Stepwise co-delivery of an enzyme and prodrug based on a multi-responsive nanoplatform for accurate tumor therapy

Tumors have characteristic physiochemical conditions different from normal tissue, which makes therapy combining chemotherapeutic drugs and tumor microenvironment-responsive nanocarriers a promising route for cancer treatment. Here, we introduce a concept of integrating catalytic nanomedicine and selective chemotherapy for accurate therapy of early stage tumors by co-delivery of enzymes and prodrugs into tumor sites through a multi-responsive nanoplatform. The nanoplatform consists of a polyester-hyaluronic acid-doxorubicin (PE-HA_1000k-DOX) prodrug as the corona, physiologically biodegradable silica containing disulfide bonds as the shell and hyaluronidase (absent in early stage tumors) as the core. This nanoplatform is able to quickly enter tumor cells through CD44-HA affinity. Then, the esterase and glutathione rich in tumor cells would respectively degrade the polyester and silica to release HA-DOX and hyaluronidase in a stepwise manner. Finally, highly toxic dissociative DOX is produced through decomposition of the resulting HA-DOX, catalyzed by hyaluronidase, for the apoptosis and death of the tumor cells. The properties of tumor-targeting uptake, tumor microenvironment responsiveness, efficient co-delivery of the enzyme and prodrug, and intracellular enzymatic reaction induced cytotoxicity resulted in a four-fold efficacy against tumor cells over normal cells, indicating that our nanoplatform is a promising material able to achieve both selectivity and efficiency concurrently for tumor therapeutics.