Rational Design of Redox‐Responsive and P‐gp‐Inhibitory Lipid Nanoparticles with High Entrapment of Paclitaxel for Tumor Therapy

Abstract An insufficient drug concentration at the target site and drug efflux resulting in poor efficacy is recognized as important obstacles in tumor treatment. Herein, novel lipid nanoparticles (LNPs) with redox‐responsive properties based on disulfide bond‐contained, quercetin (Qu)‐grafted glyceryl caprylate‐caprate (Gcc) are introduced (Qu‐SS‐Gcc LNPs). Qu‐SS‐Gcc LNPs show good entrapment of paclitaxel (PTX) due to π–π stacking between the aromatic rings of Qu and PTX. In vitro experiments indicate that Qu‐SS‐Gcc LNPs can selectively respond to high levels of reducing substances by breakdown of disulfide bonds, thus achieving rapid and efficient drug release, and only dissociate rapidly in tumor cells rather than in normal cells. Meanwhile, the Qu released concomitantly with the breakdown of disulfide bonds combines with P‐gp and inhibits the drug efflux triggered by P‐gp. Using an orthotopic 4T1 mouse mammary tumor model in BALB/c mice, PTX/Qu‐SS‐Gcc LNPs exhibit superior antitumor efficacy compared to Taxol, in addition better biosafety and inhibition of chemotherapy‐triggered P‐gp overexpression are achieved. Taken together, this work designs and implements redox‐responsive drug release and drug efflux inhibition in tumor cells via modified LNPs, which not only leads to efficient drug release but also solves the problem of drug efflux that exists in stimulus‐responsive systems.