Efficient Subcellular Targeting to the Cell Nucleus of Quantum Dots Densely Decorated with a Nuclear Localization Sequence Peptide
Efficient Subcellular Targeting to the Cell Nucleus of Quantum Dots Densely Decorated with a Nuclear Localization Sequence Peptide
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DOI：
10.1021/acsami.5b10295
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发表时间：
2016-01-27
影响因子：
9.5
通讯作者：
Stepensky, David
中科院分区：
文献类型：
--
作者：
Maity, Amit Ranjan;Stepensky, David
细胞器靶向给药可以提高细胞内作用药物的效率，降低其毒性。我们用三步修饰法制备了密集修饰NLS多肽靶向残基的核壳型CdSe-ZnS量子点，并研究了它们的内吞和核靶向效率。在不同的修饰阶段(16.3、18.9和21.9 nm)，生成的量子点的直径逐渐增大，Zeta电位变得不那么负(-33.2、17.5和11.9 mV)，FTIR光谱出现了特征变化。最后修饰阶段的定量分析表明，分别有37.9%和33.2%的炔改性NLS基团与量子点表面发生共价键合或吸附。这些数字相当于63.6和55.7个多肽被结合或吸附到一个量子点上(42和37个结合和吸附在量子点表面上的多肽的表面密度)，这比以前报道的用于核靶向药物输送的制剂的装饰效率的大多数研究要高。与其他研究的量子点制剂相比，用NLS多肽修饰的量子点具有更有效的内吞作用，并在细胞核或其附近积累更高程度(QD-COOH、QD-叠氮和QD-NLS制剂的平均细胞吞噬的量子点的11.9%、14.6%和56.1%)。我们的结论是，用NLS残基致密修饰量子点增加了它们的内吞作用，并导致了它们的核靶向性(优先聚集在细胞核内或靠近细胞核)。本研究中使用的实验系统和研究工具可以定量研究控制量子点核靶向的机制及其对配方性能的依赖。这些发现将有助于开发亚细胞靶向DDSS，将特定药物输送到靶细胞的细胞核，并将提高这些药物的疗效和降低这些药物的毒性。
Organelle -targeted drug delivery can enhance the efficiency of the intracellularly acting drugs and reduce their toxicity. We generated core shell type CdSe-ZnS quantum dots (QDs) densely decorated with NLS peptidic targeting residues using a 3 -stage decoration approach and investigated their endocytosis and nuclear targeting efficiencies. The diameter of the generated QDs increased following the individual decoration stages (16.3, 18.9, and 21.9 nm), the zeta-potential became less negative (-33.2, 17.5, and 11.9 mV), and characteristic changes appeared in the FTIR spectra following decoration with the linker and NLS peptides. Quantitative analysis of the last decoration stage revealed that 37.9% and 33.2% of the alkyne-modified NLS groups that were added to became covalently attached or adsorbed to the QDs surface, respectively. These numbers correspond to 63.6 and 55.7 peptides conjugated or adsorbed to a single QD (the surface density of 42 and 37 conjugated and adsorbed peptides per 1000 nm2 of the QDs surface), which is higher than in the majority Of previous studies that reported decoration efficiencies of formulations intended for nuclear -targeted drug delivery. QDs decorated with NLS peptides undergo more efficient endocytosis, as compared to other investigated QDs formulations, and accumulated to a higher extent in the cell nucleus or in close vicinity to it (11.9%, 14.6%, and 56.1% of the QDs endocytosed by an average cell for the QD-COOH, QD-azide, and QD-NLS formulations, respectively). We conclude that dense decoration of QDs with NLS residues increased their endocytosis and led to their nuclear targeting (preferential accumulation, in the cells nuclei or in close vicinity to them). The experimental system and research tools that were used in this study allow quantitative investigation of the mechanisms that govern the QDs nuclear targeting and their dependence on the formulation properties. These findings will contribute to the development of subcellularly targeted DDSs that will deliver specific drugs to the nuclei of the target cells and will enhance efficacy and reduce toxicity of these drugs.