ABSTRACT

Background

Successful delivery of anticancer drugs to intracellular targets requires different properties of the nanocarrier to overcome multiple transport barriers. However, few nanocarrier systems, to date, possess such properties, despite knowledge about the biological fate of inorganic and polymeric nanocarriers in relation to their fixed size, shape and surface properties. Herein, a polymer-lipid hybrid nanoparticle (PLN) system is described with size and shape transformability and its mechanisms of cellular uptake and intracellular trafficking are studied.

Methods

Pharmaceutical lipids were screened for use in transformable PLN. Mechanisms of cellular uptake and the role of fatty acid-binding proteins in intracellular trafficking of PLN were investigated in breast cancer cells. Intra-tumoral penetration and retention of doxorubicin (DOX) were evaluated by confocal microscopy.

Results

The lead PLNs showed time-dependent size reduction and shape change from spherical to spiky shape. This transformability of PLNs and lipid trafficking pathways facilitated intracellular transport of DOX-loaded PLN (DOX-PLN) into mitochondria and nuclei. DOX-PLN significantly increased DOX penetration and retention over free DOX or non-transformable liposomal DOX particles at 4 h post-intravenous administration.

Conclusion

Transformability of PLN and lipid-biology interplay can be exploited to design new nanocarriers for effective drug delivery to tumor cells and intracellular targets.

中文翻译：

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探索聚合物-脂质杂化纳米粒子的可转化性和纳米材料-生物学相互作用，以促进抗癌药物的肿瘤渗透、细胞摄取和细胞内靶向

摘要

背景

将抗癌药物成功输送到细胞内靶标需要纳米载体的不同特性来克服多种运输障碍。然而，迄今为止，尽管了解无机和聚合物纳米载体与其固定尺寸、形状和表面特性相关的生物学命运，但迄今为止，很少有纳米载体系统具有此类特性。在此，描述了一种聚合物-脂质杂化纳米颗粒 (PLN) 系统，其具有尺寸和形状可转换性，并研究了其细胞摄取和细胞内运输的机制。

方法

筛选用于可转化 PLN 的药物脂质。在乳腺癌细胞中研究了细胞摄取的机制和脂肪酸结合蛋白在 PLN 细胞内运输中的作用。通过共聚焦显微镜评估阿霉素 (DOX) 的肿瘤内渗透和保留。

结果

铅 PLN 显示出随时间变化的尺寸减小和形状从球形变为尖状的变化。PLN 的这种可转化性和脂质运输途径促进了装载 DOX 的 PLN (DOX-PLN) 向线粒体和细胞核的细胞内运输。在静脉给药后 4 小时，与游离 DOX 或不可转化脂质体 DOX 颗粒相比，DOX-PLN 显着增加了 DOX 渗透和保留。

结论

PLN 的可转化性和脂质-生物学相互作用可用于设计新的纳米载体，以将药物有效递送至肿瘤细胞和细胞内靶标。