Wang Zhiren, Li Wenpan, Jiang Yanhao, Ma Teng, Li Mengwen, Wu Shuang, Tran Tuyen Ba, Cordova Leyla Estrella, Lin Ethan, Scott Aaron James, Erdrich Jennifer, Schroeder Joyce, Chalasani Pavani, Lu Jianqin
Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, R. Ken Coit College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
Clinical and Translational Oncology Program, The University of Arizona Cancer Center, Tucson, AZ, USA.
Nat Cancer. 2025 Aug 21. doi: 10.1038/s43018-025-01029-7.
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.
紫杉醇和白蛋白结合型紫杉醇是美国食品药品监督管理局批准的紫杉醇（PTX）制剂，它们分别因辅料导致超敏反应，以及因肿瘤渗透不足而疗效一般。在此，我们通过将PTX与鞘磷脂共价偶联，开发了一种鞘脂衍生的PTX纳米囊泡（紫杉醇体），其改善了药代动力学，增强了转移性三阴性乳腺癌和胰腺癌雌性小鼠的疗效，并减轻了骨髓抑制。为了增强肿瘤渗透并减少吞噬作用，我们通过在紫杉醇体中安装超pH敏感的氮杂环庚烷（AZE）探针，并使用CD47“自我”肽（CD47p）掩盖纳米囊泡表面，设计了一种能够实现阳离子化转胞吞作用的机制。所得的CD47p/AZE-紫杉醇体同步共递送吉西他滨或卡铂，以增强肿瘤抑制作用，并在晚期KPC-Luc胰腺癌模型中根除转移，在雌性小鼠术后4T1-Luc2三阴性乳腺癌模型中预防肿瘤复发并延长生存期。CD47p/AZE-紫杉醇体也优于先前有前景的PTX纳米制剂。最后，将这一系列纳米颗粒修饰应用于喜树碱，证明了其通用性。
