Self-assembling a natural small molecular inhibitor that shows aggregation-induced emission and potentiates antitumor efficacy,Nanoscale Horizons

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Self-assembling a natural small molecular inhibitor that shows aggregation-induced emission and potentiates antitumor efficacy
Nanoscale Horizons ( IF 8.0 ) Pub Date : 2020-11-02 , DOI: 10.1039/d0nh00469c
Xiaona Chen ₁ , Zhen Hu , Liqian Zhou , Fu Zhang , Jianqin Wan , Hangxiang Wang

Affiliation

Targeted therapy using small molecular inhibitors has been developed to rewire key signaling pathways in tumor cells, but these inhibitors have had mixed success in the clinic due to their poor pharmaceutical properties and suboptimal intratumoral concentrations. Here, we developed a “self-assembling natural molecular inhibitor” strategy to test the efficacy and feasibility of the water-insoluble agent dasatinib (DAS), a tyrosine kinase inhibitor, for cancer therapy. By exploiting a facile reprecipitation protocol, the DAS inhibitor self-assembled into soluble supramolecular nanoparticles (termed sDNPs) in aqueous solution, without an exogenous excipient. This strategy is applicable for generating systemically injectable and colloid-stable therapeutic nanoparticles of hydrophobic small-molecule inhibitors. Concurrently, during this process, we observed aggregation-induced emission (AIE) of fluorescence for this self-assembled DAS, which makes sDNPs suitable for bioimaging and tracing of cellular trafficking. Notably, in an orthotopic model of breast cancer, administration of sDNPs induced a durable inhibition of primary tumors and reduced the metastatic tumor burden, significantly surpassing the effects of the free DAS inhibitor after oral delivery. In addition, low toxicity was observed for this platform, with effective avoidance of immunotoxicity. To the best of our knowledge, our studies provide the first successful demonstration of self-assembling natural molecular inhibitors with AIE and highlight the feasibility of this approach for the preparation of therapeutic nanoparticles for highly lethal human cancers and many other diseases.

中文翻译：

自组装天然小分子抑制剂，显示聚集诱导发射并增强抗肿瘤功效

已经开发出使用小分子抑制剂的靶向治疗来重新连接肿瘤细胞中的关键信号通路，但由于这些抑制剂的药物特性差和肿瘤内浓度欠佳，在临床上取得了不同的成功。在这里，我们开发了一种“自组装天然分子抑制剂”策略来测试水不溶性药物达沙替尼 (DAS)（一种酪氨酸激酶抑制剂）用于癌症治疗的有效性和可行性。通过利用简单的再沉淀方案，DAS 抑制剂自组装成可溶性超分子纳米粒子（称为sDNPs) 水溶液，不含外源性赋形剂。该策略适用于生成疏水性小分子抑制剂的全身可注射且胶体稳定的治疗性纳米粒子。同时，在此过程中，我们观察到这种自组装 DAS 的聚集诱导发射 (AIE) 荧光，这使得sDNPs适用于生物成像和细胞运输追踪。值得注意的是，在乳腺癌的原位模型中，sDNPs 的给药诱导对原发性肿瘤的持久抑制并减少转移性肿瘤负荷，显着超过口服给药后游离 DAS 抑制剂的效果。此外，该平台观察到低毒性，有效避免了免疫毒性。据我们所知，我们的研究首次成功证明了具有 AIE 的自组装天然分子抑制剂，并强调了这种方法用于制备治疗高致死性人类癌症和许多其他疾病的治疗性纳米颗粒的可行性。

更新日期：2020-11-27

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