Department of Pharmaceutics, School of Pharmaceutical Science, Shandong University, 44 Wen Hua Xi Road, Ji'nan 250012, Shandong, People's Republic of China.
Department of Pharmaceutics, School of Pharmaceutical Science, Shandong University, 44 Wen Hua Xi Road, Ji'nan 250012, Shandong, People's Republic of China.
Colloids Surf B Biointerfaces. 2015 Feb 1;126:531-40. doi: 10.1016/j.colsurfb.2015.01.006. Epub 2015 Jan 14.
The greatest challenge in combining chemotherapy and gene therapy is the construction of a suitable platform for the co-delivery of the drug and the therapeutic gene. In this study, a simplified and effective system for the co-loading and intracellular co-delivery of doxorubicin (Dox) and siRNA was developed. Oligodeoxynucleotides with CGA repeating units (CGA-ODNs) were introduced to load Dox. The loading mechanism was based on the ability of Dox to intercalate within double-stranded 5'-GC-3' or 5'-CG-3' sequences. Poly(ethyleneimine) (PEI) was used to condense siRNA and Dox loaded CGA-ODNs (CGA-ODNs-Dox) to obtain Dox and siRNA co-loaded nanocomplexes (PEI/CGA-ODNs-Dox&siRNA, PDR). The cellular uptake of PDR in A549 and HepG2 cells was 39.52% and 36.78%, respectively, indicating that the co-loading and co-delivery effect was achieved through the mono-loading method. An in vitro drug release study indicated that CMCS-poly(ethylene glycol) (PEG)-NGR (CPN) modified PDR (CPN-PDR) displayed a pH-triggered drug release property due to the reversed surface charge of CMCS in an acidic environment. Cellular uptake studies also confirmed that the disassembly of CPN-PDR was induced by an acidic pH in the extracellular matrix. Moreover, lysosomal escape of both Dox and siRNA was observed. Successful accumulation of Dox in the cell nucleus and siRNA in the cytoplasm was also demonstrated. Consequently, the novel construction of a simplified loading method and high co-delivery efficiency was proven to be a promising platform for the co-delivery of drug and siRNA.
将化疗和基因治疗相结合的最大挑战是构建一个合适的平台，用于共同递送药物和治疗基因。在这项研究中，开发了一种用于共同加载和细胞内共递delivery 的简化有效系统，用于共递delivery 阿霉素（Dox）和 siRNA。具有 CGA 重复单元的寡脱氧核苷酸（CGA-ODNs）被引入来加载 Dox。加载机制基于 Dox 在双链 5'-GC-3' 或 5'-CG-3' 序列内嵌入的能力。聚（亚乙基亚胺）（PEI）用于凝聚 siRNA 和加载 CGA-ODNs 的 Dox（CGA-ODNs-Dox）以获得 Dox 和 siRNA 共加载纳米复合物（PEI/CGA-ODNs-Dox&siRNA，PDR）。PDR 在 A549 和 HepG2 细胞中的细胞摄取率分别为 39.52%和 36.78%，表明通过单加载方法实现了共加载和共递delivery 效果。体外药物释放研究表明，由于 CMCS 在酸性环境中带相反电荷，CMCS-聚（乙二醇）（PEG）-NGR（CPN）修饰的 PDR（CPN-PDR）显示出 pH 触发的药物释放特性。细胞摄取研究还证实，CPN-PDR 在细胞外基质的酸性 pH 下诱导解组装。此外，观察到 Dox 和 siRNA 的溶酶体逃逸。还证明了 Dox 在细胞核中的成功积累和 siRNA 在细胞质中的成功积累。因此，这种简化加载方法和高共递delivery 效率的新构建被证明是药物和 siRNA 共递delivery 的有前途的平台。
