title: Nanoparticle-mediated measurement of target-drug binding in cancer cells.
abstract: 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.
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, 185 Cambridge Street, CPZN 5206, Boston, Massachusetts 02114, USA.
authors.forename: Adeeti V
authors.initials: AV
authors.lastname: Ullal
authors.forename: Thomas
authors.initials: T
authors.lastname: Reiner
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Yang
authors.forename: Rostic
authors.initials: R
authors.lastname: Gorbatov
authors.forename: Changwook
authors.initials: C
authors.lastname: Min
authors.forename: David
authors.initials: D
authors.lastname: Issadore
authors.forename: Hakho
authors.initials: H
authors.lastname: Lee
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
mesh_terms: D015374:Biosensing Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D058990:Molecular Targeted Therapy; D053758:Nanoparticles / Q000737:chemistry*; D036103:Nanotechnology / Q000379:methods*; D010793:Phthalazines / Q000378:metabolism* / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology; D019095:Point-of-Care Systems; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib