For cancer therapy, treatment resistance poses a major hurdle. Even aggressive treatments such as immunotherapies or nanomedicines may fail to eliminate all cancer cells, allowing new mutations to develop that may cause relapse. In a new study published in the June issue of ACS Nano, bioengineers at Brigham and Women's Hospital report that the reason combination therapies are not always successful and can lead to resistance could be a result of spatial proximity of each drug in the combination 'pair.' By engineering a single nanoparticle that comprises a synergistic drug pair, they demonstrate that the mechanisms of resistance can be shut down to a degree that had never been achieved before. The findings have implications for how combination therapy is administered in the clinic and the use of complementary drug pairs for the treatment of cancer.
Using computational approaches, the team designed a supramolecular nanotherapeutic that tied together two cancer therapies: the chemotherapy drug docetaxel and a targeted therapy known as a PI3K inhibitor. By pairing the two drugs in a single structure, the team was able to deliver both therapeutic agents to the same cells, more effectively eliminating cancer cells in preclinical models and resulting in greater tumor inhibition.
"We were inspired by the mathematical understanding that a cancer cell rewires the mechanisms of resistance in a defined way," said study author Aaron Goldman, PhD, of BWH's Renal Division. "By developing a 2-in-1 nanomedicine, we could ensure the same cell that was acquiring this new resistance saw the lethal drug combination, shutting down the survival program and eliminating the evidence of resistance. This 2-in-1 punch could redefine how clinicians deliver the '1-2 punch' combination of drugs."
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