Department of Surgery, Pennsylvania State University, Hershey, Pennsylvania 17033, USA.
Biomacromolecules. 2009 Mar 9;10(3):505-16. doi: 10.1021/bm801026k.
This study describes novel quaternary ammonium beta-cyclodextrin (QAbetaCD) nanoparticles as drug delivery carriers for doxorubicin (DOX), a hydrophobic anticancer drug, across the blood-brain barrier (BBB). QAbetaCD nanoparticles show 65-88 nm hydrodynamic radii with controllable cationic properties by adjusting the incorporated amount of quaternary ammonium group in their structure. ATR-FTIR studies confirm the complexation between the QAbetaCD nanoparticles and DOX. QAbetaCD nanoparticles are not toxic to bovine brain microvessel endothelial cells (BBMVECs) at concentrations up to 500 microg x mL(-1). They also do not change the integrity of BBMVEC monolayers, an in vitro BBB model, including transendothelial electrical resistance value, Lucifer yellow permeability, tight junction protein occludin and ZO-1 expression and morphology, cholesterol extraction, and P-glycoprotein (P-gp) expression and efflux activity, at a concentration of 100 microg x mL(-1). Some QAbetaCD nanoparticles not only are twice as permeable as dextran (M(w) = 4000 g x mol(-1)) control, but also enhance DOX permeability across BBMVEC monolayers by 2.2 times. Confocal microscopy and flow cytometry measurements imply that the permeability of QAbetaCD nanoparticles across the in vitro BBB is probably due to endocytosis. DOX/QAbetaCD complexes kill U87 cells as effectively as DOX alone. However, QAbetaCD nanoparticles completely protect BBMVECs from cytotoxicity of DOX at 5 and 10 microM after 4 h incubation. The developed QAbetaCD nanoparticles have great potential in safely and effectively delivering DOX and other therapeutic agents across the BBB.
本研究描述了新型季铵-β-环糊精（QAbetaCD）纳米粒子作为一种药物递送载体，用于将疏水性抗癌药物阿霉素（DOX）递送至血脑屏障（BBB）。通过调整其结构中季铵基团的掺入量，QAbetaCD 纳米粒子表现出 65-88nm 的水动力半径和可控的阳离子特性。ATR-FTIR 研究证实了 QAbetaCD 纳米粒子与 DOX 的络合。在高达 500μg x mL(-1)的浓度下，QAbetaCD 纳米粒子对牛脑微血管内皮细胞（BBMVEC）没有毒性。在浓度为 100μg x mL(-1)时，它们也不会改变体外 BBB 模型即 BBMVEC 单层的完整性，包括跨内皮电阻值、荧光黄通透性、紧密连接蛋白 occludin 和 ZO-1 的表达和形态、胆固醇提取以及 P-糖蛋白（P-gp）的表达和外排活性。一些 QAbetaCD 纳米粒子不仅通透性是分子量为 4000g/mol 的葡聚糖的两倍，而且还能将 DOX 透过 BBMVEC 单层的通透性提高 2.2 倍。共聚焦显微镜和流式细胞术测量表明，QAbetaCD 纳米粒子透过体外 BBB 的通透性可能是由于内吞作用。DOX/QAbetaCD 复合物对 U87 细胞的杀伤效果与单独使用 DOX 一样有效。然而，在 4 小时孵育后，QAbetaCD 纳米粒子在 5 和 10μM 时完全保护 BBMVEC 免受 DOX 的细胞毒性。开发的 QAbetaCD 纳米粒子在安全有效地将 DOX 和其他治疗剂递送至 BBB 方面具有巨大的潜力。
