Overcoming transporter-mediated multidrug resistance in cancer: failures and achievements of the last decades.

Multidrug resistance (MDR) is a complex phenomenon caused by numerous reasons in cancer chemotherapy. It is related to the abnormal tumor metabolism, precisely increased glycolysis and lactic acid production, extracellular acidification, and drug efflux caused by transport proteins. There are few strategies to increase drug delivery into cancer cells. One of them is the inhibition of carbonic anhydrases or certain proton transporters that increase extracellular acidity by proton extrusion from the cells. This prevents weakly basic chemotherapeutic drugs from ionization and increases their penetration through the cancer cell membrane. Another approach is the inhibition of MDR proteins that pump the anticancer agents into the extracellular milieu and decrease their intracellular concentration. Physical methods, such as ultrasound-mediated sonoporation, are being developed, as well. To increase the efficacy of sonoporation, various microbubbles are used. Ultrasound causes microbubble cavitation, i.e., periodical pulsation of the microbubble, and destruction which results in formation of temporary pores in the cellular membrane and increased permeabilization to drug molecules. This review summarizes the main approaches to reverse MDR related to the drug penetration along with its applications in preclinical and clinical studies.