State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China.
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, PR China.
J Control Release. 2020 Jan 10;317:109-117. doi: 10.1016/j.jconrel.2019.11.028. Epub 2019 Nov 25.
Subcellular delivery of nanomedicines has emerged as a promising approach to enhance the therapeutic efficacy of anticancer drugs. Nuclear accumulation of anticancer drugs are essential for its therapeutic efficacy because their targets are generally located within the nucleus. However, strategies for the nuclear accumulation of nanomedicines with anticancer drugs rarely reported. In this study, we reported a promising nanomedicine, comprising a drug-peptide amphiphile, with enhanced cellular uptake and nuclear accumulation capability for cancer therapy. The drug-peptide amphiphile consisted of the peptide ligand PMI (TSFAEYWNLLSP), which was capable of activating the p53 gene by binding with the MDM2 and MDMX located in the cell nucleus. Peptide conformations could be finely tuned by using different strategies including heating-cooling and enzyme-instructed self-assembly (EISA) to trigger molecular self-assembly at different temperatures. Due to the different peptide conformations, the drug-peptide amphiphile self-assembled into nanomedicines with various properties, including stabilities, cellular uptake, and nuclear accumulation. The optimized nanomedicine formed by EISA strategy at a low temperature of 4 °C showed enhanced cellular uptake and nuclear accumulation capability, and thus exhibited superior anticancer ability both in vitro and in vivo. Overall, our study provides a useful strategy for finely tuning the properties and activities of peptide-based supramolecular nanomaterials, which may lead to optimized nanomedicines with enhanced performance.
纳米医学的亚细胞递送已成为提高抗癌药物治疗效果的一种有前途的方法。抗癌药物的核积累对于其治疗效果至关重要，因为它们的靶标通常位于细胞核内。然而，将具有抗癌作用的纳米药物递送到细胞核内的策略却很少有报道。在这项研究中，我们报告了一种有前途的纳米药物，由一种药物-肽两亲物组成，具有增强的细胞摄取和核积累能力，可用于癌症治疗。该药物-肽两亲物由肽配体 PMI（TSFAEYWNLLSP）组成，该肽配体能够通过与位于细胞核内的 MDM2 和 MDMX 结合来激活 p53 基因。通过使用不同的策略，包括加热-冷却和酶指导的自组装（EISA），可以精细地调整肽的构象，以在不同的温度下触发分子自组装。由于肽构象的不同，药物-肽两亲物自组装成具有不同性质的纳米药物，包括稳定性、细胞摄取和核积累。通过 EISA 策略在 4°C 的低温下形成的优化纳米药物表现出增强的细胞摄取和核积累能力，因此在体外和体内均表现出优异的抗癌能力。总体而言，我们的研究为精细调整基于肽的超分子纳米材料的性质和活性提供了一种有用的策略，这可能导致具有增强性能的优化纳米药物的出现。
