State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering , Southeast University , 2 Sipailou Road , Nanjing 210096 , P. R. China.
Department of Chemistry , University of Michigan , 930 North University Avenue , Ann Arbor , Michigan 48109 , United States.
J Am Chem Soc. 2018 Mar 21;140(11):4062-4070. doi: 10.1021/jacs.7b13672. Epub 2018 Feb 20.
Research on nanomedicines has rapidly progressed in the past few years. However, due to the limited size of nuclear pores (9-12 nm), the nuclear membrane remains a difficult barrier to many nucleus-targeting agents. Here, we report the development of a general platform to effectively deliver chemical compounds such as drug molecules or nanomaterials into cell nuclei. This platform consists of a polyamine-containing polyhedral oligomeric silsesquioxane (POSS) unit, a hydrophilic polyethylene glycol (PEG) chain, and the photosensitizer rose bengal (RB), which can self-assemble into nanoparticles (denoted as PPR NPs). Confocal fluorescence imaging showed that PPR NPs mainly located in lysosomes after cellular internalization. After mild light irradiation, however, PPR NPs effectively disrupted lysosomal structures by singlet oxygen (O) oxidation and substantially accumulated on nuclear membranes, which enabled further disruption of the membrane integrity and promoted their final nuclear entry. Next, we selected two chemotherapeutic agents (10-hydroxycamptothecine and docetaxel) and a fluorescent dye (DiD) as payloads of PPR NPs and successfully demonstrated that this nanocarrier could efficiently deliver them into cell nuclei in a light-controlled manner. In addition to molecular compounds, we have also demonstrated that PPR NPs could facilitate the nuclear entry of nanomaterials, including Prussian blue NPs as well as gold nanorods. Compared to traditional strategies for nuclear delivery, this highly controllable nanoplatform avoids complicated modification of nucleus-targeting ligands and is generally applicable to both molecular compounds and nanomaterials.
在过去的几年中，纳米医学的研究取得了飞速的进展。然而，由于核孔（9-12nm）的尺寸有限，核膜仍然是许多核靶向试剂的一个难以逾越的障碍。在这里，我们报告了一种通用平台的开发，该平台可有效将化学化合物（如药物分子或纳米材料）递送到细胞核内。该平台由含多胺的笼型倍半硅氧烷（POSS）单元、亲水性的聚乙二醇（PEG）链和光敏剂玫瑰红（RB）组成，可自组装成纳米颗粒（表示为 PPR NPs）。共焦荧光成像显示，PPR NPs 在细胞内化后主要位于溶酶体中。然而，经过轻微的光照后，PPR NPs 通过单线态氧（O）氧化有效地破坏了溶酶体结构，并大量聚集在核膜上，从而进一步破坏了膜的完整性，并促进了它们最终进入核内。接下来，我们选择了两种化疗药物（10-羟基喜树碱和多西紫杉醇）和一种荧光染料（DiD）作为 PPR NPs 的有效载荷，并成功地证明了这种纳米载体可以以光控的方式将它们有效地递送到细胞核内。除了分子化合物外，我们还证明了 PPR NPs 可以促进纳米材料进入细胞核，包括普鲁士蓝 NPs 和金纳米棒。与传统的核递药策略相比，这种高度可控的纳米平台避免了对核靶向配体的复杂修饰，并且普遍适用于分子化合物和纳米材料。
