Promoting Tumor Accumulation of Anticancer Drugs by Hierarchical Carrying of Exogenous and Endogenous Vehicles

Promoting tumor accumulation of active pharmaceutical ingredients is crucial for targeted anticancer therapy. However, this issue has not yet been addressed because of the fast clearance or premature degradation, slow drug release kinetics, and nonspecific biodistribution of the reported formulations. Herein, a new drug delivery paradigm is proposed based on supramolecular hierarchical recognition to achieve high tumor accumulation of anticancer drugs by overcoming these three challenges. The prepared supramolecular ternary formulation of paclitaxel (PTX) contains two steps of molecular recognition: exogenous recognition of PTX by an artificial macrocyclic carrier, sulfonated azocalix[5]arene (SAC5A) in vitro, and endogenous recognition of PTX@SAC5A by intrinsic serum albumin in vivo. The ternary PTX@SAC5Acalbumin concurrently accomplishes prolonged blood circulation, rapid drug release, and dual passive and hypoxia-responsive targeting. As a result, the PTX@SAC5Acalbumin formulation exhibits more efficient tumor accumulation than free PTX and albumin-based, solvent based, liposome-based, and sulfobutyl ether-beta-cyclodextrin-based PTX formulations, thereby contributing to better therapeutic efficacy. The current strategy paves the way for promoting the tumor accumulation of drugs, showing the advantages of simplicity, universality, and reproducibility.