SCIENCE TRANSLATIONAL MEDICINE – Resistance to drugs is common in cancer and is often caused by the multidrug resistance protein 1 (MDR1). To get to the bottom of this mechanism of drug resistance—and hopefully develop better therapeutics from this knowledge—Laughney et al. created a fluorescent cancer drug and probed tissue distribution and kinetics at both the single-cell and population levels. The authors developed a mouse model of drug-resistant human cancer, with tumors that were heterogeneously resistant (various levels of MDR1 expression).
By tracking the fluorescent drug eribulin in vivo, they saw that MDR1-expressing cells accumulated less drug than their wild-type counterparts—and this was a function of distance from blood vessels. MDR1 inhibitors did not appear to increase drug uptake in MDR1-overexpressing cells in vivo, so the authors redesigned the MDR inhibitor as a nanoparticle. In mice, inhibitor loaded in nanoparticles demonstrated bioactivity in the tumor. The combination of single-cell pharmacokinetics, intravital imaging, and drug reengineering suggests a new platform for understanding and overcoming resistance in human cancer.
