Facile Synthesis of Thioketal-Functionalized Poly(amino acid) Nanocarriers for ROS-Triggered Drug Release in Cancer Therapy

Polymer nanocarriers offer significant advantages in antitumor drug delivery; however, achieving a balance between minimizing nonspecific drug release in blood circulation and maximizing specific intracellular drug release remains a critical challenge. To address this, this study developed a cross-linked poly(amino acid) nanocarrier sensitive to intracellular reactive oxygen species (ROS). A novel thioketal-functionalized, ROS-sensitive bicyclic amino acid N -carboxyanhydride (NCA) monomer was designed and synthesized, and ROS-responsive poly(amino acid)s were prepared via ring-opening polymerization. Polymeric nanomicelles loaded with doxorubicin (DOX) were successfully fabricated using a microemulsion method, and their ROS-responsive properties were systematically evaluated. In vitro release experiments demonstrated that the nanocarrier exhibited H 2 O 2 concentration-dependent, ROS-triggered drug release characteristics. The oxidative response behavior of the drug-loaded nanomicelles was further validated in cellular and animal models by introducing the ROS scavenger N-acetylcysteine (NAC). In a 4T1 tumor-bearing mouse model, these drug-loaded nanomicelles showed enhanced tumor retention and superior tumor suppression compared to free DOX. This study demonstrates that thioketal-functionalized poly(amino acid) nanocarriers hold promise in balancing blood circulation stability and intracellular specific drug release, providing a novel design strategy for developing efficient and safe poly(amino acid)-based anticancer nanomedicines.