Transcytosis-Enabled Paclitaxel Prodrugs for Potentiated Chemotherapy

Transcytosis has emerged as an important transport mode to enhance the penetration of nanomedicines into tumors. Herein, we synthesized N- and N-oxide-modified paclitaxel prodrugs (PN and PNO), which can assemble into stable DPN NPs and DPNO NPs in the presence of distearoyl phosphoethanolamine-PEG₂₀₀₀. The N and N-oxide moiety of nanoprodrugs promotes the protonation at the pH 6.5 condition, enhances cellular endocytosis, and initiates active transcytosis, thus resulting in high cytotoxicity toward tumor cells. After intravenous (i.v.) injection, DPNO NPs exhibited more preferential tumor accumulation compared with DPN NPs because of the antiprotein absorption and transcytosis capability. Compared with clinically used Taxol and Abraxane, DPNO NPs exhibited more robust antitumor efficacy in vivo with negligible systemic toxicity. Our work provides insight into designing simple prodrugs with transcytosis function for improving chemotherapy.