Division of Functional Materials and Nano Devices, Ningbo Institute of Materials Technology & Engineering, Key Laboratory of Magnetic Materials and Devices, Chinese Academy of Sciences, Ningbo, Zhejiang, 315201, China.
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, China.
Biomaterials. 2015 Nov;70:1-11. doi: 10.1016/j.biomaterials.2015.08.022. Epub 2015 Aug 10.
One big challenge with active targeting of nanocarriers is non-specific binding between targeting molecules and non-target moieties expressed on non-cancerous cells, which leads to non-specific uptake of nanocarriers by non-cancerous cells. Here, we propose a novel Trojan-horse targeting strategy to hide or expose the targeting molecules of nanocarriers on-demand. The non-specific uptake by non-cancerous cells can be reduced because the targeting molecules are hidden in hydrophilic polymers. The nanocarriers are still actively targetable to cancer cells because the targeting molecules can be exposed on-demand at tumor regions. Typically, Fe3O4 nanocrystals (FN) as magnetic resonance imaging (MRI) contrast agents were encapsulated into albumin nanoparticles (AN), and then folic acid (FA) and pH-sensitive polymers (PP) were grafted onto the surface of AN-FN to construct PP-FA-AN-FN nanoparticles. Fourier transform infrared spectroscopy (FT-IR), dynamic light scattering (DLS), transmission electron microscope (TEM) and gel permeation chromatography (GPC) results confirm successful construction of PP-FA-AN-FN. According to difference of nanoparticle-cellular uptake between pH 7.4 and 5.5, the weight ratio of conjugated PP to nanoparticle FA-AN-FN (i.e. graft density) and the molecular weight of PP (i.e. graft length) are optimized to be 1.32 and 5.7 kDa, respectively. In vitro studies confirm that the PP can hide ligand FA to prevent it from binding to cells with FRα at pH 7.4 and shrink to expose FA at pH 5.5. In vivo studies demonstrate that our Trojan-horse targeting strategy can reduce the non-specific uptake of the PP-FA-AN-FN by non-cancerous cells. Therefore, our PP-FA-AN-FN might be used as an accurately targeted MRI contrast agent.
主动靶向纳米载体的一个主要挑战是靶向分子与非癌细胞上表达的非靶部分之间的非特异性结合,这导致非癌细胞对纳米载体的非特异性摄取。在这里,我们提出了一种新的特洛伊木马靶向策略,以按需隐藏或暴露纳米载体的靶向分子。由于靶向分子隐藏在亲水性聚合物中,因此可以减少非癌细胞的非特异性摄取。纳米载体仍然可以主动靶向癌细胞,因为可以按需在肿瘤区域暴露靶向分子。通常,将 Fe3O4 纳米晶体 (FN) 作为磁共振成像 (MRI) 造影剂包封在白蛋白纳米颗粒 (AN) 中,然后将叶酸 (FA) 和 pH 敏感聚合物 (PP) 接枝到 AN-FN 的表面上,构建 PP-FA-AN-FN 纳米颗粒。傅里叶变换红外光谱 (FT-IR)、动态光散射 (DLS)、透射电子显微镜 (TEM) 和凝胶渗透色谱 (GPC) 结果证实了 PP-FA-AN-FN 的成功构建。根据 pH 值为 7.4 和 5.5 时纳米颗粒-细胞摄取的差异,优化了接枝到纳米颗粒 FA-AN-FN 上的 PP 的重量比(即接枝密度)和 PP 的分子量(即接枝长度)分别为 1.32 和 5.7 kDa。体外研究证实,PP 可以在 pH 值为 7.4 时隐藏配体 FA,以防止其与 FRα 结合的细胞结合,并在 pH 值为 5.5 时收缩以暴露 FA。体内研究表明,我们的特洛伊木马靶向策略可以减少非癌细胞对 PP-FA-AN-FN 的非特异性摄取。因此,我们的 PP-FA-AN-FN 可能被用作一种精确靶向的 MRI 造影剂。