficiency in vitro and in vivo. Results: The vector showed controlled degradation. It was very stable and showed excellent buffering capacity. The particle sizes of the OTMCS-PEI/DNA complexes were around 150-200 nm with proper zeta potentials from 10 mV to 30 mV. The polymer could protect plasmid DNA from being digested by DNase I at a concentration of 2.25 U DNase I/µg DNA. Furthermore, they were resistant to dissociation induced by 50% fetal bovine serum and 1100 µg/mL sodium heparin. OTMCS-PEI revealed lower cytotoxicity, even at higher doses. Compared with PEI 25 KDa, the OTMCS-PEI/DNA complexes also showed higher transfection efficiency in vitro and in vivo. Conclusion: OTMCS-PEI was a potential candidate as a safe and efficient gene vector for gene therapy.

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“…23 Therefore, covalent linkage with nonionic and hydrophilic polymers, such as polyethylene glycol, has been used to minimize the toxicity of polyethylenimine. [24][25][26] Polyethylene glycol has also improved the solubility of polyethylene glycol-grafted polyethylenimine (PEG-PEI) complexes, minimized aggregation, and reduced nonspecific interactions with proteins in physiological fluids. [27][28][29] To our knowledge, there are few studies reported on the use of PEG-PEI to prepare PEG-PEI/DNA nanoparticles for gene delivery into mesenchymal stem cells.…”

Section: Introductionmentioning

confidence: 99%

Plasmid-encapsulated polyethylene glycol-grafted polyethylenimine nanoparticles for gene delivery into rat mesenchymal stem cells

Chen

Zhang²,

He³

et al. 2011

IJN

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Background: Mesenchymal stem cell transplantation is a promising method in regenerative medicine. Gene-modified mesenchymal stem cells possess superior characteristics of specific tissue differentiation, resistance to apoptosis, and directional migration. Viral vectors have the disadvantages of potential immunogenicity, carcinogenicity, and complicated synthetic procedures. Polyethylene glycol-grafted polyethylenimine (PEG-PEI) holds promise in gene delivery because of easy preparation and potentially targeting modification. Methods: A PEG8k-PEI25k graft copolymer was synthesized. Agarose gel retardation assay and dynamic light scattering were used to determine the properties of the nanoparticles. MTT reduction, wound and healing, and differentiation assays were used to test the cytobiological characteristics of rat mesenchymal stem cells, fluorescence microscopy and flow cytometry were used to determine transfection efficiency, and atomic force microscopy was used to evaluate the interaction between PEG-PEI/plasmid nanoparticles and mesenchymal stem cells. Results: After incubation with the copolymer, the bionomics of mesenchymal stem cells showed no significant change. The mesenchymal stem cells still maintained high viability, resettled the wound area, and differentiated into adipocytes and osteoblasts. The PEG-PEI completely packed plasmid and condensed plasmid into stable nanoparticles of 100–150 nm diameter. After optimizing the N/P ratio, the PEG-PEI/plasmid microcapsules delivered plasmid into mesenchymal stem cells and obtained an optimum transfection efficiency of 15%–21%, which was higher than for cationic liposomes. Conclusion: These data indicate that PEG-PEI is a valid gene delivery agent and has better transfection efficiency than cationic liposomes in mesenchymal stem cells.

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Uronic acids functionalized polyethyleneimine (PEI)–polyethyleneglycol (PEG)-graft-copolymers as novel synthetic gene carriers

Cited by 42 publications

References 30 publications

Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus

Protection of adenovirus from neutralizing antibody by cationic PEG derivative ionically linked to adenovirus

Degradable copolymer based on amphiphilic N-octyl-N-quatenary chitosan and low-molecular weight polyethylenimine for gene delivery

Plasmid-encapsulated polyethylene glycol-grafted polyethylenimine nanoparticles for gene delivery into rat mesenchymal stem cells

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