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In this study, we investigated galacturonic (GalAc)- and mannuronic (ManAc) acids as novel targeting ligands for receptor-mediated gene delivery. GalAc and ManAc were coupled to either polyethyleneimine (PEI) or PEIpolyethyleneglycol (PEG). Furthermore, lactobionic acid (LacAc), which comprises a GalAc-related carbohydrate ring, was coupled to each of the polymers through its open-chain gluconic acid moiety. The molar mass distributions of the polymers were characterized by analytical ultracentrifugation and size exclusion chromatography. PEI-conjugatepDNA complexes were transfected into HepG2-, HeLa-, and 16HBE14o--cells. Gene expression mediated by GalAc- and LacAc-functionalized PEI-conjugates was lower than for PEI. In contrast, gene expression mediated by ManAc-functionalized PEI-conjugates was up to three orders of magnitude higher than for the other tested PEI-conjugates, in particular for negatively charged gene vectors at low N/P ratios, independent of the cell line. Pre-incubation of cells with an excess of ManAc before transfection significantly inhibited transfection rates only for ManAc-functionalized PEI-conjugates. Coupling of methyl-α-D-mannuronic acid to PEI resulted in significantly lower transfection rates than for ManAc-PEI based complexes. Together with fluorescence microscopy images of fluorescein-labelled ManAc-functionalized dextrans and FACS analyses of cells, these results demonstrate that receptor-mediated endocytosis of ManAcPEI-conjugatepDNA complexes via ManAc-specific receptors was involved in gene transfer. In conclusion, ManAc-modification of PEI-polymers represents a novel strategy for receptor-mediated gene delivery which could be promising for in vivo application.
Synthesis of terpene-poly(ethylene oxide)s by t-BuP4-promoted anionic ring-opening polymerization
(2012)
Terpene alcohols (menthol, retinol, cholesterol, and betulin) together with the phosphazene base t-BuP4 were used as initiating systems for anionic ring-opening polymerization of ethylene oxide. The polymerizations were conducted in a controlled manner with the initial molar ratio of t-BuP4 to hydroxyl groups of 0.01–0.2, yielding a series of biohybrid polymers comprising terpene entities and poly(ethylene oxide) (PEO) chains with low polydispersities and tunable compositions (57–87 wt% of PEO). Samples were characterized by NMR and UV/visible spectroscopy, MALDI-TOF mass spectrometry, and size exclusion chromatography; thermal properties were studied by differential scanning calorimetry. The concept of this study opens a new toolbox of terpene-based biohybrid polymers with variable properties and functions.