A sphingolipid-derived paclitaxel nanovesicle enhances efficacy of combination therapies in triple-negative breast cancer and pancreatic cancer

Zhiren Wang, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Wenpan Li, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Yanhao Jiang, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Teng Ma, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Mengwen Li, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Shuang Wu, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Tuyen Ba Tran, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Leyla Estrella Cordova, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Ethan Lin, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Aaron James Scott, Clinical and Translational Oncology Program, The University of Arizona Cancer Center, Tucson, AZ, USA.
Jennifer Erdrich, Department of Surgery, Division of Surgical Oncology, The University of Arizona College of Medicine, Tucson, AZ, USA.
Joyce Schroeder, Department of Molecular and Cellular Biology, The University of Arizona, Tucson, AZ, USA.
Pavani Chalasani, Division of Hematology and Oncology, George Washington Cancer Center, George Washington University, Washington, DC, USA.
Jianqin Lu, Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA. lu6@arizona.edu.

Document Type

Journal Article

Publication Date

8-21-2025

Journal

Nature cancer

DOI

10.1038/s43018-025-01029-7

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.

Department

Medicine

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