Enabling P-glycoprotein inhibition in multidrug resistant cancer through the reverse targeting of a quinidine-PEG conjugate.
الكلمات الدالة
نبذة مختصرة
Previously identified as a key mediator of multidrug resistance, the drug efflux behavior of P-glycoprotein (P-gp) remains a prominent challenge in cancer treatment. P-gp belongs to the ATP-binding cassette transporter family of membrane proteins, and modulates the efflux of many drugs at the cell membrane, resulting in inadequate retention of chemotherapeutic drugs in cancer cells. Here, we explore the FDA-approved drug quinidine as a P-gp inhibitor. Although used clinically for the treatment of malaria, arrhythmia, and pseudobulbar effect, quinidine can induce acquired long QT syndrome and torsade de pointes through its interaction with the Purkinje fibers, which hinders its clinical application as a P-gp inhibitor. We hypothesize that the conjugation of quinidine to a polymer will permit its use as a P-gp inhibitor through mitigation of its distribution into the myocardium. Methoxypolyethylene glycol (mPEG) was conjugated to quinidine through a glycine linker, making a monovalent quinidine-polymer conjugate, which was then evaluated for its interactions with P-gp in vitro. The mPEG-glycine-quinidine conjugate retained its ability to inhibit the function of P-gp (log IC50 of 4.20 nM for quinidine and 4.61 nM for the mPEG-glycine-quinidine conjugate). Additionally, the distribution of quinidine into perfused mouse myocardium was decreased by almost an order of magnitude, strongly supporting our working hypothesis (2.28 × 10-3 μmol/g tissue for quinidine and ~4.10 × 10-4 μmol/g tissue for the conjugate). The results suggest the potential use of such polymer-drug conjugates to reverse multidrug resistance through P-gp inhibition and to mitigate the off-target pharmacologic effects that complicate their clinical use.