Department of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China.
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, P. R. China.
Sci Rep. 2016 Jul 1;6:28848. doi: 10.1038/srep28848.
Biomacromolecular pKa shifting is considered as one of the most ubiquitous processes in biochemical events, e.g., the enzyme-catalyzed reaction and protein conformational stabilization. In this paper, we report on the construction of biocompatible polysaccharide nanoparticle with targeting ability and lower toxicity by supramolecular pKa shift strategy. This was realized through a ternary assembly constructed by the dual host‒guest interactions of an adamantane-bis(diamine) conjugate (ADA) with cucurbit[6]uril (CB[6]) and a polysaccharide. The potential application of such biocompatible nanostructure was further implemented by the selective transportation of small interfering RNA (siRNA) in a controlled manner. It is demonstrated that the strong encapsulation of the ADA's diammonium tail by CB[6] not only reduced the cytotoxicity of the nano-scaled vehicle but also dramatically enhanced cation density through an obvious positive macrocycle-induced pKa shift, which eventually facilitated the subsequent siRNA binding. With a targeted polysaccharide shell containing a cyclodextrin‒hyaluronic acid conjugate, macrocycle-incorporated siRNA polyplexes were specifically delivered into malignant human prostate PC-3 cells. The supramolecular polysaccharide nanoparticles, the formation of which was enabled and promoted by the complexation-assisted pKa shift, may be used as a versatile tool for controlled capture and release of biofunctional substrates.
生物大分子的 pKa 移动被认为是生化事件中最普遍的过程之一，例如酶催化反应和蛋白质构象稳定。在本文中，我们报告了通过超分子 pKa 移动策略构建具有靶向能力和更低毒性的生物相容性多糖纳米颗粒。这是通过由金刚烷-双（二胺）缀合物（ADA）与葫芦[6]脲（CB[6]）和多糖的双重主体-客体相互作用构建的三元组装来实现的。通过以受控方式选择性输送小干扰 RNA（siRNA），进一步实现了这种生物相容性纳米结构的潜在应用。结果表明，CB[6]对 ADA 的二铵尾的强包封不仅降低了纳米级载体的细胞毒性，而且通过明显的大环诱导的 pKa 移动极大地增强了阳离子密度，从而最终促进了随后的 siRNA 结合。通过含有环糊精-透明质酸缀合物的靶向多糖壳，将包含大环的 siRNA 超分子聚合物特异性递送至恶性人前列腺 PC-3 细胞。超分子多糖纳米颗粒的形成是通过复合物辅助的 pKa 移动来实现和促进的，可作为控制生物功能底物捕获和释放的通用工具。
