Remodeling the tumor microenvironment to improve drug permeation and antitumor effects by co-delivering quercetin and doxorubicin.

The tumor microenvironment (TM) plays a critical role in the progress of tumors. However, the TM remodeling effects of currently available therapies remain largely unexplored in many previous reports. In our study, a hyaluronic acid (HA)-modified zeolitic imidazolate framework (ZIF) was successfully fabricated (HA/ZIF) and employed to load doxorubicin (Dox) and quercetin (Que) simultaneously for cancer therapy. The Que and Dox co-loaded HA/ZIF (HA/ZIF/DQ) showed preferable stability under physiological conditions, pH-responsive drug release in an acidic environment and preferential homing capacity to the CD44 receptor-overexpressed HepG2/ADR cells. More importantly, our results revealed that enhanced anticancer efficacy was achieved through the combination of Que and Dox via the tumor microenvironment remodeling effect of Que to potentiate drug penetration into deep tumor tissues.