The Influence of Densely Organized Maltose Shells on the Biological Properties of Poly(propylene imine) Dendrimers: New Effects Dependent on Hydrogen Bonding

Abstract

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.

Differentiating Prion Strains Using Dendrimers

“…[19,20] In contrast to this, a neutral surface charge is present for the dense shell glycodendrimer mPPIg5. [19,20] The structure and molecular weights of the dendrimers used in this study are presented in Figure 1.…”

“…[20,37] PPIg4 and PAMAMg5 have a cationic surface charge, whilst the surface charge of 0.5mPPIg5 is also cationic, but lower in comparison to PPIg5. [19,20] In contrast to this, a neutral surface charge is present for the dense shell glycodendrimer mPPIg5. [19,20] The structure and molecular weights of the dendrimers used in this study are presented in Figure 1.…”

“…A minimum of three repeats was performed. [19,20] (A). Molecular structure of cationic 4 th generation poly(propylene imine) (PPIg4) with the smallest size used in biological experiments (B).…”

“…Dendrimers with cationic surface groups (PPIg4, PAMAMg5 and 0.5mPPIg5) were generally more potent and effective against a wider range of prion strains than mPPIg5, a dendrimer with neutral maltose surface groups (recently demonstrated to possess anti-prion properties due to H-bond driven interactions with PrP res ). [19,20] In fact mPPIg5 only exhibited activity against a single prion strain (RML) and required high concentrations to exhibit this effect (54 and 72µM). The potency of the different cationic dendrimers examined varied, indicating structure and size of dendrimer are important features in determining the efficacy of a dendrimer.…”

Influence of Surface Functionality of Poly(propylene imine) Dendrimers on Protease Resistance and Propagation of the Scrapie Prion Protein

“…PAMAM, PPI and phosphorous dendrimers changed kinetic parameters of aggregation for the prion peptide PrP185-208, such as nucleation and elongation rate and reduced the final amount of amyloid fibrils formed [46][47][48][49] . A generation dependent effect on both the inhibition of fibril aggregation and the disruption of fibrils of the PrP185-208 peptide was observed for PAMAM dendrimers 48 .…”