Tumor‐Triggered Disassembly of a Multiple‐Agent‐Therapy Probe for Efficient Cellular Internalization

• Published in: Angewandte Chemie International Edition Vol. 59; no. 46; pp. 20405 - 20410
• Main Authors: Yang, Juliang, Dai, Jun, Wang, Quan, Cheng, Yong, Guo, Jingjing, Zhao, Zujin, Hong, Yuning, Lou, Xiaoding, Xia, Fan
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 09.11.2020
• Edition: International ed. in English
• Subjects: Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Caveolae; caveolae-mediated endocytosis; Chemical compounds; Endocytosis; Endocytosis - drug effects; Humans; Internalization; macropinocytosis; Molecular Probes - chemistry; multiple-agent-therapy probes; Nanofibers; nanofibers/gene/ROS; Neoplasms - pathology; Neoplasms - therapy; Optimization; peptide-conjugated-AIEgens; Pharmacology; Physicochemical properties; RNA, Small Interfering - administration & dosage; siRNA; Tumor cells; Tumors; caveolae-mediated endocytosis; macropinocytosis; nanofibers/gene/ROS; multiple-agent-therapy probes; peptide-conjugated-AIEgens
• DOI: 10.1002/anie.202009196
• ISSN: 1433-7851

Integration of multiple agent therapy (MAT) into one probe is promising for improving therapeutic efficiency for cancer treatment. However, MAT probe, if entering the cell as a whole, may not be optimal for each therapeutic agent (with different physicochemical properties), to achieve their best performance, hindering strategy optimization. A peptide‐conjugated‐AIEgen (FC‐PyTPA) is presented: upon loading with siRNA, it self‐assembles into FCsiRNA‐PyTPA. When approaching the region near tumor cells, FCsiRNA‐PyTPA responds to extracellular MMP‐2 and is cleaved into FCsiRNA and PyTPA. The former enters cells mainly by macropinocytosis and the latter is internalized into cells mainly through caveolae‐mediated endocytosis. This two‐part strategy greatly improves the internalization efficiency of each individual therapeutic agent. Inside the cell, self‐assembly of nanofiber precursor F, gene interference of CsiRNA, and ROS production of PyTPA are activated to inhibit tumor growth. A multiple‐agent‐therapy probe based on a peptide‐conjugated‐AIEgen was developed with extracellular MMP‐2 and intracellular CB response. When approaching tumor cells, it can be separated into different agents, which then enter the tumor cells by their dominant pathway with high cellular internalization efficiency and effective multimodal cancer therapy.