| Abstract: | Four acyclic maleimide‐based enediyne compounds with different hydrophilicity were synthesized through Sonogashira reaction to reveal a self‐delivery antitumor drug platform. As proved by ESR analysis, the enediyne compounds undergo Bergman‐like cyclization and generate diradical intermediates at physiological temperature, which are able to induce DNA‐cleavage through the abstraction of H atoms from the sugar‐phosphate backbones. When the critical aggregation concentration is reached in water, the amphiphilic enediyne compounds self‐assemble into nanoparticles and possess the self‐delivery ability to be facilely admitted by tumor cells, resulting in greatly improved cytotoxicity (IC50 down to 10 μmol·L–1) and much higher tumor cell apoptosis rate (up to 86.6%) in comparison with either the hydrophilic or the lipophilic enediyne compound. The enhanced endocytosis of the amphiphilic enediyne compounds was further confirmed through confocal laser scanning microscopy analysis. The unveiled relationship between the hydrophilicity of enediyne drugs and their therapeutic efficacy will provide a guideline for the design of new self‐delivery drugs employed in medicinal applications. |
