Development of drug loaded nanoparticles for tumor targeting. Part 1: Synthesis, characterization, and biological evaluation in 2D cell cultures.
Development of drug loaded nanoparticles for tumor targeting. Part 1: Synthesis, characterization, and biological evaluation in 2D cell cultures.
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DOI：
10.1039/c3nr33777d
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发表时间：
2013-05-07
期刊：
影响因子：
6.7
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
El-Dakdouki MH;Puré E;Huang X
纳米颗粒（NP）作为药物输送载体正在被广泛研究，但它们在肿瘤内的渗透性通常有限。我们设想，通过靶向细胞表面的内吞受体，可以通过受体介导的内吞作用显着增强纳米颗粒的摄取。此外，如果受体被回收到细胞表面，纳米粒子货物可以被转运出细胞，然后被邻近细胞吸收，从而增强实体瘤的渗透。为了验证我们的假设，在两篇文章的第一篇中，我们报道了负载阿霉素 (DOX) 的透明质酸 (HA) 包被的二氧化硅纳米颗粒 (SNP) 的合成，该纳米颗粒包含一个高荧光核心，可靶向 CD44（癌细胞表面表达的一种受体）。 HA 缀合到通过油/水微乳液方法制备的胺功能化 SNP 上。细胞毒性药物 DOX 的固定化是通过酸敏感的腙键实现的。通过透射电子显微镜 (TEM)、动态光散射 (DLS)、zeta 电位测量、热重分析 (TGA)、紫外-可见光吸收和核磁共振 (NMR) 对纳米粒子进行了全面表征。初步的生物学评估实验表明，与无配体的 SNP 相比，在 2D 单层细胞培养物中进行评估时，表达 CD44 的 SKOV-3 卵巢癌细胞对 HA-SNP 的摄取显着增强。机制研究表明，HA-SNP 的细胞摄取主要是通过 CD44 介导的内吞作用。固定有 DOX 的 HA-SNP 也能被 SKOV-3 细胞有效内吞。 HA-SNP 增强的肿瘤渗透和药物递送特性将在后续论文中在 3D 肿瘤模型中进行评估。
Nanoparticles (NPs) are being extensively studied as carriers for drug delivery, but they often have limited penetration inside tumor. We envision that by targeting an endocytic receptor on cell surface, the uptake of NPs can be significantly enhanced through receptor mediated endocytosis. In addition, if the receptor is recycled to cell surface, the NP cargo can be transported out of the cells, which are then taken up by neighboring cells thus enhancing solid tumor penetration. To validate our hypothesis, in the first of two articles, we report the synthesis of doxorubicin (DOX)-loaded, hyaluronan (HA) coated silica nanoparticles (SNP) containing a highly fluorescent core to target CD44, a receptor expressed on cancer cell surface. HA was conjugated onto amine-functionalized SNPs prepared through an oil/water microemulsion method. The immobilization of the cytotoxic drug DOX was achieved through an acid sensitive hydrazone linkage. The NPs were fully characterized by transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential measurements, thermal gravimetric analysis (TGA), UV-vis absorbance, and nuclear magnetic resonance (NMR). Initial biological evaluation experiments demonstrated that compared to ligand-free SNPs, the uptake of HA-SNP by the CD44-expressing SKOV-3 ovarian cancer cells was significantly enhanced when evaluated in the 2D monolayer cell culture. Mechanistic studies suggested that cellular uptake of HA-SNP was mainly through CD44 mediated endocytosis. HA-SNPs with DOX immobilized were endocytosed efficiently by the SKOV-3 cells as well. The enhanced tumor penetration and drug delivery properties of HA-SNP will be evaluated in 3D tumor models in the subsequent paper.
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