Regulating the Cytotoxicity of Anticancer Drugs by Pillar[6]arene‐based Host‐Guest Complex

Creating molecular-level host-guest complexes with properties responsive to endogenous substance stimuli-responsive as drug delivery systems, is critical for improving drug stability, reducing side effects, and amplifying therapeutic efficacy. Herein, a delivery system for the chemotherapeutic drug chlorambucil (CLB) was developed using the host-guest interaction with amino-pillar[6]arene (NP6). NP6 exhibits a high affinity for CLB (Ka=3.5×10³ M^-1), resulting in a 1 : 1 host-guest complex NP6@CLB. This complex not only effectively prevents premature drug leakage and improves drug stability but also significantly reduces the cytotoxicity of CLB on L-02 cells. Notably, NP6 also demonstrated superior complexation (Ka=3.6×10³ M^-1) with ATP, an endogenous substance in cells. During NP6@CLB delivery, ATP can compete with CLB to form a host-guest complex with NP6. This process blocks drug efflux while releasing CLB, thereby synergistically enhancing the antitumor effects on HeLa cells. This "one stone, two birds" design strategy-where host-guest complexes facilitate both direct drug delivery and synergistic enhancement of antitumor properties via ATP binding, opens a new perspective for constructing multifunctional supramolecular chemotherapeutic platforms based on pillar[n]arene.