School of Basic Medical Sciences and State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, 200032, P. R. China.
School of Pharmacy and, Key Laboratory of Smart Drug Delivery (Ministry of Education), Fudan University, Shanghai, 201203, P. R. China.
Adv Healthc Mater. 2017 Dec;6(23). doi: 10.1002/adhm.201700709. Epub 2017 Aug 25.
Glioma is among the most formidable brain cancers due to location in the brain. Cholera toxin subunit B (CTB) is investigated to facilitate multifunctional glioma-targeted drug delivery by targeting the glycosphingolipid GM1 expressed in the blood-brain barrier (BBB), neovasulature, and glioma cells. When modified on the surface of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CTB-NPs), CTB fully retains its bioactivity after 24 h incubation in the fresh mouse plasma. The formed protein corona (PC) of CTB-NP and plain PLGA nanoparticles (NP) after incubation in plasma is analyzed using liquid chromatography tandem massspectrometry (nano-LC-MS/MS). CTB modification does not alter the protein components of the formed PC, macrophage phagocytosis, or pharmacokinetic profiles. CTB-NP can efficiently penetrate the in vitro BBB model and target glioma cells and human umbilical vascular endothelial cells. Paclitaxel is loaded in NP (NP/PTX) and CTB-NP (CTB-NP/PTX), and their antiglioma effects are assessed in nude mice bearing intracranial glioma. CTB-NP/PTX can efficiently induce apoptosis of intracranial glioma cells and ablate neovasulature in vivo, resulting in significant prolongation of survival of nude mice bearing intracranial glioma (34 d) in comparison to those treated with NP/PTX (29 d), Taxol (24 d), and saline (21 d). The present study suggests a potential multifunctional glioma-targeted drug delivery system enabled by cholera toxin subunit B.
神经胶质瘤由于位于大脑中，是最具挑战性的脑癌之一。研究霍乱毒素亚单位 B（CTB）是为了通过靶向血脑屏障（BBB）、新生血管和神经胶质瘤细胞中表达的糖鞘脂 GM1，促进多功能神经胶质瘤靶向药物传递。当修饰在聚（乳酸-共-乙醇酸）（PLGA）纳米颗粒（CTB-NP）的表面时，CTB 在新鲜小鼠血浆中孵育 24 小时后完全保留其生物活性。使用液相色谱串联质谱法（nano-LC-MS/MS）分析 CTB-NP 和普通 PLGA 纳米颗粒（NP）在血浆中孵育后形成的蛋白质冠（PC）。CTB 修饰不会改变形成的 PC 的蛋白质成分、巨噬细胞吞噬作用或药代动力学特征。CTB-NP 可以有效地穿透体外 BBB 模型并靶向神经胶质瘤细胞和人脐静脉内皮细胞。紫杉醇被装载在 NP（NP/PTX）和 CTB-NP（CTB-NP/PTX）中，并在携带颅内神经胶质瘤的裸鼠中评估其抗神经胶质瘤作用。CTB-NP/PTX 可以有效地诱导颅内神经胶质瘤细胞凋亡，并在体内消融新生血管，从而显著延长携带颅内神经胶质瘤的裸鼠的存活时间（34 天）与 NP/PTX（29 天）、紫杉醇（24 天）和生理盐水（21 天）相比。本研究表明，霍乱毒素亚单位 B 可作为一种潜在的多功能神经胶质瘤靶向药物传递系统。
