Membrane Translocation and Organelle-Selective Delivery Steered by Polymeric Zwitterionic Nanospheres
Membrane Translocation and Organelle-Selective Delivery Steered by Polymeric Zwitterionic Nanospheres
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DOI：
10.1021/acs.biomac.6b00172
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发表时间：
2016-04-01
影响因子：
6.2
通讯作者：
Winnik, Francoise M.
中科院分区：
文献类型：
--
作者：
Morimoto, Nobuyuki;Wakamura, Masaru;Winnik, Francoise M.
设计用于药物和成像剂的细胞递送的大多数纳米颗粒通过内吞途径进入细胞，导致它们被截留在内体中，内体对纳米颗粒在细胞内的进一步运输提供了强大的屏障。已知一些物质，例如细胞穿透肽（CPP），不仅通过内吞作用进入细胞，而且还通过细胞膜进入细胞质，成功绕过内体。我们在这里报告，3-二甲基（甲基丙烯酰氧基乙基）丙磺酸铵和聚（乙二醇）甲基丙烯酸酯，p（DMAPS-ran-PEGMA）的无规共聚物，在细胞内主要是通过易位通过细胞膜，而不是胞吞作用。动态光散射，共聚焦荧光显微镜和流式细胞术的聚合物的性质和它们的摄取模式进行了系统的研究。在人宫颈癌细胞系（HeLa）中使用细胞摄取机制的特异性抑制剂，我们表明这些无毒的合成聚两性离子以自组装纳米球的形式存在于细胞培养基中，当它们吸附在质膜上并通过质膜移位时，这些纳米球会散开。（DMAPS-ran-PEGMA）与罗丹明B选择性地递送至线粒体，而多柔比星（Dox）p-（DMAPS-ran-PEGMA）缀合物在细胞核和线粒体中积累，有效地诱导HeLa细胞的凋亡。这些发现表明，无细胞毒性和易于合成的p（DMAPS-ran-PEGMA）可以作为生物成像工具和药物纳米载体的应用。
The majority of nanoparticles designed for cellular delivery of drugs and imaging agents enter the cell via endocytotic pathways leading to their entrapment in endosomes that present a robust barrier to further trafficking of the nanoparticles within the cells. A few materials, such as the cell penetrating peptides (CPPs), are known to enter cells not only via endocytosis, but also via translocation through the cell membrane into the cytoplasm, successfully bypassing the endosomes. We report here that random copolymers of 3-dimethyl(methacryloyloxyethyl)ammonium propanesulfonate and poly(ethylene glycol) methacrylate, p(DMAPS-ran-PEGMA), are internalized in cells primarily via translocation through the cell membrane rather than endocytosis. The properties of the polymers and their modes of uptake were investigated systematically by dynamic light scattering, confocal fluorescence microscopy, and flow cytometry. Using specific inhibitors of the cellular uptake machinery in a human cervical carcinoma cell line (HeLa), we show that these nontoxic synthetic polyzwitterions exist in cell media as self assembled nanospheres that unravel as they adsorb on the plasma membrane and translocate through it. Conjugates of p(DMAPS-ran-PEGMA) with rhodamine B were delivered selectively to the mitochondria, whereas doxorubicin (Dox)p-(DMAPS-ran-PEGMA) conjugates were accumulated in both the nucleus and the mitochondria, effectively inducing apoptosis in HeLa cells. These findings suggest that the noncytotoxic and readily synthesized p(DMAPS-ran-PEGMA) can find applications as bioimaging tools and drug nanocarriers.