Tumor-targeted delivery of siRNA using fatty acyl-CGKRK peptide conjugates.
Tumor-targeted delivery of siRNA using fatty acyl-CGKRK peptide conjugates.
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DOI：
10.1038/s41598-017-06381-y
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发表时间：
2017-07-21
影响因子：
4.6
通讯作者：
Aliabadi HM
中科院分区：
文献类型：
--
作者：
Sharma M;El-Sayed NS;Do H;Parang K;Tiwari RK;Aliabadi HM
肿瘤靶向载体提供化疗剂至肿瘤组织的有效递送。CGKRK是已知的肿瘤靶向肽之一，对血管生成血管和肿瘤细胞具有显著的特异性。在这里，我们设计了脂肪酰基缀合的CGKRK肽，基于疏水修饰的CGKRK肽可以增强靶向肿瘤细胞的siRNA的细胞渗透和递送以有效沉默所选蛋白质的假设。我们合成了六个脂肪酰基肽共轭物，使用饱和和不饱和脂肪酸的不同链来研究这种方法的效率。在肽：siRNA重量/重量比为10：1（N/P = 13.6）时，几乎所有的肽都显示出与siRNA的完全结合，并且在w/w比为20：1（N/P = 27.3）时，观察到siRNA完全保护免于早期酶降解。缀合的肽和肽/siRNA复合物在所选细胞系中未显示出显著的细胞毒性。油酸缀合的肽在肽：siRNA w/w比为80：1（N/P = 109）时显示出最高的siRNA摄取和驱动蛋白纺锤体蛋白沉默效率。对于所有脂肪酰基-肽缀合物，siRNA内化到非致瘤性肾细胞中是可忽略的。这些结果表明，脂肪酸与CGKRK的缀合可以产生特异性地在肿瘤细胞中siRNA沉默的有效递送系统。
Tumor-targeted carriers provide efficient delivery of chemotherapeutic agents to tumor tissue. CGKRK is one of the well-known tumor targeting peptides with significant specificity for angiogenic blood vessels and tumor cells. Here, we designed fatty acyl conjugated CGKRK peptides, based on the hypothesis that hydrophobically-modified CGKRK peptide could enhance cellular permeation and delivery of siRNA targeted to tumor cells for effective silencing of selected proteins. We synthesized six fatty acyl-peptide conjugates, using a diverse chain of saturated and unsaturated fatty acids to study the efficiency of this approach. At peptide:siRNA weight/weight ratio of 10:1 (N/P ≈ 13.6), almost all the peptides showed complete binding with siRNA, and at a w/w ratio of 20:1 (N/P ≈ 27.3), complete protection of siRNA from early enzymatic degradation was observed. Conjugated peptides and peptide/siRNA complexes did not show significant cytotoxicity in selected cell lines. The oleic acid-conjugated peptide showed the highest efficiency in siRNA uptake and silencing of kinesin spindle protein at peptide:siRNA w/w ratio of 80:1 (N/P ≈ 109). The siRNA internalization into non-tumorigenic kidney cells was negligible with all fatty acyl-peptide conjugates. These results indicate that conjugation of fatty acids to CGKRK could create an efficient delivery system for siRNA silencing specifically in tumor cells.
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影响因子：
3.7
作者：
Landry B;Aliabadi HM;Samuel A;Gül-Uludağ H;Jiang X;Kutsch O;Uludağ H
通讯作者：
Uludağ H
影响因子：
4.9
作者：
Alexis F;Pridgen E;Molnar LK;Farokhzad OC
通讯作者：
Farokhzad OC
影响因子：
4.6
作者：
Aliabadi, Hamidreza Montazeri;Landry, Breanne;Uludag, Hasan
通讯作者：
Uludag, Hasan
影响因子：
12.4
作者：
Agemy, Lilach;Kotamraju, Venkata R.;Ruoslahti, Erkki
通讯作者：
Ruoslahti, Erkki
使用预功能化聚合物的 pH 响应复合物将阿霉素和 siRNA 同步递送至癌细胞
影响因子：
14
作者：
Dong, Da-Wen;Xiang, Bai;Qi, Xian-Rong
通讯作者：
Qi, Xian-Rong