Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells,Biomacromolecules

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Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells
Biomacromolecules ( IF 5.5 ) Pub Date : 2018-05-16 00:00:00 , DOI: 10.1021/acs.biomac.8b00507
Hyun Su Min ₁ , Hyun Jin Kim ₂ , Jooyeon Ahn ₁ , Mitsuru Naito ₂ , Kotaro Hayashi ₃ , Kazuko Toh ₃ , Beob Soo Kim ₁ , Yasuhiro Matsumura ₄ , Ick Chan Kwon ₅ , Kanjiro Miyata ₁ , Kazunori Kataoka _{3,

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Affiliation

Antibody fragment (Fab′)-installed polyion complex (PIC) micelles were constructed to improve targetability of small interfering RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized a block copolymer of azide-functionalized poly(ethylene glycol) and poly(l-lysine) and prepared PIC micelles with siRNA. Then, a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF) Fab′ was conjugated to azido groups on the micellar surface. A fluorescence correlation spectroscopic analysis revealed that 1, 2, or 3 molecule(s) of Fab′(s) were installed onto one micellar nanoparticle according to the feeding ratio of Fab′ (or DBCO) to micelle (or azide). The resulting micelles exhibited ∼40 nm in hydrodynamic diameter, similar to that of the parent micelles before Fab′ conjugation. Flow cytometric analysis showed that three molecules of Fab′-installed PIC micelles (3(Fab′)-micelles) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress TF on their surface. The 3(Fab′)-micelles also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore, the 3(Fab′)-micelles exhibited high penetrability and the highest cellular internalization amounts in BxPC3 spheroids compared with one or two molecule(s) of Fab′-installed PIC micelles. These results demonstrate the potential of anti-TF Fab′-installed PIC micelles for active targeting of stroma-rich pancreatic tumors.

中文翻译：

调整抗组织因子抗体片段在装载 siRNA 的聚离子复合胶束上的密度，以优化胰腺癌细胞的靶向性

构建了安装有抗体片段 (Fab') 的聚离子复合物 (PIC) 胶束，以提高小干扰 RNA (siRNA) 递送至胰腺癌细胞的靶向性。为此，我们合成了叠氮官能化聚乙二醇和聚赖氨酸的嵌段共聚物，并制备了带有siRNA的PIC胶束。然后，将二苄基环辛炔 (DBCO) 修饰的抗人组织因子 (TF) Fab' 与胶束表面的叠氮基缀合。荧光相关光谱分析表明，根据Fab'（或DBCO）与胶束（或叠氮化物）的进料比，1、2或3个Fab'分子被安装到一个胶束纳米颗粒上。所得胶束的流体动力学直径约为 40 nm，与 Fab' 缀合前的亲本胶束相似。流式细胞术分析表明，安装有 Fab' 的 PIC 胶束 (3(Fab')-micelles) 的三个分子对培养的胰腺癌 BxPC3 细胞具有最高的结合亲和力，已知胰腺癌 BxPC3 细胞在其表面过度表达 TF。 3(Fab')-胶束还对培养的癌细胞中的 polo 样激酶 1 mRNA 表现出最有效的基因沉默活性。此外，与安装一两个分子的 Fab' PIC 胶束相比，3(Fab')-胶束在 BxPC3 球体中表现出高渗透性和最高的细胞内化量。这些结果证明了安装抗 TF Fab' 的 PIC 胶束在主动靶向富含基质的胰腺肿瘤方面的潜力。

更新日期：2018-05-16

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