Lonidamine dimer-based nanomedicine for overcoming multidrug resistance by manipulating energy metabolism and disrupting redox homeostasis

Multidrug resistance, in particular the challenge of drug efflux transporter-mediated chemoresistance, remains the major obstacle for effective chemotherapy. Therefore, manipulating energy metabolism in cancer cells to reduce the expression of P-glycoprotein (P-gp) and disrupt redox homeostasis may be a potential strategy to surmount cancer therapeutic resistance. Herein, a PEGylated co-delivery nanoplatform (LND-DOX NPs) that is capable of decreasing chemotherapeutic drug efflux and increasing the sensitivity of tumor cells to DOX by manipulating energy metabolism and disrupting redox homeostasis is rationally designed. As a result, the LND-DOX NPs increased DOX retention in MCF-7/Adr cells and displayed remarkable antitumor capabilities. The IC50 value of LND-DOX NPs in MCF-7/Adr cells was about 5 μM. Therefore, this study provides a potentially effective strategy against cancer therapeutic resistance.