Tandem Coordination, Ring-Opening, Hyperbranched Polymerization for the Synthesis of Water-Soluble Core-Shell Unimolecular Transporters.

A water-soluble molecular transporter with a dendritic core-shell nanostructure has been prepared by a tandem coordination, ring-opening, hyperbranched polymerization process. Consisting of hydrophilic hyperbranched polyglycerol shell grafted from hydrophobic dendritic polyethylene core, the transporter has a molecular weight of 951 kg/mol and a hydrodynamic diameter of 17.5 ± 0.9 nm, as determined by static and dynamic light scattering, respectively. Based on evidence from fluorescence spectroscopy, light scattering, and electron microscopy, the core-shell copolymer transports the hydrophobic guests pyrene and Nile red by a unimolecular transport mechanism. Furthermore, it was shown that the core-shell copolymer effectively transports the hydrophobic dye Nile red into living cells under extremely high and biologically relevant dilution conditions, which is in sharp contrast to a small molecule amphiphile. These results suggest potential applicability of such core-shell molecular transporters in the administration of poorly water-soluble drugs.

Size-dependant cellular uptake of dendritic polyglycerol.

To study the mechanism of cellular internalization, hyperbranched polyether derivatives consisting of amino-bearing hyperbranched polyglycerols (HPGs) of varied molecular mass and size range are designed and synthesized. HPGs were further fluorescently labelled by conjugating maleimido indocarbocyanine dye (ICC-mal). The conjugates are characterized by UV-vis spectroscopy, fluorescence profile, zeta potential, and dynamic light scattering. The uptake mechanism is studied by fluorescence-activated cell sorting (FACS) analysis, fluorescence spectroscopy, and confocal microscopy with human lung cancer cells A549, human epidermoid carcinoma cells A431, and human umbilical vein endothelial cells (HUVEC) cells. For the first time, the results suggest that the higher-molecular-weight HPGs (40-870 kDa) predominantly accumulate in the cytoplasm much better than their low-molecular-weight counterparts (2-20 kDa). The HPG nanocarriers discussed here have many biomedical implications, particularly for delivering drugs to the targeted site.

The inhibitor of growth 1 (ING1) proteins suppress angiogenesis and differentially regulate angiopoietin expression in glioblastoma cells.

The inhibitor of growth 1 (ING1) homologue ING4 has previously been implicated as a negative regulator of angiogenesis in a murine glioma and a multiple myeloma model. An association between ING1 and angiogenesis has not been reported yet. Our previous studies using tumor samples from patients have shown that ING1 levels are downregulated in glioblastoma multiforme (GBM), one of the most highly vascularized malignancies. Based on this background, the goal of this study was to test the effects of the major ING1 splicing isoforms, p47ING1a and p33ING1b, on pathological angiogenesis induced by human GBM cells. We used a chorioallantoic membrane (CAM) assay to examine whether LN229 human GBM cells can induce angiogenesis and whether alterations in ING1 expression, such as ING1 knockdown by siRNA or ectopic ING1 overexpression using ING1a and ING1b expression constructs, can affect this process. Increased ING1 protein expression significantly suppressed LN229 cell-induced angiogenesis in the CAM assay. While no effects on the proangiogenic factors VEGF or IL-8 were noted, the expression of angiopoietins (Ang) 1 and 4 were increased by the p47ING1a, but not by the p33ING1b isoform. Levels of Ang-2 were not sensitive to altered ING1 levels. Our data are the first to suggest that ING1 proteins suppress neoangiogenesis in GBM. Moreover, our results may support the idea that ING1 proteins regulate the expression of proteins that are critical for angiogenesis in GBM such as the angiopoietins.