Mineralization of pH sensitive Doxorubicin Prodrug in ZIF-8 to Enable the Target Delivery to Solid Tumors.

Zeolitic imidazolate framework (ZIF-8), composed of zinc ion and dimethylimidazole, is widely used in drug delivery, due to the easy fabrication process and the good biosafety. However, ZIF-8 suffers from low affinity to non-electric-rich drugs and does not have surface functional groups. Here, to target deliver doxorubicin (DOX) with ZIF-8, DOX was firstly modified with pH-sensitive linker containing two carboxyl groups to form the inactive prodrug CAD and subsequently seeded inside ZIF-8 by a 5 min mineralization process. CAD has high affinity to ZIF-8 due to the carboxyl groups and can anchor to the ZIF-8 surface to enable the surface modification with folic acid for tumor targeting. Moreover, the DOX release is precisely controlled by three steps of acidic pH-response, with the dissociation of FA layer, the breakdown of ZIF-8 structure, and the cleavage of pH-sensitive linker in prodrug. This novel "prodrug-ZIF-8" strategy has opened new horizon in drug delivery.