Advanced Pharmaceutics & Drug Delivery Laboratory, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
Departments of Medical Biophysics and Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, Toronto, Ontario, M5G 2M9, Canada.
Pharm Res. 2021 Nov;38(11):1897-1914. doi: 10.1007/s11095-021-03122-9. Epub 2021 Oct 15.
Chemotherapy for glioblastoma multiforme (GBM) remains ineffective due to insufficient penetration of therapeutic agents across the blood-brain barrier (BBB) and into the GBM tumor. Herein, is described, the optimization of the lipid composition and fabrication conditions for a BBB- and tumor penetrating terpolymer-lipid-hybrid nanoparticle (TPLN) for delivering doxorubicin (DOX) to GBM.
The composition of TPLNs was first screened using different lipids based on nanoparticle properties and in vitro cytotoxicity by using 2 full factorial experimental design. The leading DOX loaded TPLNs (DOX-TPLN) were prepared by further optimization of conditions and used to study cellular uptake mechanisms, in vitro cytotoxicity, three-dimensional (3D) glioma spheroid penetration, and in vivo biodistribution in a murine orthotopic GBM model.
Among various lipids studied, ethyl arachidate (EA) was found to provide excellent nanoparticle properties e.g., size, polydispersity index (PDI), zeta potential, encapsulation efficiency, drug loading, and colloidal stability, and highest anticancer efficacy for DOX-TPLN. Further optimized EA-based TPLNs were prepared with an optimal particle size (103.8 ± 33.4 nm) and PDI (0.208 ± 0.02). The resultant DOX-TPLNs showed ~ sevenfold higher efficacy than free DOX against human GBM U87-MG-RED-FLuc cells in vitro. The interaction between the TPLNs and the low-density lipoprotein receptors also facilitated cellular uptake, deep penetration into 3D glioma spheroids, and accumulation into the in vivo brain tumor regions of DOX-TPLNs.
This work demonstrated that the TPLN system can be optimized by rational selection of lipid type, lipid content, and preparation conditions to obtain DOX-TPLN with enhanced anticancer efficacy and GBM penetration and accumulation.
由于治疗药物难以穿透血脑屏障（BBB）进入脑胶质瘤多形性（GBM）肿瘤，替莫唑胺化疗对 GBM 仍无效。本文描述了优化 BBB 和肿瘤穿透性三嵌段聚合物-脂质-杂化纳米粒子（TPLN）的脂质组成和制备条件，以递送阿霉素（DOX）至 GBM。
首先根据纳米颗粒特性和体外细胞毒性，使用 2 全因子实验设计筛选 TPLN 的组成。通过进一步优化条件，制备载 DOX 的 TPLN（DOX-TPLN），并用于研究细胞摄取机制、体外细胞毒性、三维（3D）脑胶质瘤球体穿透性以及在小鼠原位 GBM 模型中的体内生物分布。
在所研究的各种脂质中，发现乙基花生酸（EA）可提供出色的纳米颗粒特性，例如粒径、多分散指数（PDI）、Zeta 电位、包封效率、载药量和胶体稳定性，以及对 DOX-TPLN 的最佳抗癌效果。进一步优化的基于 EA 的 TPLN 的最佳粒径（103.8±33.4nm）和 PDI（0.208±0.02）。结果表明，与游离 DOX 相比，DOX-TPLN 在体外对人 GBM U87-MG-RED-FLuc 细胞的疗效提高了约 7 倍。TPLN 与低密度脂蛋白受体之间的相互作用还促进了细胞摄取、深入穿透 3D 脑胶质瘤球体以及 DOX-TPLN 在体内脑肿瘤区域的积累。
本工作表明，可以通过合理选择脂质类型、脂质含量和制备条件来优化 TPLN 系统，以获得具有增强的抗癌效果和 GBM 穿透和积累能力的 DOX-TPLN。
