Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery.
Folic acid-decorated polyamidoamine dendrimer exhibits high tumor uptake and sustained highly localized retention in solid tumors: Its utility for local siRNA delivery.
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DOI：
10.1016/j.actbio.2017.04.023
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发表时间：
2017-07-15
影响因子：
9.7
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Xu L;Yeudall WA;Yang H
研究了叶酸（FA）修饰的聚酰胺胺树状聚合物G4（G4-FA）作为载体用于siRNA的局部递送的效用。在头颈部鳞状细胞癌（HNSCC）的异种移植HN 12（或HN 12-YFP）肿瘤小鼠模型中，瘤内（i.t.）根据近红外（NIR）成像评估，注射的G4-FA表现出高的肿瘤摄取和持续的高度局部保留在肿瘤中。选择针对血管内皮生长因子A（siVEGFA）的siRNA作为治疗方式。与非治疗性处理组（PBS溶液或与非治疗性绿色荧光蛋白siRNA [siGFP]复合的树枝状聚合物）相比，G4-FA/siVEGFA在单剂量和两剂量方案研究中显示出肿瘤抑制作用。特别地，两个剂量的G4-FA/siVEGFA i.t.间隔八天给药导致肿瘤生长的更深刻抑制，伴随着血管生成的显著减少，如通过CD 31染色和微血管计数所判断的。通过YFP肿瘤的活体荧光成像半定量地确定了两次给药方案研究中的肿瘤大小减小，并独立地支持了G4-FA/siVEGFA的抗肿瘤作用。总之，G4-FA显示出高肿瘤摄取和持续保留特性，使其成为局部递送siRNA以治疗容易获得的癌症（如HNSCC）的合适平台。
The utility of folic acid (FA)-decorated polyamidoamine dendrimer G4 (G4-FA) as a vector was investigated for local delivery of siRNA. In a xenograft HN12 (or HN12-YFP) tumor mouse model of head and neck squamous cell carcinomas (HNSCC), intratumorally (i.t.) injected G4-FA exhibited high tumor uptake and sustained highly localized retention in the tumors according to near infrared (NIR) imaging assessment. siRNA against vascular endothelial growth factor A (siVEGFA) was chosen as a therapeutic modality. Compared to the nontherapeutic treatment groups (PBS solution or dendrimer complexed with nontherapeutic green fluorescent protein siRNA [siGFP]), G4-FA/siVEGFA showed tumor inhibition effects in single-dose and two-dose regimen studies. In particular, two doses of G4-FA/siVEGFA i.t. administered eight days apart resulted in a more profound inhibition of tumor growth, accompanied with significant reduction in angiogenesis, as judged by CD31 staining and microvessel counts. Tumor size reduction in the two-dose regimen study was ascertained semi-quantitatively by live fluorescence imaging of YFP tumors and independently supported antitumor effects of G4-FA/siVEGFA. Taken together, G4-FA shows high tumor uptake and sustained retention properties, making it a suitable platform for local delivery of siRNAs to treat cancers that are readily accessible such as HNSCC.
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