Design and evaluation of nanoscale materials with programmed responsivity towards epigenetic enzymes
Design and evaluation of nanoscale materials with programmed responsivity towards epigenetic enzymes
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DOI：
10.1039/d4tb00514g
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发表时间：
2024-07-02
影响因子：
7
通讯作者：
Quadir，Mohiuddin
中科院分区：
文献类型：
--
作者：
Ray，Priyanka;Sedigh，Abbas;Quadir，Mohiuddin
能够响应特定酶调节其组装特性的自组装材料在推进生物技术应用的“智能”封装平台方面发挥着关键作用。在这里，我们介绍了一类以前未报道的合成纳米材料，它们以编程方式与组蛋白脱乙酰酶 (HDAC) 相互作用，作为分解的触发刺激。这些纳米材料由包含聚(乙酰基L-赖氨酸)和聚(乙二醇)嵌段的共聚肽组成。在中性pH条件下，它们自组装成颗粒。颗粒的流体动力学直径通常在 108-190 nm 范围内，具体取决于疏水嵌段的乙酰化程度。然而，它们的稳定性在暴露于 HDAC 后会受到损害，具体取决于酶浓度和暴露时间。我们的研究利用 HDAC8 作为模型酶，揭示了分解背后的主要机制涉及由于颗粒疏水域内赖氨酸残基的脱乙酰化而导致嵌段共聚物内两亲性的降低。为了阐明响应机制，我们将荧光染料封装在这些纳米颗粒内。与 HDAC 一起孵育后，纳米颗粒结构崩溃，导致染料随着时间的推移而受控释放。值得注意的是，这种释放不是由变性的 HDAC8、其他蛋白水解酶（如胰蛋白酶）或 HDAC8 及其抑制剂的共存触发的。我们还展示了这些材料在不同类型抗癌细胞系（例如 MIA PaCa-2、PANC-1、癌样干细胞 (CSC) 和非癌 HPNE 细胞）中药物递送的生物相容性和细胞效应。我们观察到模型药物（例如 STAT3 通路抑制剂 Napabucasin）的释放可以加载到这些纳米颗粒中，在 HDAC8 酶的影响下以受控方式在 3 小时内释放超过 90% 的剂量。此外，我们进行了全面的计算研究，以揭示酶和颗粒之间可能的相互作用机制。通过与天然存在的组蛋白的机制进行比较，这项研究代表了开发能够利用 HDAC 等表观遗传酶活性的功能材料的开创性一步。
Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly(acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. The hydrodynamic diameters of particles were typically withing the range of 108–190 nm, depending on degree of acetylation of the hydrophobic block. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles' hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We also demonstrated the biocompatibility and cellular effects of these materials in the context of drug delivery in different types of anticancer cell lines, such as MIA PaCa-2, PANC-1, cancer like stem cells (CSCs), and non-cancerous HPNE cells. We observed that the release of a model drug (such as a STAT3 pathway inhibitor, Napabucasin) can be loaded into these nanoparticles, with >90% of the dosage can be released over 3 h under the influence of HDAC8 enzyme in a controlled fashion. Further, we conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.