Study on the Mechanism and Molecular Design of Targeted Drug Release for a Tetravalent Oxaliplatin Prodrug Modified with Reactive Oxygen Species-Responsive Phenylboronic Ester

Oxaliplatin is the core drug for the first-line chemotherapy of colorectal cancer. It inhibits tumor cell proliferation by forming platinum-DNA adducts, but lacks tumor-targeting selectivity. Long-term use is easy to induce multidrug resistance, which limits its clinical application. The level of reactive oxygen species (ROS) in the tumor microenvironment is significantly higher than that of normal tissue, and this oxidative stress difference provides an ideal endogenous trigger condition for the construction of intelligent response prodrugs. With its axially modifiable site, a tetravalent platinum prodrug can introduce phenylborate ROS-sensitive joints, giving the prodrug microenvironment recognition ability. Based on the molecular design theory of tetravalent platinum prodrugs, this paper systematically sorts out the structural characteristics and response mechanism of phenylborate joints, compares the stability differences of prodrugs in normal low-ROS and tumor high-ROS environments, and deeply explains the oxidative fracture of the phenylborate bond and the targeted activation of active divalent oxaliplatin in situ reduction and release. Process, clarifying the drug-free advantages of "tumor activation and normal tissue passivation" of the system. On this basis, the law of the influence of structural factors such as connecting arm length, hydrophobic modified groups, and other structural factors on the water solubility, circulation stability, and response sensitivity of the prodrug is further summarized. For ROS, the rational molecular design and clinical transformation of responsive platinum prodrugs provide a systematic theoretical reference.