Institute for Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology , Baldiri Reixac 15-21, 08028 Barcelona, Spain.
Department of Organic Chemistry, School of Chemistry, Faculty of Exact Sciences, Tel-Aviv University , Tel-Aviv 6997801, Israel.
J Am Chem Soc. 2017 Nov 22;139(46):16677-16687. doi: 10.1021/jacs.7b08351. Epub 2017 Nov 8.
The dynamic nature of polymeric assemblies makes their stability in biological media a crucial parameter for their potential use as drug delivery systems in vivo. Therefore, it is essential to study and understand the behavior of self-assembled nanocarriers under conditions that will be encountered in vivo such as extreme dilutions and interactions with blood proteins and cells. Herein, using a combination of fluorescence spectroscopy and microscopy, we studied four amphiphilic PEG-dendron hybrids and their self-assembled micelles in order to determine their structure-stability relations. The high molecular precision of the dendritic block enabled us to systematically tune the hydrophobicity and stability of the assembled micelles. Using micelles that change their fluorescent properties upon disassembly, we observed that serum proteins bind to and interact with the polymeric amphiphiles in both their assembled and monomeric states. These interactions strongly affected the stability and enzymatic degradation of the micelles. Finally, using spectrally resolved confocal imaging, we determined the relations between the stability of the polymeric assemblies in biological media and their cell entry. Our results highlight the important interplay between molecular structure, micellar stability, and cell internalization pathways, pinpointing the high sensitivity of stability-activity relations to minor structural changes and the crucial role that these relations play in designing effective polymeric nanostructures for biomedical applications.
聚合物组装体的动态性质使其在生物介质中的稳定性成为其作为体内药物传递系统潜在用途的关键参数。因此，研究和理解自组装纳米载体在体内遇到的条件下的行为，如极端稀释以及与血液蛋白和细胞的相互作用，是至关重要的。在此，我们使用荧光光谱和显微镜相结合的方法，研究了四种两亲性 PEG-树枝状聚合物杂化物及其自组装胶束，以确定它们的结构-稳定性关系。树枝状块的高分子精度使我们能够系统地调节组装胶束的疏水性和稳定性。使用在组装和单体状态下荧光性质发生变化的胶束，我们观察到血清蛋白与聚合物两亲体结合并相互作用。这些相互作用强烈影响胶束的稳定性和酶降解。最后，我们使用光谱分辨共聚焦成像，确定了生物介质中聚合物组装体的稳定性与其细胞进入之间的关系。我们的结果强调了分子结构、胶束稳定性和细胞内化途径之间的重要相互作用，指出稳定性-活性关系对微小结构变化的高度敏感性以及这些关系在设计用于生物医学应用的有效聚合物纳米结构中的关键作用。
