Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Hyderabad, 500 046, Telangana State, India.
Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research, Uppal Road, Hyderabad, 500 007, Telangana State, India.
Sci Rep. 2017 Jul 26;7(1):6602. doi: 10.1038/s41598-017-06888-4.
Targeted delivery of drugs to the brain is challenging due to the restricted permeability across the blood brain barrier (BBB). Gliomas are devastating cancers and their positive treatment outcome using Temozolomide (TMZ) is limited due to its short plasma half-life, systemic toxicity and limited access through the blood-brain barrier (BBB). Nanoparticles made of Lactoferrin (Lf) protein, have been shown to enhance the pharmacological properties of drugs. Here, we report the specific ability of Lf nanoparticles to cross BBB and target over-expressed Lf receptors on glioma for enhanced TMZ delivery. TMZ-loaded Lf nanoparticles (TMZ-LfNPs) were prepared by our previously reported sol-oil method. While the Lf protein in the NP matrix aids in transcytosis across the BBB and preferential tumor cell uptake, the pH responsiveness leads to TMZ release exclusively in the tumor microenvironment. Delivery through LfNPs results in an enhanced and sustained intracellular concentration of TMZ in GL261 cells in vitro along with improving its in vivo pharmacokinetics and brain accumulation. TMZ-LfNPs treatment results in a significant reduction of tumor volume, higher tumor cell apoptosis and improved median survival in glioma bearing mice. These results demonstrate that LfNPs present an efficient TMZ delivery platform for an effective treatment of gliomas.
由于血脑屏障（BBB）的限制，药物靶向递送到大脑具有挑战性。神经胶质瘤是一种具有破坏性的癌症，由于替莫唑胺（TMZ）的血浆半衰期短、全身毒性和通过血脑屏障（BBB）的有限进入，其治疗效果有限。乳铁蛋白（Lf）蛋白制成的纳米颗粒已被证明可以增强药物的药理特性。在这里，我们报告了 Lf 纳米颗粒穿过 BBB 并靶向过度表达的 Lf 受体以增强 TMZ 递送至脑肿瘤的特定能力。TMZ 负载的 Lf 纳米颗粒（TMZ-LfNPs）是通过我们之前报道的溶剂-油方法制备的。虽然 NP 基质中的 Lf 蛋白有助于穿过 BBB 的转胞吞作用和优先的肿瘤细胞摄取，但 pH 响应导致 TMZ 仅在肿瘤微环境中释放。通过 LfNPs 递送导致体外 GL261 细胞中 TMZ 的细胞内浓度增强和持续增加，同时改善其体内药代动力学和脑蓄积。TMZ-LfNPs 治疗可显著减小肿瘤体积、增加肿瘤细胞凋亡并提高荷瘤小鼠的中位生存时间。这些结果表明，LfNPs 为 TMZ 的有效递送提供了一种有效的治疗神经胶质瘤的平台。
