Dual pH and Ca2+‐Responsive PEG‐Modified Pillar[5]arene‐Based Supramolecular Nanodrug Delivery System: Excellent Cargo Encapsulation and Minimal Drug Toxicity

Abstract Chemotherapy is one of the most employed strategies in clinical treatment of cancer. However, reducing medication adverse effects and improving the biological activity remains a significant issue for chemotherapy. We developed a pH and Ca 2+ ‐responsive pillar[5]arene‐based supramolecular nanodrug delivery system (NDDS) WP5⊃EV@DOX to address the aforementioned challenges. The formation of this NDDS began with the spontaneous formation of supramolecular nanodrug carrier WP5⊃EV in water from PEG‐modified pillar[5]arene and the bipyridilium salt derivative EV through simple host‐guest interaction. Then the antitumor drug doxorubicin DOX was efficiently loaded with a high encapsulation rate of 84.6 %. Cytotoxicity results indicated that the constructed nanoplatform not only reduced DOX toxicity and side effects on normal cell (293T), but also significantly enhanced the antitumor activity on cancer cell (HepG2). Moreover, in vivo experiments showed that WP5⊃EV@DOX had a longer half‐life and higher bioavailability in the blood of mice compared to the nake drug DOX, with increases to 212 % and 179 %, respectively. Therefore, WP5⊃EV@DOX has great potential in tumor therapy and provides a new idea for host‐guest drug delivery system.