Tuning Proapoptotic Activity of a Phosphoric‐Acid‐Tethered Tetraphenylethene by Visible‐Light‐Triggered Isomerization and Switchable Protein Interactions for Cancer Therapy

• Published in: Angewandte Chemie 2022-09, Vol.134 (36), p.n/a
• Main Authors: Huang, Yanyan, Zhan, Chi, Yang, Yang, Wang, Lingna, Zhong, Huifei, Yu, Yang, Zhang, Xi‐Sha, Li, Cheng, Jin, Yulong, Zhang, Guanxin, Zhao, Rui, Zhang, Deqing
• Format: Article
• Language: English
• Subjects: Albumin; Albumins; Alkaline phosphatase; Anticancer properties; Apoptosis; Biocompatibility; Biological activity; Cancer therapies; cancer therapy; Chemistry; Internalization; Irradiation; Isomerization; Isomers; Light irradiation; Microenvironments; Modulation; Protein interaction; protein interactions; Proteins; Selectivity; tetraphenylethene derivative
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202208378

We herein report a phosphoric‐acid‐substituted tetraphenylethene (T‐P) capable of adapting its geometric configuration and biological activity to the microenvironment upon light irradiation for apoptosis modulation. Different from most ultraviolet‐responsive isomerization, T‐P undergoes cis‐trans isomerization under visible light irradiation, which is biocompatible and thus photo‐modulation is possible in living biosystems. By using alkaline phosphatase (ALP) and albumin as dual targets, T‐P isomers display different protein binding selectivity, cancer‐cell internalization efficiency and apoptosis‐inducing ability. The proapoptotic activity was found to be kinetically controlled by the enzymatic reaction with ALP and regulated by co‐existing albumin. Motivated by these findings, two‐way modulation of proapoptotic effect and on‐demand boosting anticancer efficacy were realized in vitro and in vivo using light and endogenous proteins as multiple non‐invasive switching stimuli. The visible‐light‐triggered trans‐cis isomerization of a phosphoric‐acid‐substituted tetraphenylethene can be tuned by interaction with albumin. The trans and cis isomers show different interactions toward alkaline phosphatase and albumin, and have different cellular uptake efficiency and proapoptotic activity. Thus, on‐demand activating and deactivating the proapoptotic effect has been achieved in vitro and in vivo by using visible light and proteins as switching elements.