Klajnert Barbara, Appelhans Dietmar, Komber Hartmut, Morgner Nina, Schwarz Simona, Richter Sven, Brutschy Bernhard, Ionov Maksim, Tonkikh Anatoly K, Bryszewska Maria, Voit Brigitte
Department of General Biophysics, University of Lodz, 12/16 Banacha Street, Lodz, Poland.
Chemistry. 2008;14(23):7030-41. doi: 10.1002/chem.200800342.
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.
麦芽糖修饰的聚（丙烯亚胺）（PPI）树枝状大分子是通过在过量麦芽糖存在下对未修饰的第二代至第五代PPI树枝状大分子进行还原胺化反应合成的。通过使用（1）H NMR、（13）C NMR和红外光谱对树枝状大分子进行了表征；激光诱导液束电离/解吸质谱；动态光散射分析；以及聚电解质滴定。它们的支架具有增强的分子刚性，并且其外层球体（两个麦芽糖单元与表面上以前的伯氨基键合）具有形成氢键的特性。此外，结构特征揭示了存在致密壳层。进行了涉及包封（1-苯胺基萘-8-磺酸）和生物学性质（溶血以及与人血清白蛋白（HSA）和朊病毒肽185-208的相互作用）的实验，以比较修饰后的树枝状大分子与未修饰的树枝状大分子。这些实验得到了以下结果：（1）与未修饰的PPI树枝状大分子的界面摄取特性相反，修饰后的树枝状大分子通过树枝状盒效应捕获了一种低分子量荧光染料。（2）含有麦芽糖单元的低代和高代树枝状大分子均显示出明显降低的毒性。（3）生物相互作用的理想特征取决于树枝状大分子的代数；它们在麦芽糖取代后得以保留，但现在主要由涉及麦芽糖单元的非特异性氢键氢键相互作用所支配。修饰后的树枝状大分子与HSA的相互作用与母体化合物一样强烈，并且似乎具有作为抗朊病毒剂的潜在用途。这些改进将启动下一个糖树枝状大分子平台的开发，在该平台中可以将明显相反的性质结合起来，这将使得例如能够合成更高效、毒性更小的抗淀粉样蛋白药物等治疗产品。
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