Nanomedicine solutions to intricate physiological-pathological barriers and molecular mechanisms of tumor multidrug resistance.

Cancer multidrug resistance (MDR) has been a fatal factor for the failure of clinical chemotherapy, accompanying with tumor metastasis and recurrence. The mechanisms of MDR are extremely complicated, diversifying from tumor physiological-pathological barriers to molecular mechanisms of cellular factors. Especially, certain hard biological barriers (such as tumor tissue barriers and tumor subcellular compartments) are found to have close relationship with multidrug resistance, and increasing attentions are paid to address the MDR-related physiopathologic barriers for optimal drug distribution and bioavailability. Molecular and genetic factors of multidrug resistance are also gradually disclosed, such as decreased drug influx, increased drug efflux, altered drug targets, aberrant apoptotic pathway and activated DNA repair. To cope with these challenges, diverse nanomedicine solutions have been developed for overcoming physiological-pathological barriers and molecular mechanisms in the treatment of drug-resistant tumors. This review first introduces that multifunctional nanomedicines break through sequential physiological-pathological barriers to reverse MDR, including prolonged in vivo blood circulation, improved drug tumor penetration and intratumoral distribution, increased cellular internalization, optimized subcellular targeting and sufficient drug release. For another, nanomedicine solutions also show immense potentials on provoking multiple mechanisms for MDR reversal, such as decreasing drug efflux, strengthening tumor apoptosis and suppressing anti-apoptosis.