Deep Drug Penetration of Nanodrug Aggregates at Tumor Tissues by Fast Extracellular Drug Release

Abstract Herein, a new nanodrug of azobenzene‐functionalized interfacial cross‐linked reverse micelles (AICRM) with 5‐fluorouracil loading (5‐FU@AICRM) is reported. Upon irradiation with 530 nm light in water, the surface azobenzenes of the nanoparticles change from polar cis ‐conformation to nonpolar trans ‐conformation, resulting in the aggregation of 5‐FU@AICRM within minutes. Simultaneously, the conformation change unlocks hydrophilic 5‐FU with a strong water immigration propensity, allowing them to spray out from the AICRM quickly. This fast release ensures a thorough release of the drug, before the aggregates are internalized by adjacent cells, making it possible to achieve deep tissue penetration. A study of in vivo anticancer activity in A549 tumor‐bearing nude mice shows that the tumor inhibition rate (TIR) of 5‐FU@AICRM is up to ≈86.2%, 31.6% higher than that of group without green light irradiation and 20.7% higher than that of carmofur (CF, a hydrophobic analog of 5‐FU)‐loaded AICRM (CF@AICRM), in which CF is released slowly under light irradiation because of its hydrophobicity. Fast drug release upon nanodrug aggregation provides a good solution for balancing the contradiction of “aggregation and penetration” in tumor treatment with nanodrugs.