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

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 per...

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Bibliographic Details
Published in:Angewandte Chemie International Edition 2020-11, Vol.59 (46), p.20405-20410
Main Authors: Yang, Juliang, Dai, Jun, Wang, Quan, Cheng, Yong, Guo, Jingjing, Zhao, Zujin, Hong, Yuning, Lou, Xiaoding, Xia, Fan
Format: Article
Language: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
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Summary: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.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202009196