Molecular design and synthesis of self-assembling camptothecin drug amphiphiles
Molecular design and synthesis of self-assembling camptothecin drug amphiphiles
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DOI：
10.1038/aps.2016.151
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发表时间：
2017-06-01
影响因子：
8.2
通讯作者：
Cui, Honggang
中科院分区：
文献类型：
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作者：
Cheetham, Andrew G.;Lin, Yi-an;Cui, Honggang
将小分子疏水抗癌药物偶联到具有整体亲水性的短肽上，以创建自组装的药物两亲体，提供了一种新的前药策略，可以产生具有高定量药物负载的定义良好的离散纳米结构。在这里，我们展示了详细的合成过程，以及分子结构如何影响自组装前体药物的合成及其组装的物理化学性质。采用固溶相结合的方法合成了一系列喜树碱类两亲药物，并利用多种成像和光谱技术对其自组装纳米结构的理化性质进行了研究。我们发现掺入药物分子的数量强烈影响药物两亲体形成的速度，对任何额外的药物施加空间位阻，需要延长反应时间。研究发现，肽序列的选择会影响缀合物的溶解度，进而影响形成的丝状纳米结构的临界聚集浓度和轮廓长度。在自组装药物两亲体的设计中，缀合药物分子的数目和多肽序列的选择对所形成的纳米结构有显著影响。这些观察结果可能允许对特定药物递送应用的物理化学性质进行微调，即系统递送与局部递送。
The conjugation of small molecular hydrophobic anticancer drugs onto a short peptide with overall hydrophilicity to create self-assembling drug amphiphiles offers a new prodrug strategy, producing well-defined, discrete nanostructures with a high and quantitative drug loading. Here we show the detailed synthesis procedure and how the molecular structure can influence the synthesis of the self-assembling prodrugs and the physicochemical properties of their assemblies. A series of camptothecin-based drug amphiphiles were synthesized via combined solid-and solution-phase synthetic techniques, and the physicochemical properties of their self-assembled nanostructures were probed using a number of imaging and spectroscopic techniques. We found that the number of incorporated drug molecules strongly influences the rate at which the drug amphiphiles are formed, exerting a steric hindrance toward any additional drugs to be conjugated and necessitating extended reaction time. The choice of peptide sequence was found to affect the solubility of the conjugates and, by extension, the critical aggregation concentration and contour length of the filamentous nanostructures formed. In the design of self-assembling drug amphiphiles, the number of conjugated drug molecules and the choice of peptide sequence have significant effects on the nanostructures formed. These observations may allow the fine-tuning of the physicochemical properties for specific drug delivery applications, ie systemic vs local delivery.