Kaneshiro Todd L, Lu Zheng-Rong
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108, USA.
Biomaterials. 2009 Oct;30(29):5660-6. doi: 10.1016/j.biomaterials.2009.06.026.
Codelivery of different therapeutics has a potential to efficaciously treat human diseases via their synergetic effects. We have recently developed a new class dendrimers, poly(l-lysine) dendrimers with a silsesquioxane cubic core (nanoglobules). These dendrimers have compact globular and well-defined structures and highly functionalized surfaces, and can be used as versatile carriers for biomedical applications. In this study, a generation-3 (G3) nanoglobular dendrimer was used to conjugate a peptide c(RGDfK) with a PEG spacer for codelivery of doxorubicin (DOX) and siRNA. Doxorubicin (DOX) was coupled to the RGD targeted nanoglobule via a degradable disulfide spacer to give G3-[PEG-RGD]-[DOX]. G3-[PEG-RGD]-[DOX] showed higher cytotoxicity than free DOX at high doses in glioblastoma U87 cells. G3-[PEG-RGD]-[DOX] was further complexed with siRNA and such complexes were readily internalized by U87 cells as shown by confocal microscopy. The siRNA complexes of the targeted conjugate resulted in significantly higher gene silencing efficiency in U87-Luc cells than those of control conjugates G3-[PEG-RGD] and G3-[DOX]. The nanoglobules are promising carriers for the codelivery of nucleic acids and chemotherapeutic agents.
递送不同的治疗药物有可能通过协同效应有效治疗人类疾病。我们最近开发了一类新型树枝状聚合物，即具有倍半硅氧烷立方核的聚（L-赖氨酸）树枝状聚合物（纳米球）。这些树枝状聚合物具有紧密的球状且结构明确，表面高度功能化，可作为生物医学应用的通用载体。在本研究中，使用第三代（G3）纳米球树枝状聚合物通过聚乙二醇（PEG）间隔基连接肽c(RGDfK)，用于共递送阿霉素（DOX）和小干扰RNA（siRNA）。阿霉素（DOX）通过可降解的二硫键间隔基与RGD靶向纳米球偶联，得到G3-[PEG-RGD]-[DOX]。在高剂量下，G3-[PEG-RGD]-[DOX]在胶质母细胞瘤U87细胞中显示出比游离DOX更高的细胞毒性。G3-[PEG-RGD]-[DOX]进一步与siRNA复合，共聚焦显微镜显示此类复合物很容易被U87细胞内化。靶向偶联物的siRNA复合物在U87-Luc细胞中的基因沉默效率显著高于对照偶联物G3-[PEG-RGD]和G
