Overcoming Cancer Multi-drug Resistance (MDR): Reasons, mechanisms, nanotherapeutic solutions, and challenges

Multi-drug resistance (MDR) in cancer cells, either intrinsic or acquired through various mechanisms, signifi-cantly hinders the therapeutic efficacy of drugs. Typically, the reduced therapeutic performance of various drugs is predominantly due to the inherent over expression of ATP-binding cassette (ABC) transporter proteins on the cell membrane, resulting in the deprived uptake of drugs, augmenting drug detoxification, and DNA repair. In addition to various physiological abnormalities and extensive blood flow, MDR cancer phenotypes exhibit improved apoptotic threshold and drug efflux efficiency. These severe consequences have substantially directed researchers in the fabrication of various advanced therapeutic strategies, such as co-delivery of drugs along with various generations of MDR inhibitors, augmented dosage regimens and frequency of administration, as well as combinatorial treatment options, among others. In this review, we emphasize different reasons and mechanisms responsible for MDR in cancer, including but not limited to the known drug efflux mechanisms mediated by permeability glycoprotein (P-gp) and other pumps, reduced drug uptake, altered DNA repair, and drug targets, among others. Further, an emphasis on specific cancers that share pathogenesis in executing MDR and effluxed drugs in common is provided. Then, the aspects related to various nanomaterials-based supramolecular pro-grammable designs (organic-and inorganic-based materials), as well as physical approaches (light-and ultrasound-based therapies), are discussed, highlighting the unsolved issues and future advancements. Finally, we summarize the review with interesting perspectives and future trends, exploring further opportunities to overcome MDR.

Automated summary

Multi-drug resistance (MDR) in cancer cells is a significant obstacle in effective drug therapy, resulting from over expression of ATP-binding cassette (ABC) transporter proteins. Various strategies have been proposed to overcome MDR, including co-delivery of drugs with MDR inhibitors, increased dosage and frequency of administration, and combination therapies. This review discusses the reasons and mechanisms behind MDR, such as drug efflux mediated by permeability glycoprotein (P-gp) and other pumps, reduced drug uptake, altered DNA repair, and drug targets. It also explores nanomaterials-based supramolecular designs and physical approaches for MDR treatment.