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

Abstract

P-glycoprotein (P-gp) is a promiscuous small molecule transporter whose overexpression in cancer is associated with multidrug resistance (MDR). In these instances, anticancer drugs can select for P-gp-overexpressing cells, leading to cancer recurrence with an MDR phenotype. To avoid selection for MDR cancers and inform individual patient treatment plans, it is critical to noninvasively identify P-gp-overexpressing tumors prior to administration of chemotherapy. We report the facile free radical copolymerization of quinidine, a competitive inhibitor of P-gp, and acrylic acid to generate multiplexed polymeric P-gp-targeted imaging agents with tunable quinidine content. Copolymer targeting was demonstrated in a nude mouse xenograft model. In xenografts overexpressing P-gp, copolymer distribution was enhanced over two-fold compared to the negative control of poly(acrylic acid) regardless of quinidine content. In contrast, accumulation of the copolymers in xenografts lacking P-gp was equivalent to poly(acrylic acid). This work forms the foundation for a unique approach toward the phenotype-specific noninvasive imaging of MDR tumors and is the first in vivo demonstration of copolymer accumulation through the active targeting of P-gp.

Nanoparticle-mediated delivery of peptide-based degraders enables targeted protein degradation

“…Biodistribution studies were conducted using an adaptation of a previously published method. 70 For biodistribution studies, mice (n=5 per group) were administered either 5 mg/kg free PepTAC labeled with 50% Cy5.5 or 5 mg/kg LNP-encapsulated PepTAC labeled with 50% Cy5.5 via tail vein injection (approximately 100 µL injection using a 26 G needle). 1X PBS (n=3, 100 µL injection) was used as a negative control.…”