Cross-linked Small Polyethylenimines: While Still Nontoxic, Deliver DNA Efficiently to Mammalian Cells in Vitro and in Vivo

Thomas, M. Joy; Ge, Qing; Lu, James; Chen, Jianzhu; Klibanov, Alexander M.

doi:10.1007/s11095-004-1874-y

Cited by 224 publications

(177 citation statements)

References 44 publications

(80 reference statements)

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“…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%

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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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

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“…While Lipofectamine revealed high toxicity, the hPAMAM-Glus complexes showed a very low toxicity profile during gene transfer (Thomas et al, 2005;Wang et al, 2010;Hemmati et al, 2016). Size is one of the major factors in gene transfer efficiency into cells (KukowskaLatallo et al, 1996;Zhu et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Synthesis of a novel PEGDGA-coated hPAMAM complex as an efficient and biocompatible gene delivery vector: an in vitro and in vivo study

et al. 2016

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“…106,107 Inúmeros fatores estão relacionados à eficiência da PEI, como célula-alvo, peso molecular, ramificações, razão N/P entre os grupos amina da polietilenimina (N) e os grupos fosfato do ácido nucleico (P), e tamanho do complexo. 108 A atividade superior da PEI frente a outros reagentes de transfecção é atribuída ao escape lisossomal, comumente chamado "esponja-de-prótons": devido à alta densidade de grupos amino de elevado pKa, o pH ácido da vesícula lisossomal protona esses grupamentos, levando a uma entrada de água para solvatação que colapsa a estrutura do lisossomo. 109 Entretanto, muitos autores ainda questionam a veracidade desse mecanismo.…”

Section: Protaminaunclassified

Biomateriais para formulações de base nanotecnológica visando terapia gênica ocular

et al. 2016

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Cross-linked Small Polyethylenimines: While Still Nontoxic, Deliver DNA Efficiently to Mammalian Cells in Vitro and in Vivo

Abstract: Cross-linking of small PEIs with judiciously designed amide- and ester-bearing linkers boosts their gene delivery efficiency both in vitro and in vivo without increasing the cytotoxicity. The high efficiency is dependent on the nature of the linkages and the PEIs used.

Cited by 224 publications

References 44 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

Synthesis of a novel PEGDGA-coated hPAMAM complex as an efficient and biocompatible gene delivery vector: an in vitro and in vivo study

Biomateriais para formulações de base nanotecnológica visando terapia gênica ocular

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