Maltose-modified poly(propylene imine) (PPI) dendrimers were synthesized by reductive amination of unmodified second- to fifth-generation PPI dendrimers in the presence of excess maltose. The dendrimers were characterized by using (1)H NMR, (13)C NMR, and IR spectroscopies; laser-induced liquid beam ionization/desorption mass spectrometry; dynamic light scattering analyses; and polyelectrolyte titration. Their scaffolds have enhanced molecular rigidity and their outer spheres, at which two maltose units are bonded to the former primary amino groups on the surface, have hydrogen-bond-forming properties. Furthermore, the structural features reveal the presence of a dense shell. Experiments involving encapsulation (1-anilinonaphthalene-8-sulfonic acid) and biological properties (hemolysis and interactions with human serum albumin (HSA) and prion peptide 185-208) were performed to compare the modified with the unmodified dendrimers. These experiments gave the following results: 1) The modified dendrimers entrapped a low-molecular-weight fluorescent dye by means of a dendritic box effect, in contrast to the interfacial uptake characteristic of the unmodified PPI dendrimers. 2) Both low- and high-generation dendrimers containing maltose units showed markedly reduced toxicity. 3) The desirable features of bio-interactions depended on the generation of the dendrimer; they were retained after maltose substitution, but were now mainly governed by nonspecific hydrogen-bonding interactions involving the maltose units. The modified dendrimers interacted with HSA as strongly as the parent compounds and appeared to have potential use as antiprion agents. These improvements will initiate the development of the next platform of glycodendrimers in which apparently contrary properties can be combined, and this will enable, for example, therapeutic products such as more efficient and less toxic antiamyloid agents to be synthesized.
We present a rapid synthetic method for the development of hyperbranched PEIs decorated with different oligosaccharide architectures as carrier systems (CS) for drugs and bioactive molecules for in vitro and in vivo experiments. Reductive amination of hyperbranched PEI with readily available oligosaccharides results in sugar functionalized PEI cores with oligosaccharide shells of different densities. These core-shell architectures were characterized by NMR spectroscopy, elemental analysis, SLS, DLS, IR, and polyelectrolyte titration experiments. ATP complexation of theses polycations was examined by isothermal titration calorimetry to evaluate the binding energy and ATP/CS complexation ratios under physiological conditions. In vitro experiments showed an enhanced cellular uptake of ATP/CS complexes compared to those of the free ATP molecules. The results arise to initiate further noncovalent complexation studies of pharmacologically relevant molecules that may lead to the development of therapeutics based on this polymeric delivery platform.
Accumulation of PrPSc , an insoluble and protease-resistant pathogenic isoform of the cellular prion protein (PrP C ) is a hallmark in prion diseases. Branched polyamines, including PPI (poly(propylene imine)) dendrimers are able to remove protease resistant PrP Sc and abolish infectivity, offering possible applications for therapy. These dendrimer types are thought to act through their positively charged amino surface groups. In the present study the molecular basis of the anti-prion activity of dendrimers was further investigated employing modified PPI dendrimers, in which the positively charged amino surface groups were substituted with neutral carbohydrate units of maltose (mPPI) or maltotriose (m3PPI). Modification of surface groups greatly reduced the toxicity associated with unmodified PPI, but did not abolish its anti-prion activity, suggesting that the presence of cationic surface groups is not essential for dendrimer action. PPI and mPPI dendrimer of generation 5 were equally effective in reducing levels of protease-resistant PrP Sc (PrP res ) in a dose-and time-dependent manner in ScN2a cells, and in preexisting aggregates in homogenates from infected brain. Solubility assays revealed that total levels of PrP Sc in scrapie infected mouse neuroblastoma (ScN2a) cells were reduced by mPPI. Coupled with the known ability of polyamino dendrimers to render protease-resistant PrP Sc in pre-existing aggregates of PrP Sc susceptible to proteolysis, these findings strongly suggest that within infected cells dendrimers reduce total amounts of PrP Sc by mediating its denaturation and subsequent elimination.
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