Hypoxia-Initiated Supramolecular Free Radicals Induce Intracellular Polymerization for Precision Tumor Therapy
Mian Tang, Zhiqing Yang, Xingchen Tang, He Ma, Beibei Xie, Jiang‐Fei Xu, Gao Cheng, David Bardelang, Ruibing Wang
Abstract
Despite the development of various controlled release systems for antitumor therapies, off-target side effects remain a persistent challenge. In situ therapeutic synthesis from biocompatible substances offers a safer and more precise alternative. This study presents a hypoxia-initiated supramolecular free radical system capable of inducing intracellular polymerization, thereby disrupting the cytoskeleton and organelles within 4T1 cells. The system utilizes a 2:1 supramolecular host-guest complex of cucurbit[7]uril (CB[7]) and perylene diimide derivative (PDI), termed PDI+2CB[7], which is selectively reduced by the tumor's hypoxic and reducing environment to generate delocalized free radical anions. CB[7] effectively stabilizes these anions, enabling the PDI+2CB[7] complex to initiate free radical polymerization with 2-hydroxyethyl methacrylate (HEMA) inside the 4T1 cells. The resulting in situ polymerization significantly disrupts tumor metabolism, leading to a strong antitumor response without systemic toxicity. This study demonstrates that stable, endogenous stimulus-induced supramolecular free radicals can trigger intracellular polymerization reactions, achieving a selective and effective antitumor therapy without conventional chemotherapeutic agents.