Rational Design of Metal Organic Framework Nanocarrier-Based Codelivery System of Doxorubicin Hydrochloride/Verapamil Hydrochloride for Overcoming Multidrug Resistance with Efficient Targeted Cancer Therapy

Conventional organic and inorganic drug nanocarriers suffer from serious drawbacks such as low drug-storage capacity and uncontrolled release. Moreover, multidrug resistance (MDR) has been one of the primary causes leading to chemotherapy failure for cancers. The main reason for MDR is the overexpressed active efflux transporters such as P-glycoprotein. Here, zeolitic imidazolate framework ZIF-8, as one of the biocompatible metal organic frameworks (MOFs), is reported for the first time as the multidrug carrier to realizing the efficient codelivery of verapamil hydrochloride (VER) as the P-glycoprotein inhibitor as well as doxorubicin hydrochloride (DOX) as an anticancer drug to overcome the MDR in addition to realize the active targeted ability for an efficient anticancer effect. Uniform ZIF-8 nanoparticles encapsulating DOX and VER are achieved by a facile one-pot process, in which the VER is used to overcome the multidrug resistance. Furthermore, methoxy poly(ethylene glycol)-folate (PEG-FA) is used to stabilize the (DOX+VER)@ZIF-8 to realize prolonged circulations and an active targeting drug delivery. In particular, the ZIF-8 exhibits high drug loading content up to ∼40.9% with a pH-triggered release behavior. Importantly, the PEG-FA/(DOX+VER)@ZIF-8 shows enhanced therapeutic efficiencies with much safety compared with the direct administration of free DOX both in vitro and in vivo. Near infrared fluorescent (NIRF) imaging indicates that the PEG-FA/(DOX+VER)@ZIF-8 can increase the drug accumulations in tumors for targeted cancer therapy. Therefore, the PEG-FA/(DOX+VER)@ZIF-8 multidrug delivery system can be used as a promising efficient formulation in reversing the multidrug resistance for targeted cancer therapy.