Stabilization and Movable Ligand-Modification by Folate-Appended Polyrotaxanes for Systemic Delivery of siRNA Polyplex,ACS Macro Letters

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Stabilization and Movable Ligand-Modification by Folate-Appended Polyrotaxanes for Systemic Delivery of siRNA Polyplex
ACS Macro Letters ( IF 5.1 ) Pub Date : 2022-10-10 , DOI: 10.1021/acsmacrolett.2c00462
Ahmed Fouad Abdelwahab Mohammed _{1,

2,

3} , Mahmoud H Othman _{1,

4,

5} , Toru Taharabaru ₁ , Khaled M Elamin ₁ , Kohzo Ito ₆ , Masamichi Inoue ₁ , Mahmoud El-Badry ₅ , Khaled I Saleh ₄ , Risako Onodera ₁ , Keiichi Motoyama ₁ , Taishi Higashi _{1,

2,

7}

Affiliation

To achieve a systemic targeted delivery of siRNA using polymeric carriers, there is a dilemma between ligand modification and stabilization of the polyplex. Namely, ligand modification often leads to destabilization of the polyplex in the blood circulation. In fact, we previously developed cyclodextrin (CD)/polyamidoamine dendrimer conjugates (CDE) as siRNA carriers, and the interaction of CDE/siRNA was decreased by the conjugation with folate-polyethylene glycol, leading to the destabilization. To overcome this dilemma, in this study, folate-appended polyrotaxanes (Fol-PRX) were developed. Fol-PRX stabilized CDE/siRNA polyplex by intermolecularly connecting CDE molecules through a host–guest interaction between adamantane at the terminals of Fol-PRX and β-CD in the polyplex. Moreover, the intermolecular connection of the polyplex with Fol-PRX provided movable folate moieties on the surface. As a result, Fol-PRXs enhanced the in vivo antitumor activity of the polyplex after intravenous administration, suggesting their utility as the dual-functional materials for systemic delivery of siRNA polyplexes.

中文翻译：

叶酸附加聚轮烷对 siRNA Polyplex 系统递送的稳定性和可移动配体修饰

为了使用聚合物载体实现 siRNA 的全身靶向递送，配体修饰和复合物的稳定化之间存在两难选择。也就是说，配体修饰通常会导致血液循环中复合物的不稳定。事实上，我们之前开发了环糊精 (CD)/聚酰胺胺树枝状大分子缀合物 (CDE) 作为 siRNA 载体，CDE/siRNA 的相互作用因与叶酸-聚乙二醇的缀合而降低，导致不稳定。为了克服这一困境，在这项研究中，开发了附加叶酸的聚轮烷 (Fol-PRX)。Fol-PRX 通过 Fol-PRX 末端的金刚烷和复合物中的 β-CD 之间的主客体相互作用，通过分子间连接 CDE 分子来稳定 CDE/siRNA 复合物。而且，复合物与 Fol-PRX 的分子间连接在表面提供了可移动的叶酸部分。因此，Fol-PRXs 增强了静脉内给药后复合物的体内抗肿瘤活性，表明它们可用作全身递送 siRNA 复合物的双功能材料。

更新日期：2022-10-10

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