Department of Fibre and Polymer Technology, KTH Royal Institute of Technology , Teknikringen 56-68, 100 44, Stockholm, Sweden.
Department of Neurobiology, Care Sciences and Society, Section of Neurodegeneration, Center for Alzheimer Research, Karolinska Institutet , Blickagången 6, SE-141 57 Huddinge, Sweden.
Biomacromolecules. 2017 Dec 11;18(12):4323-4330. doi: 10.1021/acs.biomac.7b01364. Epub 2017 Nov 22.
Amine functional polymers, especially cationically charged, are interesting biomacromolecules for several reasons, including easy cell membrane entrance, their ability to escape endosomes through the proton sponge effect, spontaneous complexation and delivery of drugs and siRNA, and simple functionalization in aqueous solutions. Dendrimers, a subclass of precision polymers, are monodisperse and exhibit a large and exact number of peripheral end groups in relation to their size and have shown promise in drug delivery, biomedical imaging and as antiviral agents. In this work, hydroxyl functional dendrimers of generation 1 to 5 based on 2,2-bis(methylol)propionic acid (bis-MPA) were modified to bear 6 to 96 peripheral amino groups through esterification reactions with beta-alanine. All dendrimers were isolated in high yields and with remarkable monodispersity. This was successfully accomplished utilizing the present advantages of fluoride-promoted esterification (FPE) with imidazole-activated monomers. Straightforward postfunctionalization was conducted on a second generation amino-functional dendrimer with tetraethylene glycol through NHS-amidation and carbonyl diimidazole (CDI) activation to full conversion with short reaction times. Fast biodegradation of the dendrimers through loss of peripheral beta-alanine groups was observed and generational- and dose-dependent cytotoxicity was evaluated with a set of cell lines. An increase in neurotoxicity compared to hydroxyl-functional dendrimers was shown in neuronal cells, however, the dendrimers were slightly less neurotoxic than commercially available poly(amidoamine) dendrimers (PAMAMs). Additionally, their effect on bacteria was evaluated and the second generation dendrimer was found unique inhibiting the growth of Escherichia coli at physiological conditions while being nontoxic toward human cells. Finally, these results cement a robust and sustainable synthetic route to amino-functional polyester dendrimers with interesting chemical and biological properties.
胺基功能聚合物，特别是带正电荷的聚合物，由于以下几个原因而成为有趣的生物大分子，包括易于进入细胞膜、通过质子海绵效应从内涵体中逃脱、自发地将药物和 siRNA 进行复合和传递，以及在水溶液中简单地进行功能化。树状大分子是一类精确聚合物的子类，具有单分散性，并在与其大小相关的大而精确数量的外围末端基团方面表现出优势，并且在药物传递、生物医学成像和作为抗病毒剂方面显示出了潜力。在这项工作中，基于 2,2-双（羟甲基）丙酸（bis-MPA）的 1 至 5 代羟基功能树状大分子通过与 β-丙氨酸的酯化反应被修饰为带有 6 至 96 个外围氨基。所有树状大分子都以高产率和显著的单分散性被分离出来。这是通过利用氟化物促进酯化（FPE）与咪唑活化单体的现有优势来成功实现的。通过 NHS-酰胺化和羰基二咪唑（CDI）活化，对第二代氨基功能树状大分子进行了简单的后功能化，在短反应时间内完全转化。通过外围 β-丙氨酸基团的丢失观察到树状大分子的快速生物降解，并通过一系列细胞系评估了代际和剂量依赖性细胞毒性。与羟基功能树状大分子相比，神经元细胞中的神经毒性增加，但与市售的聚（酰胺-胺）树状大分子（PAMAMs）相比，树状大分子的神经毒性略低。此外，还评估了它们对细菌的影响，发现第二代树状大分子在生理条件下独特地抑制大肠杆菌的生长，而对人类细胞无毒。最后，这些结果为具有有趣的化学和生物学性质的氨基功能聚酯树状大分子提供了一种稳健且可持续的合成途径。
