Cancer cells frequently develop the ability to expel anticancer drugs before they can work -- a phenomenon called multidrug resistance (MDR) -- which is one of the leading reasons why chemotherapy fails in patients. This research addresses that problem with a fundamentally new strategy: instead of simply increasing drug doses or switching drugs, researchers engineered nanoparticles that first disable the cancer cell's drug-expulsion mechanism, and only then release the anticancer drug. By combining this sequential drug delivery approach with photothermal therapy (using near-infrared laser light to heat and destroy the tumor), complete tumor elimination and 100% survival in a mouse model of drug-resistant cancer was achieved, with no detectable toxicity to normal tissues.
This remarkable drug delivery system was developed by an international research team led by Professor Eijiro Miyako at Tohoku University, who is also a Visiting Professor at Japan Advanced Institute of Science and Technology, in collaboration with the group of Drs. Alberto Bianco and Cécilia Ménard-Moyon at the French National Centre for Scientific Research (CNRS)/University of Strasbourg. The findings were published in the prestigious Journal of Controlled Release on May 6, 2026.
Multidrug resistance (MDR) is one of the most formidable obstacles in cancer chemotherapy. MDR cancer cells overexpress P-glycoprotein (P-gp), a drug efflux pump that actively expels chemotherapeutic agents before they can exert their therapeutic effect, drastically reducing intracellular drug concentrations. Previous studies have looked at a combined, simultaneous release of P-gp inhibitors with anticancer drugs as a treatment for MDR cancer, but showed limited efficacy.
"We wanted to first inhibit the expelling action of P-gp before anticancer drugs are introduced, so we developed a unique, sequential release mechanism to achieve this," explains Miyako. "Afterall, you need to patch up a hole in a leaky bucket before adding more water, instead of trying to do both at the same time."
The controlled, timed release allows for more targeted care. The research team developed porous amino acid nanoparticles (NPs) that were able to contain the anticancer drug doxorubicin (Dox), and the P-gp inhibitor quinidine. The NPs integrate three therapeutic functions: sequential drug release, photothermal therapy, and active tumor targeting.
The results of in vitro experiments on cells far exceed the efficacy of either chemotherapy or photothermal therapy alone. Similarly, tumor-bearing mice undergoing this three-pronged treatment showed complete tumor regression compared to photothermal alone, which showed only transient regression followed by recurrence.
Multidrug resistance affects a wide range of cancers and remains a largely unsolved clinical challenge. This platform offers a new and potentially broadly applicable strategy to restore chemotherapy sensitivity in tumors that have stopped responding to treatment.
"We are hopeful that this approach could become a beacon of hope for patients with cancer one day," says Miyako. "The nanoparticles are constructed entirely from amino acid-derived building blocks and biocompatible materials, which underscores the potential for clinical translatability in humans."