用于胶质母细胞瘤动物模型中靶向细胞内递送的树状大分子-siRNA 偶联物,ACS Applied Materials & Interfaces

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用于胶质母细胞瘤动物模型中靶向细胞内递送的树状大分子-siRNA 偶联物
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2022-10-10 , DOI: 10.1021/acsami.2c13129
Wathsala Liyanage ₁ , Tony Wu _{1,

2} , Sujatha Kannan _{1,

3,

4,

5} , Rangaramanujam M Kannan _{1,

2,

4,

5,

6}

Affiliation

小干扰 RNA (siRNA) 是基因沉默的有力武器，有机会纠正缺陷基因并停止不良蛋白质的产生，在中枢神经系统 (CNS) 疾病中有许多应用。然而，将 siRNA 成功递送至脑实质面临着诸如血脑屏障 (BBB)、脑组织穿透和特定细胞靶向等障碍。此外，siRNA 在生理条件下不稳定，易受蛋白质结合和酶降解的影响，需要更高的剂量才能保持有效。为了解决这些问题并推进 siRNA 的传递，我们报告了共价偶联羟基封端聚（酰胺胺）（PAMAM）树枝状大分子-siRNA 偶联物的开发，利用谷胱甘肽敏感的接头用针对 GFP (siGFP) 偶联物 (D-siGFP) 的 siRNA 进行了证明。这允许精确的核酸装载，保护有效载荷免于过早降解，将 siRNA 货物输送到细胞中，并实现显着的 GFP 敲低体外（~40%）和体内（~30%）。与市售的递送系统（如 RNAi Max 和 Lipofectamine）相比，D-siGFP在体外保留了 siRNA 的效力. 此外，树枝状大分子-siGFP 偶联物显着提高了 siRNA 在血浆和核酸内切酶存在下的半衰期，并保持了 PAMAM 树枝状大分子对反应性小胶质细胞的被动靶向能力。当对 CX3CR-1GFP 小鼠的原位多形性胶质母细胞瘤 (GBM) 进行瘤内给药时，D-siGFP 定位于肿瘤实质内的肿瘤相关巨噬细胞 (TAM)，从而最大限度地减少其他细胞群的脱靶效应。此处介绍的树状大分子-siRNA 偶联物的简便偶联策略为靶向、系统性细胞内递送 siRNA 提供了一种有前途的方法，可作为 RNAi 疗法临床转化的潜在桥梁。

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Dendrimer–siRNA Conjugates for Targeted Intracellular Delivery in Glioblastoma Animal Models

Small interfering RNAs (siRNAs) are potent weapons for gene silencing, with an opportunity to correct defective genes and stop the production of undesirable proteins, with many applications in central nervous system (CNS) disorders. However, successful delivery of siRNAs to the brain parenchyma faces obstacles such as the blood–brain barrier (BBB), brain tissue penetration, and targeting of specific cells. In addition, siRNAs are unstable under physiological conditions and are susceptible to protein binding and enzymatic degradation, necessitating a higher dosage to remain effective. To address these issues and advance siRNA delivery, we report the development of covalently conjugated hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimer–siRNA conjugates, demonstrated with a siRNA against GFP (siGFP) conjugate (D-siGFP) utilizing glutathione-sensitive linkers. This allows for precise nucleic acid loading, protects the payload from premature degradation, delivers the siRNA cargo into cells, and achieves significant GFP knockdown in vitro (∼40%) and in vivo (∼30%). Compared to commercially available delivery systems such as RNAi Max and Lipofectamine, D-siGFP retains the potency of the siRNA in vitro. In addition, the dendrimer-siGFP conjugate significantly enhances the half-life of siRNA in the presence of plasma and endonucleases and maintains the passive targeting ability of PAMAM dendrimers to reactive microglia. When administered intratumorally to orthotopic glioblastoma multiform tumors (GBM) in CX3CR-1GFP mice, D-siGFP localizes in tumor-associated macrophages (TAMs) within the tumor parenchyma, minimizing off-target effects in other cell populations. The facile conjugation strategy for dendrimer–siRNA conjugates presented here offers a promising approach for targeted, systemic intracellular delivery of siRNA, serving as a potential bridge for the clinical translation of RNAi therapies.

更新日期：2022-10-10

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