Department of Chemistry, China Pharmaceutical University, Nanjing, P. R. China.
Department of Chemistry, China Pharmaceutical University, Nanjing, P. R. China and Key Laboratory of Biomedical Functional Materials, China Pharmaceutical University, Nanjing, P. R. China.
Nanoscale. 2021 Mar 12;13(9):5094-5102. doi: 10.1039/d0nr08741f.
Tyroservatide (YSV) belongs to a class of bioactive peptides that have drawn considerable attention in the field of drug discovery, yet it displays limited potency and often requires a millimolar concentration to execute its cellular functions. To enhance the potency of the drug through a self-assembling strategy, we designed and synthesized a series of octapeptides through conjugation of YSV with a pentapeptide sequence bearing alternating hydrophobic and hydrophilic amino acids to promote their self-assembling capabilities. Initial screening for hydrogelation gave a novel octapeptide (denoted as 1-YSV hereafter) that was capable of self-assembling under physiological conditions to afford supramolecular nanofibers with enhanced anti-cancer efficacy compared to YSV itself. Interestingly, 1-YSV formed a robust co-assembly with the anticancer drug hydroxycamptothecin (HCPT) to afford 1-YSV/HCPT hydrogel, which not only greatly improved the viscoelastic properties of hydrogels, but also stabilized HCPT in the hydrogel matrix and avoided the agglomeration of drug molecules. Compared to HCPT solution, the hydrogel formulation of 1-YSV/HCPT demonstrated better efficacy against the proliferation of non-small cell lung cancer A549 cells both in vitro and in vivo. Finally, thanks to the pure amino acid-based composition, the 1-YSV/HCPT formulation exhibited excellent biocompatibility, giving a low hemolytic rate to red blood cells, with mild local tissue reactions and negligible systematic toxicities in mice.
酪丝亮肽（YSV）属于生物活性肽类，在药物研发领域引起了广泛关注，但它的活性有限，通常需要毫摩尔浓度才能发挥其细胞功能。为了通过自组装策略提高药物的效力，我们通过将 YSV 与一个带有交替疏水和亲水氨基酸的五肽序列缀合，设计并合成了一系列八肽，以促进它们的自组装能力。初步筛选出一种能够在生理条件下自组装的新型八肽（以下简称 1-YSV），与 YSV 本身相比，它能够形成超分子纳米纤维，具有增强的抗癌功效。有趣的是，1-YSV 与抗癌药物羟基喜树碱（HCPT）形成了坚固的共组装体，形成 1-YSV/HCPT 水凝胶，不仅极大地提高了水凝胶的粘弹性，而且还稳定了 HCPT 在水凝胶基质中，避免了药物分子的聚集。与 HCPT 溶液相比，1-YSV/HCPT 的水凝胶制剂在体外和体内对非小细胞肺癌 A549 细胞的增殖均显示出更好的疗效。最后，由于 1-YSV/HCPT 制剂基于纯氨基酸组成，因此具有出色的生物相容性，对红细胞的溶血率低，在小鼠中具有轻微的局部组织反应和可忽略不计的系统毒性。
