ROS-responsive tegafur-pheophorbide a conjugate-loaded microneedles for deep drug delivery and chemo-photodynamic therapy of superficial tumors

Superficial tumors, including breast cancer, melanoma, and oral carcinoma, pose significant treatment challenges due to their anatomical location and the inherent limitations of conventional therapies, such as systemic toxicity and poor tumor specificity. Chemotherapy often leads to severe side effects, while photodynamic therapy (PDT) is hindered by the limited tissue penetration of both light and photosensitizers. To address these issues, we developed an innovative reactive oxygen species (ROS)-responsive drug delivery system based on a conjugate of tegafur (TF) and pheophorbide a (PPa) linked via a thioether bond. This prodrug (TF-TA-PPa) integrates chemotherapy and PDT into a single molecular entity, enabling synergistic anti-tumor effects. To enhance localized delivery and patient compliance, the conjugate was encapsulated into polymeric micelles and further incorporated into soluble microneedles (MNs) containing cell-penetrating peptides. The resulting TF-TA-PPa@PMN system enables painless transdermal administration, deep tumor penetration, and on-demand drug release triggered by near-infrared laser irradiation through ROS-mediated cleavage of the thioether linker. Comprehensive in vitro and in vivo evaluations demonstrated excellent biocompatibility, sustained drug release profiles, enhanced cellular uptake, and potent tumor suppression in a 4 T1 breast cancer model, achieving a remarkable tumor inhibition rate of 89.2% with minimal systemic toxicity. This integrated platform represents a promising strategy for the localized, combinatory treatment of superficial tumors with improved efficacy and reduced side effects.