Degradable Drug Carriers: Vanishing Mesoporous Silica Nanoparticles
Degradable Drug Carriers: Vanishing Mesoporous Silica Nanoparticles
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DOI：
10.1021/acs.chemmater.9b00221
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发表时间：
2019-06-25
影响因子：
8.6
通讯作者：
Bein, Thomas
中科院分区：
文献类型：
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作者：
Moeller, Karin;Bein, Thomas
介孔二氧化硅纳米颗粒（MSNs）作为细胞毒性或化学敏感（大）分子的药物递送剂的多功能潜力已在许多体外和体内研究中得到证实。尽管如此，由于几个原因，将MSN转化为临床应用似乎仍然很困难-一个突出的问题是这些纳米颗粒在体内命运的不确定性。药物载体的可降解性是避免在生命系统中应用时的潜在有害影响的先决条件。此外，及时降解甚至可以通过有效的药物释放来增强医疗功效。因此，了解药物载体系统的稳定性以及可能影响其降解过程的参数对于开发最佳载体设计非常有价值。因此，MSNs的水解稳定性/降解预期是关于介孔二氧化硅的潜在医学应用的关键特征。到目前为止，解决MSN的水解或生物降解性的结论性研究是有限的，现有的数据有时似乎是矛盾的。在这里，我们进行了一个全面的评价，比较了一些不同的MSN的生物医学相关的条件下，通过使用低颗粒浓度的降解性。我们在酸性、中性或碱性pH下合成了MSNs。在碱性pH下的MSNs被制备为纯二氧化硅MSNs和含有官能氨基和巯基以及含有额外的氧化还原敏感性二硫化物实体的混合MSNs，所有这些都通过共缩合进行整合。这些样品按照通用配方合成，即使在改变粒度时也是如此，以最大限度地减少颗粒制备对溶出动力学的影响。在不同的缓冲液中，在短时间和长时间的暴露时间内，使用原始颗粒或装饰有各种常用的表面附着物的MSN监测降解过程。通过电感耦合等离子体发射光谱法对降解过程进行定量评估，并辅以透射电子显微镜以及紫外-可见光谱和FTIR光谱。交叉极化和直接极化的Si-29固态NMR被用来识别二氧化硅网络中的连接性差异。我们发现，在低浓度下的溶解速率主要取决于（i）二氧化硅网络连接，由合成pH值和共缩合，和（ii）二氧化硅结构单元。因此，在碱性条件下制备的具有“中断”网络的共缩合MSN在几小时内降解最快且几乎完全，与粒度无关，而孔壁中的额外二硫键连接体延迟该过程。这是强烈对比的纯硅质MSNs的行为，这是非常稳定的酸性条件下，但在较高的pH值时，显示出增加的降解性。因此，在这项研究中，我们证明了介孔二氧化硅纳米粒子的水稳定性可以广泛地调整从几乎完全到几乎没有降解性在医学相关的条件下。这些结果建立了一套新的设计规则的多功能MSN的适应所需的场景中的靶向药物输送的要求。
The versatile potential of mesoporous silica nanoparticles (MSNs) as drug delivery agents for cytotoxic or chemically sensitive (macro)molecules has been demonstrated in numerous in vitro and in vivo studies. Nevertheless, translation of MSNs into clinical applications still appears to be difficult for several reasons-one prominent concern being the uncertainty about the fate of these nanoparticles in the body. The degradability of drug carriers is a prerequisite for avoiding potentially hazardous effects upon application in living systems. Furthermore, a timely degradation might even enhance medical efficacy through efficient drug release. Knowledge about the stability of drug carrier systems and about the parameters that might influence their degradation process is therefore very valuable for developing optimal carrier designs. Hence, the hydrolytic stability/degradation of MSNs is expected to be a key feature regarding potential medical applications of mesoporous silica. So far, conclusive studies addressing the hydrolytic or biodegradability of MSNs are limited and the available data sometimes appear to be contradictory. Here, we performed a comprehensive evaluation comparing the degradability of a number of different MSNs under biomedically relevant conditions by using low particle concentrations. We synthesized MSNs at acidic, neutral, or basic pH. MSNs at basic pH were prepared as pure silica MSNs and as hybrid MSNs containing functional amino and mercapto groups as well as containing additional redox-sensitive disulfide entities, all integrated via co-condensation. These samples were synthesized following a common recipe, even when changing the particle size, in order to minimize the influence of particle preparation on the dissolution kinetics. The degradation process was monitored in different buffers over short and long exposure times using pristine particles or MSNs decorated with a variety of frequently used surface attachments. The quantitative assessment of the degradation process by inductively coupled plasma-optical emission spectrometry was complemented with transmission electron microscopy as well as UV-vis and FTIR spectroscopy. Cross-polarized and directly polarized Si-29 solid-state NMR was applied to identify differences in connectivity in the silica network. We find that the dissolution rate at low concentrations is predominantly governed by (i) the silica network connectivity, determined by the synthesis pH and co-condensation, and (ii) the silica building blocks. Thus, co-condensed MSNs with "interrupted" networks made under basic conditions degrade fastest and nearly completely within a few hours independent of particle size, while additional disulfide linkers in the pore walls retard this process. This is strongly contrasted by the behavior of purely siliceous MSNs, which are very stable when made under acidic conditions but show increasing degradability when made at higher pH. Hence, in this study, we demonstrate that the aqueous stability of mesoporous silica nanoparticles can be widely tuned from almost complete to nearly no degradability under medically relevant conditions. These results establish a new set of design rules for the adaptation of multifunctional MSNs to the requirements of desired scenarios in targeted drug delivery.