Impact of molecular weight and degree of conjugation on the thermodynamics of DNA complexation and stability of polyethylenimine-graft-poly(ethylene glycol) copolymers

Smith, Ryan; Beck, Rachel W.; Prevette, Lisa E.

doi:10.1016/j.bpc.2015.04.005

Cited by 14 publications

(16 citation statements)

References 63 publications

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“…Recent advances in the identification of the ideal shielding agents with optimal molecular weight led to improved carriers with high delivery performance and reduced cytotoxicity (LPEI‐PEG2kDa) . The advantage of short PEG chains was also highlighted in more recent work . LPEI‐PEG2kDa as a biocompatible and technically feasible starting point for complete synthetic targeting conjugates was further modified by biological targeting strategies aiming to direct these synthetic gene delivery particles towards the tumor site by taking advantage of the special architecture of tumors and unique tumor properties .…”

Section: Discussionmentioning

confidence: 99%

“…51 The advantage of short PEG chains was also highlighted in more recent work. 54,72 LPEI-PEG2kDa as a biocompatible and technically feasible starting point for complete synthetic targeting conjugates was further modified by biological targeting strategies aiming to direct these synthetic gene delivery particles towards the tumor site by taking advantage of the special architecture of tumors and unique tumor properties. 13,51,56 Tumor cells are often characterized by a high proliferation rate and subsequent up-regulation of growth factor receptors such as EGFR, cMET or TfR, characteristic of rapidly dividing cells.…”

Section: Discussionmentioning

confidence: 99%

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Systemic tumor‐targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes

Urnauer

Klutz

Grünwald

et al. 2017

The Journal of Gene Medicine

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These results clearly demonstrate that systemic in vivo NIS gene transfer using nanoparticle vectors coupled to B6 tumor targeting ligand is capable of inducing tumor-specific radioiodide uptake. This promising gene therapy approach opens the exciting prospect of NIS-mediated radionuclide therapy in metastatic cancer, together with the possibility of combining several targeting ligands to enhance selective therapeutic efficacy in a broad field of cancer types with various receptor expression profiles.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Systemic tumor‐targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes

Urnauer

Klutz

Grünwald

et al. 2017

The Journal of Gene Medicine

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“…13) The observed difference may be due to the difference in the mass and architecture of the PEI used, since 600 Da branched PEI was used in our study 13) while 25 kDa linear PEI was used in the Smith et al study. 15) Another possibility for the difference in the reported equilibrium constant may come from the fitting model used for analysis. We used the model developed by Kim et al, 16) while Smith et al used the standard multiple site model.…”

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confidence: 99%

“…We used the model developed by Kim et al, 16) while Smith et al used the standard multiple site model. 15) It was difficult to analyze the ITC data in these studies since not only PEI gets protonated when it binds to DNA, but also the DNA is condensed during the binding process, 13) which complicates the interpretation of the released (absorbed) heat during the titration process. Therefore, a more comprehensive analysis of PEI-DNA interactions would be beneficial to better understand the underlying basis of PEIs' effectiveness in DNA delivery.…”

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confidence: 99%

“…Fluorescent displacement assays reveal DNA affinity through decreased fluorescence of the dye as it is displaced from its binding state on DNA to free in solution, as PEI comes in contact with DNA-dye complex. 15) This is a commonly used assay for characterizing polyplex formation for non-viral gene delivery agents. By using two fluorophores whose DNA binding mode is well established, we probed the location of the bound PEI on the DNA strand.…”

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confidence: 99%

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Low Molecular Weight Branched PEI Binding to Linear DNA

Utsuno

Kono

Tanaka

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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Polyethylenimine (PEI) is one of the most versatile non-viral vectors used in gene therapy, especially for delivering plasmid DNA to human cells. However, a good understanding of PEI binding to DNA, the fundamental basis for the functioning of PEI as a vector, has been missing in the literature. In this study, PEI (branched, 600 Da) binding to DNA was examined by isothermal titration calorimetry (ITC), quartz crystal microbalance (QCM) and a complementary set of analysis tools. We demonstrated that a separation between the binding heat and the condensation heat is needed and that the excluded site model should be used for PEI binding stage in the ITC analysis. The equilibrium constant for PEI binding to DNA was determined to be 2.5 10 5 M 1 from the ITC analysis, and as 2.3 10 5 M 1 from the QCM analysis. Additionally, we suggested that the 600 Da branched PEI binds to the major groove of DNA and the rearrangement of PEI on DNA may be difficult to occur because of the small dissociation rate. The binding analysis presented here can be employed to improve our understanding of the functioning of PEI and PEI-like non-viral vectors.Key words DNA condensation; polyethylenimine; isothermal titration calorimetry; quartz crystal microbalance; thermodynamics; kinetics The cationic polyelectrolyte polyethylenimine (PEI) is one of the most versatile polymers used for non-viral gene delivery.1-3) PEI binds to DNA via electrostatic interactions between the positively charged PEI amine groups and the negatively charged nucleic acid phosphate groups in the DNA backbone. PEI, by neutralizing the DNA molecule, facilitates its condensation into particles in the 'nano-meter' range.4) It is believed that PEI's strong transfection ability is due to its effective ability to condense the DNA molecule into a nanoparticle, 5-7) which facilitates its cellular uptake and subsequent intracellular trafficking. PEI is available in a broad range of molecular weights. Higher molecular weight PEIs have high transfection efficiency, but lead to excessive cytotoxicity. Low molecular weight PEIs have demonstrated low toxicity on cells, but they also display low transfection efficiency.5) Recently, highly efficient non-viral vectors have been developed by modifying low molecular weight (600 Da) PEI with a variety of functional groups. [8][9][10][11][12] To better understand PEI interactions with the DNA molecule, we previously determined the thermodynamic parameters of PEI binding to DNA using isothermal titration calorimetry (ITC). 13) In that study, two types of binding modes were found to describe the interactions between PEI and DNA. One type of binding involves PEI binding to the DNA groove, another likely binding mode involves external binding of PEI to the DNA phosphate backbone. Recently, Ketola et al. showed that the equilibrium constant of 25 kDa branched PEI to plasmid DNA (7164 bp) using time-resolved fluorescence spectroscopy was 7.3×10 ). 13)The observed difference may be due to the difference in the mass and architecture of the PEI u...

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Tuning with Phosphorylcholine Grafts Improves the Physicochemical Properties of PLL/pDNA Nanoparticles at Neutral pH

et al. 2019

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Impact of molecular weight and degree of conjugation on the thermodynamics of DNA complexation and stability of polyethylenimine-graft-poly(ethylene glycol) copolymers

Cited by 14 publications

References 63 publications

Systemic tumor‐targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes

Systemic tumor‐targeted sodium iodide symporter (NIS) gene therapy of hepatocellular carcinoma mediated by B6 peptide polyplexes

Low Molecular Weight Branched PEI Binding to Linear DNA

Tuning with Phosphorylcholine Grafts Improves the Physicochemical Properties of PLL/pDNA Nanoparticles at Neutral pH

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