Selective Accumulation of Near Infrared-Labeled Multivalent Quinidine Copolymers in Tumors Overexpressing P-Glycoprotein: Potential for Noninvasive Diagnostic Imaging

P-glycoprotein (P-gp) is a promiscuous small moleculetransporterwhose overexpression in cancer is associated with multidrug resistance(MDR). In these instances, anticancer drugs can select for P-gp-overexpressingcells, leading to cancer recurrence with an MDR phenotype. To avoidselection for MDR cancers and inform individual patient treatmentplans, it is critical to noninvasively identify P-gp-overexpressingtumors prior to administration of chemotherapy. We report the facilefree radical copolymerization of quinidine, a competitive inhibitorof P-gp, and acrylic acid to generate multiplexed polymeric P-gp-targetedimaging agents with tunable quinidine content. Copolymer targetingwas demonstrated in a nude mouse xenograft model. In xenografts overexpressingP-gp, copolymer distribution was enhanced over two-fold compared tothe negative control of poly(acrylic acid) regardless of quinidinecontent. In contrast, accumulation of the copolymers in xenograftslacking P-gp was equivalent to poly(acrylic acid). This work formsthe foundation for a unique approach toward the phenotype-specificnoninvasive imaging of MDR tumors and is the first in vivo demonstrationof copolymer accumulation through the active targeting of P-gp.