Degradable gene carriers based on oligomerized polyamines

Kloeckner, Julia; Wagner, Ernst; Ogris, Manfred

doi:10.1016/j.ejps.2006.08.002

Cited by 94 publications

(89 citation statements)

References 33 publications

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“…We conclude that use of the reductive principle in combination with a low-MW polycationic starting material seems to be a promising strategy for the delivery of macromolecular, negatively charged substances into cells. In contrast to other studies that investigated a cross-linking of either low-MW branched (35) or linear (20) polyamines via disulfide bonds, our choice of lPEI 2.6, 3.1 or 4.6 kDa as linear starting material not only entailed a much higher cell viability compared with the commercially available standard transfection reagents but also superior gene transfer efficacy. We could show that it is possible to achieve a high transfection efficiency (Ϸ60%) while maintaining a high cell viability.…”

Section: Resultsmentioning

confidence: 67%

“…We synthesized polymers that are reductively degradable inside cells and diminish their charge density to levels that minimize the risk of interactions with cellular components and, therefore, exert significantly less toxicity. In contrast to ester-or ␤-aminoesterlinked polyamines, for which hydrolysis half-lives of hours to days (18)(19)(20)(21)(22)(23) are a severe handicap, disulfides degrade rapidly not only inside endolysomes but also to a significant extent in the cell cytoplasm (24,25), because they do not depend on acid catalysis. To demonstrate the potential of these materials, it was first necessary to assess the ability of reductively biodegradable polymers to condense plasmid DNA into polyplexes that are suitable for cellular uptake.…”

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confidence: 99%

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Breaking up the correlation between efficacy and toxicity for nonviral gene delivery

Breunig

Lungwitz

Liebl

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

404

322

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Nonviral nucleic acid delivery to cells and tissues is considered a standard tool in life science research. However, although an ideal delivery system should have high efficacy and minimal toxicity, existing materials fall short, most of them being either too toxic or little effective. We hypothesized that disulfide cross-linked lowmolecular-weight (MW) linear poly(ethylene imine) (MW <4.6 kDa) would overcome this limitation. Investigations with these materials revealed that the extracellular high MW provided outstandingly high transfection efficacies (up to 69.62 ؎ 4.18% in HEK cells). We confirmed that the intracellular reductive degradation produced mainly nontoxic fragments (cell survival 98.69 ؎ 4.79%). When we compared the polymers in >1,400 individual experiments to seven commercial transfection reagents in seven different cell lines, we found highly superior transfection efficacies and substantially lower toxicities. This renders reductive degradation a highly promising tool for the design of new transfection materials.biodegradable ͉ polyethylenimine ͉ nucleic acid ͉ disulfide bond ͉ transfection G ene transfer into cells has become a standard procedure in life science research. Nonviral carriers have gained in importance in recent years because of their safety in handling and ease of application compared with viral vectors. Browsing databases such as PubMed or Chemical Abstracts reveals that almost every publication related to genetics, biochemistry, molecular biology, developmental biology, or neurology incorporated lipid-or polymer-based transfection as a pivotal tool for the investigation of various cellular processes. Therefore, it appears that the delivery of nucleic acids is a well established method for the transfection of mammalian cells, and, given the amount of research data that has been produced, one would assume that the procedures for nonviral transfection would be well optimized. A closer look at the contemporary literature, however, reveals that doubts seem justified. Contemporary transfection reagents are almost universally toxic because of their cationic or amphiphilic character (1-4).The dilemma that we face is exemplified by considering the polymeric transfection agent poly(ethylene imine) (PEI). Since its introduction in 1995, PEI has been considered the gold standard for polymer-based gene carriers because of the relatively high transfection efficacy of its polyplexes (complex of nucleic acid and polymer) (5, 6). However, it has been shown that both the efficacy and toxicity of PEI are strongly correlated with its molecular weight (MW) as well as its structure (branched or linear: bPEI or lPEI, respectively) (7-17). Efficacy and adverse reactions seem thereby to be strongly associated. PEI is not the only material that suffers from this ''malignant'' correlation. Nonviral transfection seems like choosing between Scylla and Charybdis: either a high transfection efficacy, which is associated with a devastating toxicity, or a low efficacy, which does not affect the cell viability at ...

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Section: Resultsmentioning

confidence: 67%

mentioning

confidence: 99%

Breaking up the correlation between efficacy and toxicity for nonviral gene delivery

Breunig

Lungwitz

Liebl

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

404

322

View full text Add to dashboard Cite

show abstract

“…2,3 Thus, an excellent in vivo transfection activity at low toxicity should be the major considerations regarding the design of novel nonviral gene delivery devices. Recently, many degradable polymers have been generated, [4][5][6][7][8][9][10][11][12][13][14] aiming to reduce the toxicity profile while maintaining transfection efficiency levels comparable to nondegradable gene vectors like polyamidoamine dendrimers [15][16][17] or optimized polyethylenimines (PEIs). 18,19 For example, promising results have been obtained 6,9 by coupling low molecular weight oligoethylenimine 800 Da (OEI) with short diacrylate linkages, thus combining the beneficial low cytotoxic properties of OEI with the higher transfection efficiency of higher molecular weight PEIs.…”

Section: Introductionmentioning

confidence: 99%

Novel degradable oligoethylenimine acrylate ester-based pseudodendrimers for in vitro and in vivo gene transfer

et al. 2007

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“…Taken together, the long-term safety of high-molecular weight PEI is further problematic. Therefore, to address the conflict, several modified PEI such as PEGylation, 13,14 acylation 15 of high molecular weight and cross-linked low-molecular-weight PEIs with biodegradable linkages (ester, 16,17 disulfide, 18 and amide, 19 linkages, etc) have been investigated as gene carriers to increase its gene delivery efficiency and reduce cytotoxicity. Recently, Zhao and colleagues 20 synthesized biodegradable PEI-triethylene glycol (TEG) based on PEI 2 kDa and TEG through biscarbamate linkages.…”

Section: Introductionmentioning

confidence: 99%

Biscarbamate cross-linked polyethylenimine derivative with low molecular weight, low cytotoxicity, and high efficiency for gene delivery

Wang¹,

Su²,

Wu³

et al. 2012

IJN

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Polyethylenimine (PEI), especially PEI 25 kDa, has been widely studied for delivery of nucleic acid drugs both in vitro and in vivo. However, it lacks degradable linkages and is too toxic for therapeutic applications. Hence, low-molecular-weight PEI has been explored as an alternative to PEI 25 kDa. To reduce cytotoxicity and increase transfection efficiency, we designed and synthesized a novel small-molecular-weight PEI derivative (PEI-Et, Mn: 1220, Mw: 2895) with ethylene biscarbamate linkages. PEI-Et carried the ability to condense plasmid DNA (pDNA) into nanoparticles. Gel retardation assay showed complete condensation of pDNA at w/w ratios that exceeded three. The particle size of polymer/pDNA complexes was between 130 nm and 180 nm and zeta potential was 5-10 mV, which were appropriate for cell endocytosis. The morphology of PEI-Et/pDNA complexes observed by atomic force microscopy (AFM) was spherically shaped with diameters of 110-190 nm. The transfection efficiency of polymer/pDNA complexes as determined with the luciferase activity assay as well as fluorescence-activated cell-sorting analysis (FACS) was higher than commercially available PEI 25 kDa and Lipofectamine 2000 in various cell lines. Also, the polymer exhibited significantly lower cytotoxicity compared to PEI 25 kDa at the same concentration in three cell lines. Therefore, our results indicated that the PEI-Et would be a promising candidate for safe and efficient gene delivery in gene therapy.

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Degradable gene carriers based on oligomerized polyamines

Cited by 94 publications

References 33 publications

Breaking up the correlation between efficacy and toxicity for nonviral gene delivery

Breaking up the correlation between efficacy and toxicity for nonviral gene delivery

Novel degradable oligoethylenimine acrylate ester-based pseudodendrimers for in vitro and in vivo gene transfer

Biscarbamate cross-linked polyethylenimine derivative with low molecular weight, low cytotoxicity, and high efficiency for gene delivery

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