Improving colloidal stability of silica nanoparticles when stored in responsive gel: application and toxicity study

When silica nanoparticles (SiNP) are stored in aqueous solution, even for few hours, they have a tendency to form agglomerates and therefore adapt inhomogeneous structures. Here we present a very practical method to store SiNP in responsive hydrogel. We have confirmed that SiNP kept in the responsive hydrogel do not undergo through undesirable morphological changes and while in storage they maintain their excellent colloidal stability. The effect of SiNP hollowing (i.e. dissolution of the core of the particles that leaves empty cavity inside) was significantly inhibited in the hydrogel, which is a critical feature for any nano-medical applications (e.g. controlled drug release). To demonstrate the applicability of the hydrogel-storing concept within a biologically relevant context, in this work we have evaluated the toxicological effects of the responsive SiNP-gel formulation in a model <i>in vitro</i> (human cell line U87GM and hemocompatibility using red blood cells) and <i>ex ovo</i> (hen’s egg test) experiments. Particles stored in the gel as well as the pure gel did not affect the hemocompatibility (hemolysis and erythrocyte aggregation) up to a concentration of 100 µg/mL. Furthermore, systemic injections into the blood circulation of the chick area vasculosa confirmed the biocompatibility in a more complex biological environment. All evaluated toxicological values (hemorrhage, thrombosis, vascular lysis, and lethality) were comparable with the negative control, and no differences in toxicological response could be observed between the SiNP stored in hydrogel and the control nanoparticles stored in the solution.

二氧化硅纳米颗粒（silica nanoparticles, SiNP）若仅在水溶液中储存，即便仅数小时，也极易发生团聚并形成非均一结构。本研究提出一种实用策略，可将SiNP储存于响应性水凝胶（responsive hydrogel）中。经证实，储存在该水凝胶内的SiNP不会发生不良形态变化，且储存过程中始终保持优异的胶体稳定性。SiNP空心化（即颗粒内核溶解形成内部空腔）的效应在水凝胶体系中可被显著抑制，这一特性对所有纳米医学应用（如控释药物制剂）而言均至关重要。为验证该水凝胶储存策略在生物学场景中的适用性，本研究针对响应性SiNP-水凝胶制剂开展了两类模型实验：其一为体外（in vitro）实验，涵盖人源细胞系U87GM的相关测试以及基于红细胞的血液相容性评价；其二为卵外（ex ovo）实验，即鸡胚实验。当浓度不超过100 μg/mL时，水凝胶中储存的SiNP以及纯水凝胶均不会对血液相容性（溶血反应与红细胞聚集）产生负面影响。此外，向鸡胚血管区血液循环系统进行系统性注射的实验结果进一步证实，该制剂在更为复杂的生物环境中仍具备良好的生物相容性。所有评估的毒理学指标（出血、血栓形成、血管溶解与致死率）均与阴性对照组无显著差异，且水凝胶储存的SiNP与溶液中储存的对照纳米颗粒之间未观察到任何毒理学反应差异。