Department of Endocrinology, Nanjing Drum Tower Hospital, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 211198, China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China.
Adv Mater. 2024 Jun;36(24):e2311760. doi: 10.1002/adma.202311760. Epub 2024 Apr 11.
Glioblastoma (GBM) is the most aggressive and prevalent primary malignant tumor of the central nervous system. Traditional chemotherapy has poor therapeutic effects and significant side effects due to drug resistance, the natural blood-brain barrier (BBB), and nonspecific distribution, leading to a lack of clinically effective therapeutic drugs. Here, 1430 small molecule compounds are screened based on a high-throughput drug screening platform and a novel anti-GBM drug, lomitapide (LMP) is obtained. Furthermore, a bionic nanodrug delivery system (RFA NPs) actively targeting GBM is constructed, which mainly consists of tetrahedral DNA nanocages (tFNA NPs) loaded with LMP as the core and a folate-modified erythrocyte-cancer cell-macrophage hybrid membrane (FRUR) as the shell. FRUR camouflage conferred unique features on tFNA NPs, including excellent biocompatibility, improved pharmacokinetic profile, efficient BBB permeability, and tumor targeting ability. The results show that the LMP RFA NPs exhibited superior and specific anti-GBM activities, reduced off-target drug delivery, prolonged lifespan, and has negligible side effects in tumor-bearing mice. This study combines high-throughput drug screening with biomimetic nanodrug delivery system technology to provide a theoretical and practical basis for drug development and the optimization of clinical treatment strategies for GBM treatment.
胶质母细胞瘤（GBM）是中枢神经系统中最具侵袭性和最常见的原发性恶性肿瘤。由于耐药性、天然血脑屏障（BBB）和非特异性分布，传统化疗的治疗效果差，副作用明显，导致缺乏临床上有效的治疗药物。在这里，我们基于高通量药物筛选平台和一种新型抗 GBM 药物洛美他派（LMP）筛选了 1430 种小分子化合物。此外，构建了一种仿生纳米药物递送系统（RFA NPs）主动靶向 GBM，它主要由负载 LMP 的四面体 DNA 纳米笼（tFNA NPs）作为核心和叶酸修饰的红细胞-癌细胞-巨噬细胞杂交膜（FRUR）作为外壳组成。FRUR 伪装赋予了 tFNA NPs 独特的特性，包括优异的生物相容性、改善的药代动力学特性、高效的 BBB 通透性和肿瘤靶向能力。结果表明，LMP RFA NPs 表现出优异的、特异性的抗 GBM 活性，减少了脱靶药物递送，延长了寿命，并且在荷瘤小鼠中几乎没有副作用。本研究将高通量药物筛选与仿生纳米药物递送系统技术相结合，为 GBM 治疗的药物开发和临床治疗策略的优化提供了理论和实践基础。
