P‐Glycoprotein‐Dependent Trafficking of Nanoparticle‐Drug Conjugates

Resistance to chemotherapy contributes to treatment failure in over 90% of patients with metastatic cancer.[1] Although, many tumors initially respond well to chemotherapies, selective pressure can lead to the proliferation and dissemination of cell subpopulations exhibiting either de novo or adaptive drug resistance, often accompanied by cross-resistance to a range of structurally diverse small molecule drugs. MDR1 P-glycoprotein (P-gp) is considered to be the most prevalent and single most important cause of multidrug-resistance (MDR) in humans,[2] where the protein facilitates recognition, intracellular trafficking, sequestration, [3] and/or cellular efflux of up to 50% of all cytotoxic chemotherapeutics (e.g. doxorubicin, paclitaxel, vinblastine, etoposide), as well as antibiotics (e.g. erythromycin, azithromycin, ketolides), and other therapeutic small molecules.