A sphingolipid-derived paclitaxel nanovesicle enhances efficacy of combination therapies in triple-negative breast cancer and pancreatic cancer
Zhiren Wang, Wenpan Li, Yanhao Jiang, Teng Ma, M J Li, Shuang Wu, Tuyen Ba Tran, Leyla Estrella Cordova, Ethan Lin, Aaron J. Scott, Jennifer Erdrich, Joyce A. Schroeder, Pavani Chalasani, Jianqin Lu
Abstract
Taxol and Abraxane, the US Food and Drug Administration-approved paclitaxel (PTX) formulations, have revealed hypersensitivity due to excipients and mediocre efficacy due to insufficient tumor penetration, respectively. Here we developed a sphingolipid-derived PTX nanovesicle (paclitaxome) via covalently conjugating PTX to sphingomyelin, which improved pharmacokinetics and enhanced efficacy in metastatic triple-negative breast cancer and pancreatic cancer female mice and reduced myelosuppression. To bolster tumor penetration and reduce phagocytosis, we engineered a cationization-enabled transcytosis machinery by installing an ultra-pH-sensitive azepane (AZE) probe into paclitaxome and masked nanovesicle surface with a CD47 'self' peptide (CD47p). The resulting CD47p/AZE-paclitaxome synchronized the co-delivery of gemcitabine or carboplatin to boost tumor inhibition and eradicate metastasis in late-stage KPC-Luc pancreatic cancer model and prevent tumor relapse and extend survival in postsurgical 4T1-Luc2 triple-negative breast cancer model in female mice. CD47p/AZE-paclitaxome also outperformed previous promising PTX nanoformulations. Finally, the series of nanoparticle modifications was applied to camptothecin, demonstrating its generalizability.