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Polyplexes shielding

Fella C, Walker GF, Ogris M, Wagner E (2008) Amine-reactive pyridylhydrazone-based PEG reagents for pH-reversible PEI polyplex shielding. Eur J Pharm Sci 34 309-320... [Pg.22]

Bioresponsive Polyplex Shielding and Endosomal Escape 3.1 Reversible Polyplex Shielding... [Pg.231]

Several of these problems can be solved by polyplex modification with polyethylene glycol (PEG). PEGylation has been broadly explored for surface shielding ( stealthing ) of many liposomal and nanoparticulate carriers. In the case of cationic polymers, Plank et al. [62] demonstrated that complement activation can be reduced when the polymers are PEGylated. Such a modification can be... [Pg.4]

Shielded polyplexes with improved blood circulating properties are interesting tools for systemic cancer therapy (see Sect. 4.2). Nanoparticles can take advantage of the enhanced permeability and retention (EPR effect) [89] for passive tumor targeting. The EPR effect is based on the leakiness of tumor vasculature, due to neovascularization in growing tumors, combined with an inadequate lymphatic drainage. Nanoparticles with an elongated plasma circulation time can extravasate and passively accumulate at the tumor site. [Pg.5]

Polyplex surface shielding solves several crucial problems, but may also create new problems. Shielding can strongly reduce the efficiency of subsequent cellular steps of the delivery process [68, 69], and also can negatively alter other polyplex characteristics. For pDNA/PEI polyplexes with optimum medium size of PEI, PEG was found to reduce the polyplex stability in vivo [64, 65, 81]. For a discussion of these aspects see Sect. 3.1. [Pg.5]

A highly stable and shielded polyplex should circulate in the blood stream without undesired interactions until it reaches the target cell. At that location, specific interactions with the cell surface should trigger intracellular uptake. While lipid membrane interaction is undesired at the cell surface, it should happen subsequently within the endosomal vesicle and mediate polyplex delivery into the cytosol. During or after intracellular transport to the site of action, the polyplex stability should be weakened to an extent that the nucleic acid is accessible to exert its function. [Pg.10]

The following sections discuss how polymers and polyplexes can be chemically designed to be bioresponsive in three key delivery functions (1) polyplex surface shielding, (2) interaction with lipid bilayers, and (3) polyplex stability. [Pg.10]

Fig. 1 Bioresponsive polyplexes. (a) Systemic circulation of shielded polyplexes in blood stream and attachment to cell surface receptor (b) endocytosis into endosomes, deshielding by cleavage of PEG linkers and activation of membrane-destabilizing component by acidic pH or other means (c) endosomal escape into cytosol (d) siRNA transfer to form a cytosolic RNA-induced silencing complex complex (e) cytosolic migration and intranuclear import of pDNA (/) presentation of pDNA in accessible form to the transcription machinery... Fig. 1 Bioresponsive polyplexes. (a) Systemic circulation of shielded polyplexes in blood stream and attachment to cell surface receptor (b) endocytosis into endosomes, deshielding by cleavage of PEG linkers and activation of membrane-destabilizing component by acidic pH or other means (c) endosomal escape into cytosol (d) siRNA transfer to form a cytosolic RNA-induced silencing complex complex (e) cytosolic migration and intranuclear import of pDNA (/) presentation of pDNA in accessible form to the transcription machinery...
A different pH-triggered deshielding concept with hydrophilic polymers is based on reversing noncovalent electrostatic bonds [78, 195, 197]. For example, a pH-responsive sulfonamide/PEl system was developed for tumor-specific pDNA delivery [195]. At pH 7.4, the pH-sensitive diblock copolymer, poly(methacryloyl sulfadimethoxine) (PSD)-hZocA -PEG (PSD-b-PEG), binds to DNA/PEI polyplexes and shields against cell interaction. At pH 6.6 (such as in a hypoxic extracellular tumor environment or in endosomes), PSD-b-PEG becomes uncharged due to sulfonamide protonation and detaches from the nanoparticles, permitting PEI to interact with cells. In this fashion PSD-b-PEG is able to discern the small difference in pH between normal and tumor tissues. [Pg.12]

Various researchers have applied the receptor-targeted strategy in pharmacological models for tumor-targeted delivery of pDNA expressing tumor necrosis factor alpha (TNFa). For example, Tf- or Tf-PEG-shielded PEI polyplexes have been used... [Pg.16]

Tf-containing PEG-shielded polyplexes have also been applied for systemic tumor-targeted delivery of siRNA [106-108]. Systemic treatment of Neuro 2A tumorbearing mice using Tf-PEG-shielded crosslinked oligoethylenimines for delivery of siRNA against Ras-related nuclear protein (Ran) led to >80% reduced Ran protein expression, associated with tumor apoptosis and reduced tumor growth [108]. [Pg.17]

Homof M, de la FM, Hallikainen M, Tammi RH, Urtti A (2008) Low molecular weight hyaluronan shielding of DNA/PEI polyplexes facilitates CD44 receptor mediated uptake in human corneal epithelial cells. J Gene Med 10 70-80... [Pg.23]

Tietze N, Pelisek J, Philipp A, Roedl W, Merdan T, Tarcha P, Ogris M, Wagner E (2008) Induction of apoptosis in murine neuroblastoma by systemic delivery of transferrin-shielded siRNA polyplexes for downregulation of Ran. Oligonucleotides 18 161-174... [Pg.24]

Knorr V, Allmendinger L, Walker GF, Paintner FF, Wagner E (2007) An acetal-based PEGylation reagent for pH-sensitive shielding of DNA polyplexes. Bioconjug Chem 18 1218-1225... [Pg.28]

Fig. 1 Targeting and reversible shielding. Incorporation of targeting ligands enhances cellular uptake due to receptor-mediated endocytosis. Reversibly attached shielding moieties protect the polyplex during blood passage the pH-sensitive bonds are cleaved in the endosome upon acidification, setting free the positively charged polymer for further activity... Fig. 1 Targeting and reversible shielding. Incorporation of targeting ligands enhances cellular uptake due to receptor-mediated endocytosis. Reversibly attached shielding moieties protect the polyplex during blood passage the pH-sensitive bonds are cleaved in the endosome upon acidification, setting free the positively charged polymer for further activity...
Gersdorff von K (2006) PEG-Shielded and EGF receptor-targeted DNA polyplexes Cellular mechanisms. PhD Thesis, Ludwig Maximilian University, Mimich, Germany, Supervisor Prof. Dr. E. Wagner, p 125 http // edoc.ub.imi-muenchen.de/5485/... [Pg.524]


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See also in sourсe #XX -- [ Pg.231 ]




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