Jugel Willi, Aigner Achim, Michen Susanne, Hagstotz Alexander, Ewe Alexander, Appelhans Dietmar, Schackert Gabriele, Temme Achim, Tietze Stefanie
Department of Neurosurgery, Section Experimental Neurosurgery and Tumor Immunology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, 04107 Leipzig, Germany.
Pharmaceutics. 2021 May 8;13(5):676. doi: 10.3390/pharmaceutics13050676.
Delivery of siRNAs for the treatment of tumors critically depends on the development of efficient nucleic acid carrier systems. The complexation of dendritic polymers (dendrimers) results in nanoparticles, called dendriplexes, that protect siRNA from degradation and mediate non-specific cellular uptake of siRNA. However, large siRNA doses are required for in vivo use due to accumulation of the nanoparticles in sinks such as the lung, liver, and spleen. This suggests the exploration of targeted nanoparticles for enhancing tumor cell specificity and achieving higher siRNA levels in tumors. In this work, we report on the targeted delivery of a therapeutic siRNA specific for BIRC5/Survivin in vitro and in vivo to tumor cells expressing the surface marker prostate stem cell antigen (PSCA). For this, polyplexes consisting of single-chain antibody fragments specific for PSCA conjugated to siRNA/maltose-modified poly(propylene imine) dendriplexes were used. These polyplexes were endocytosed by PSCA-positive 293T and PC3 cells and caused knockdown of reporter gene firefly luciferase and Survivin expression, respectively. In a therapeutic study in PC3 xenograft-bearing mice, significant anti-tumor effects were observed upon systemic administration of the targeted polyplexes. This indicates superior anti-tumor efficacy when employing targeted delivery of Survivin-specific siRNA, based on the additive effects of siRNA-mediated Survivin knockdown in combination with scFv-mediated PSCA inhibition.
用于肿瘤治疗的小干扰RNA（siRNA）递送严重依赖于高效核酸载体系统的开发。树枝状聚合物（树枝状大分子）的复合形成了纳米颗粒，称为树枝状复合物，它可以保护siRNA不被降解，并介导siRNA的非特异性细胞摄取。然而，由于纳米颗粒在肺、肝和脾等部位的积聚，体内使用时需要大剂量的siRNA。这表明需要探索靶向纳米颗粒，以提高肿瘤细胞特异性并在肿瘤中实现更高的siRNA水平。在这项工作中，我们报告了一种针对BIRC5/生存素的治疗性siRNA在体外和体内靶向递送至表达表面标志物前列腺干细胞抗原（PSCA）的肿瘤细胞的情况。为此，使用了由与siRNA/麦芽糖修饰的聚（丙烯亚胺）树枝状复合物偶联的针对PSCA的单链抗体片段组成的多聚体。这些多聚体被PSCA阳性的293T和PC3细胞内吞，分别导致报告基因萤火虫荧光素酶的敲低和生存素表达的降低。在携带PC3异种移植瘤的小鼠的治疗研究中，全身给予靶向多聚体后观察到了显著的抗肿瘤作用。这表明基于siRNA介导的生存素敲低与单链抗体片段介导的PSCA抑制的叠加效应，采用靶向递送生存素特异性siRNA时具有卓越的抗肿瘤疗效。
