Weissleder‘s team measured drug targeting in live cells and blood samples. From samples as small as 1500 cells, the investigators found that their system could detect differences in PARP expression and drug binding across different tumor types. The results, wrote the researchers, “suggest the potential for a future ‘treatment index,’ where patients with high drug-binding efficacy would receive lower therapeutic doses, while patients with low drug-binding efficacy would require higher doses or be candidates to receive alternative drugs.” The investigators are already at work on a second-generation system that would require even fewer, or even single, cells that might enable clinicians to identify the development of rare drug resistant cells.
Responses to molecularly targeted therapies can be highly variable and depend on mutations, fluctuations in target protein levels in individual cells, and drug delivery. The ability to rapidly quantitate drug response in cells harvested from patients in a point-of-care setting would have far reaching implications. Capitalizing on recent developments with miniaturized NMR technologies, we have developed a magnetic nanoparticle-based approach to directly measure both target expression and drug binding in scant human cells. The method involves covalent conjugation of the small-molecule drug to a magnetic nanoparticle that is then used as a read-out for target expression and drug-binding affinity. Using poly(ADP-ribose) polymerase (PARP) inhibition as a model system, we developed an approach to distinguish differential expression of PARP in scant cells with excellent correlation to gold standards, the ability to mimic drug pharmacodynamics ex vivo through competitive target–drug binding, and the potential to perform such measurements in clinical samples.