Phospholipid‐Like Prodrug Liposomes with High Drug‐carrier Affinity and High Tumor Selectivity: Strong Competitors of Paclitaxel Nanomedicines

Abstract Paclitaxel (PTX) is an effective agent against a wide spectrum of solid tumors. Lipusu is the first and only marketed liposomal PTX product in the world. However, it is hindered by the insufficient affinity between PTX and phospholipids, resulted in a low drug loading (≈5.68%), poor stability, and limited antitumor efficacy. Inspired by the structural characteristics of phospholipids, a phospholipid‐like PTX prodrug (PTX‐OCT) is designed to construct prodrug liposomes (PTX‐OCT PLs). Compared with Lipusu, PTX‐OCT PLs possessed a smaller particle size (135 vs 400 nm) with a higher drug loading (10.52% vs 5.68%, equal to PTX). Meanwhile, PTX‐OCT PLs would deliver PTX efficiently in vivo evidenced by the AUC higher than Lipusu (≈170‐fold) due to their superior stability. The introduction of disulfide bonds endowed PTX‐OCT PLs with the capacity of intelligent activation, which is the key element for tumor selectivity. With such characterizations, PTX‐OCT PLs exhibited potent antitumor efficacy with good tolerance in 4T1‐bearing model, even better than Abraxane and Lipusu. To summarize, this work designed PTX nanomedicines with potential market competitiveness and enriched the theoretical basis of designing advanced nanomedicines for efficient cancer treatment.