Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 501 Haike Road, Shanghai 201203, China.
Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University , Tianjin 300070, China.
ACS Nano. 2016 Nov 22;10(11):9999-10012. doi: 10.1021/acsnano.6b04268. Epub 2016 Nov 8.
Nutrient transporters have been explored for biomimetic delivery targeting the brain. The albumin-binding proteins (e.g., SPARC and gp60) are overexpressed in many tumors for transport of albumin as an amino acid and an energy source for fast-growing cancer cells. However, their application in brain delivery has rarely been investigated. In this work, SPARC and gp60 overexpression was found on glioma and tumor vessel endothelium; therefore, such pathways were explored for use in brain-targeting biomimetic delivery. We developed a green method for blood-brain barrier (BBB)-penetrating albumin nanoparticle synthesis, with the capacity to coencapsulate different drugs and no need for cross-linkers. The hydrophobic drugs (i.e., paclitaxel and fenretinide) yield synergistic effects to induce albumin self-assembly, forming dual drug-loaded nanoparticles. The albumin nanoparticles can penetrate the BBB and target glioma cells via the mechanisms of SPARC- and gp60-mediated biomimetic transport. Importantly, by modification with the cell-penetrating peptide LMWP, the albumin nanoparticles display enhanced BBB penetration, intratumoral infiltration, and cellular uptake. The LMWP-modified nanoparticles exhibited improved treatment outcomes in both subcutaneous and intracranial glioma models, with reduced toxic side effects. The therapeutic mechanisms were associated with induction of apoptosis, antiangiogenesis, and tumor immune microenvironment regulation. It provides a facile method for dual drug-loaded albumin nanoparticle preparation and a promising avenue for biomimetic delivery targeting the brain tumor based on combination therapy.
营养转运蛋白已被探索用于仿生递药靶向大脑。白蛋白结合蛋白（如 SPARC 和 gp60）在许多肿瘤中过度表达，用于将白蛋白作为氨基酸和能量源转运到快速生长的癌细胞中。然而，它们在脑递药中的应用很少被研究。在这项工作中，在神经胶质瘤和肿瘤血管内皮细胞上发现了 SPARC 和 gp60 的过表达；因此，探索了这些途径用于脑靶向仿生递药。我们开发了一种绿色方法用于血脑屏障（BBB）穿透白蛋白纳米颗粒的合成，该方法能够共包封不同的药物，并且不需要交联剂。疏水性药物（即紫杉醇和芬维 A 胺）产生协同作用，诱导白蛋白自组装，形成双载药纳米颗粒。白蛋白纳米颗粒可以通过 SPARC 和 gp60 介导的仿生转运机制穿透 BBB 并靶向神经胶质瘤细胞。重要的是，通过细胞穿透肽 LMWP 的修饰，白蛋白纳米颗粒显示出增强的 BBB 穿透、肿瘤内渗透和细胞摄取。LMWP 修饰的纳米颗粒在皮下和颅内神经胶质瘤模型中均显示出改善的治疗效果，同时减少了毒副作用。治疗机制与诱导细胞凋亡、抗血管生成和肿瘤免疫微环境调节有关。它为双载药白蛋白纳米颗粒的制备提供了一种简便的方法，并为基于联合治疗的脑肿瘤仿生递药提供了一个有前途的途径。
