Oligoethylenimine-grafted polypropylenimine dendrimers as degradable and biocompatible synthetic vectors for gene delivery

Ruß, Verena; Günther, Michael; Halama, Anna; Ogris, Manfred; Wagner, Ernst

doi:10.1016/j.jconrel.2008.09.003

Cited by 107 publications

(83 citation statements)

References 35 publications

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“…As a continuation of this work, a novel class of branched polycations was synthesized based on oligoethylenimine (OEI)-grafted polypropylenimine dendrimers (G2-HD-OEI; ref. 26). Low toxicity in association with high transfection efficiency was observed in different tumor cell lines in vitro using these polymers.…”

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confidence: 93%

“…Therefore, several biodegradable polymers were developed for gene transfer (22,23), aiming to reduce the toxicity profile while maintaining high transduction efficiency comparable with the standard synthetic gene vectors. We have recently developed a series of biodegradable carriers based on low molecular weight polycations cross-linked either via ester or disulfide bonds (24)(25)(26), showing very promising toxicity profiles and similar or even superior transfection efficiency in comparison with LPEI (25). As a continuation of this work, a novel class of branched polycations was synthesized based on oligoethylenimine (OEI)-grafted polypropylenimine dendrimers (G2-HD-OEI; ref.…”

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confidence: 99%

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Targeted Radioiodine Therapy of Neuroblastoma Tumors following Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene

Klutz

Ruß

Willhauck

et al. 2009

Clinical Cancer Research

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Purpose: We recently reported the significant therapeutic efficacy of radioiodine therapy in various tumor mouse models following transcriptionally targeted sodium iodide symporter (NIS) gene transfer. These studies showed the high potential of NIS as a novel diagnostic and therapeutic gene for the treatment of extrathyroidal tumors. As a next crucial step towards clinical application of NIS-mediated radionuclide therapy we aim at systemic delivery of the NIS gene to target extrathyroidal tumors even in the metastatic stage. Experimental Design: In the current study, we used synthetic polymeric vectors based on pseudodendritic oligoamines with high intrinsic tumor affinity (G2-HD-OEI) to target a NIS-expressing plasmid (CMV-NIS-pcDNA3) to neuroblastoma (Neuro2A) cells. Results: Incubation with NIS-containing polyplexes (G2-HD-OEI/NIS) resulted in a 51-fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. The exact mechanism by which iodide is actively transported across the basolateral membrane of thyroid follicular cells was clarified by the cloning and characterization of the sodium iodide symporter (NIS) 13 years ago (1-3). NIS, an intrinsic transmembrane glycoprotein with 13 putative transmembrane domains, is responsible for the ability of the thyroid gland to concentrate iodide, the first and rate-limiting step in the process of thyroid hormonogenesis (4, 5). Moreover, due to its expression in follicular cell-derived thyroid cancer cells, NIS provides the molecular basis for the diagnostic and therapeutic application of radioiodine, which has been successfully used for more than 60 years in the treatment of thyroid cancer patients and therefore represents the most effective form of systemic anticancer radiotherapy available to the clinician today (6). Since its cloning in 1996 NIS has been identified and characterized as a novel promising target gene for the treatment of extrathyroidal tumors following selective NIS gene transfer into tumor cells that allows diagnostic and therapeutic application of radioiodine and alternative radionuclides, such as 188 Re and 211 At (6-9). We have proven the feasibility of extrathyroidal radioiodine therapy after induction of iodide uptake by ex vivo

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confidence: 93%

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confidence: 99%

Targeted Radioiodine Therapy of Neuroblastoma Tumors following Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene

Klutz

Ruß

Willhauck

et al. 2009

Clinical Cancer Research

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“…62 Transfection levels of OEI-grafted dendrimer pDNA polyplexes were the best, similar to or even higher than those of standard PEI polyplexes. Intravenous injection of OEI-grafted PPI polyplexes into tumor-bearing mice mediated transgene expression predominantly in the subcutaneous tumors.…”

Section: Reviewmentioning

confidence: 83%

Nucleic Acid Carriers Based on Precise Polymer Conjugates

Troiber

Wagner

2011

Bioconjugate Chem.

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Polymer polydispersity, random conjugation of functional groups, and poorly understood structure–activity relationships have constantly hampered progress in the development of nucleic acid carriers. This review focuses on the synthetic concepts for the generation of precise polymers, site-specific conjugation strategies, and multifunctional conjugates for nucleic acid transport. Dendrimers, defined peptide carriers, sequence-defined polyamidoamines assembled by solid-phase supported synthesis, and precise lipopeptides or lipopolymers have been characterized for pDNA and siRNA delivery. Conjugation techniques such as click chemistries and peptide ligation are available for conjugating polymers with functional transport elements such as targeting or shielding domains and for direct covalent modification of therapeutic nucleic acids in a site-specific mode.

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“…RBC hemolysis assay was tested as previously described (10). Human red blood cells (RBCs) were freshly isolated and washed four times in phosphate-buffered saline by centrifugation at 800g for 10 min at 4°C.…”

Section: Hemolysis Assaymentioning

confidence: 99%

“…Therefore, several modifications have been made on this dendrimer which have resulted in improved transfection and reduction in toxicity. Some of these modifications include addition of arginine, guanidyl groups, oligoethyleneimine; quarternerization of primary amines by methylation; and targeting of PPI dendrimers by transferrin, folate galactose, and dextran (8)(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

Preparation of Effective and Safe Gene Carriers by Grafting Alkyl Chains to Generation 5 Polypropyleneimine

et al. 2015

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Abstract. Gene therapy is a novel method to treat a variety of diseases including genetic disorders and cancer. Nonviral gene carriers have now gained considerable attention as gene carrier systems. Polyamidoamine (PAMAM) and polypropyleneimine (PPI) are the two most widely used denderimers in gene delivery studies. The aim of the current study was to investigate the effects of modification of generation 5 polypropyleneimine (G5 PPI) dendrimers with alkanoate groups as hydrophobic moieties on DNA transfection and cytotoxicity. Six, 10, and 16 carbon derivatives of bromoalkanoic acids were conjugated onto PPI with 10%, 30%, and 50% of surface amine grafting. Ethidium bromide exclusion assay results proved the ability of modified carriers to condense DNA. Transfection assay showed higher DNA delivery potential for 30% and 50% grafting with decanoate moieties compared to native G5 PPI and Superfect TM . 3-(4,5-Dimethylthiazol-2-yl)-2,5-di phenyltetrazolium bromide (MTT) and apoptosis experiments showed lower toxicity for modified carriers compared to unmodified PPI. The hemolytic effect of grafted carriers was not significantly different from G5 PPI. Size and zeta potential measurements revealed that polyplex size was less than 200 nm and electrical charges were in the range 14-25 mV. The hydrophobic modifications improved transfection activity and toxicity of G5 PPI without negatively affecting hemocompatibility. These modified carriers are therefore promising candidates for further in vivo investigations.

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Oligoethylenimine-grafted polypropylenimine dendrimers as degradable and biocompatible synthetic vectors for gene delivery

Cited by 107 publications

References 35 publications

Targeted Radioiodine Therapy of Neuroblastoma Tumors following Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene

Targeted Radioiodine Therapy of Neuroblastoma Tumors following Systemic Nonviral Delivery of the Sodium Iodide Symporter Gene

Nucleic Acid Carriers Based on Precise Polymer Conjugates

Preparation of Effective and Safe Gene Carriers by Grafting Alkyl Chains to Generation 5 Polypropyleneimine

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