Targeted RNAi of BIRC5/Survivin Using Antibody-Conjugated Poly(Propylene Imine)-Based Polyplexes Inhibits Growth of PSCA-Positive Tumors

被引：13

作者：

Jugel, Willi ^{[1
]}

Aigner, Achim ^{[2
]}

Michen, Susanne ^{[1
]}

Hagstotz, Alexander ^{[1
]}

Ewe, Alexander ^{[2
]}

Appelhans, Dietmar ^{[3
]}

Schackert, Gabriele ^{[1
,4
,5
,6
]}

Temme, Achim ^{[1
,4
,5
,6
]}

Tietze, Stefanie ^{[1
]}

机构：

[1] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Sect Expt Neurosurg & Tumor Immunol, Dept Neurosurg, Fetscherstr 74, D-01307 Dresden, Germany

[2] Univ Leipzig, Fac Med, Rudolf Boehm Inst Pharmacol & Toxicol, Clin Pharmacol, D-04107 Leipzig, Germany

[3] Leibniz Inst Polymer Res Dresden, Hohe Str 6, D-01069 Dresden, Germany

[4] German Canc Consortium DKTK, Partner Site Dresden, Fetscherstr 74, D-01307 Dresden, Germany

[5] German Canc Res Ctr, Neuenheimer Feld 280, D-69120 Heidelberg, Germany

[6] Natl Ctr Tumor Dis NCT, Fetscherstr 74, D-01307 Dresden, Germany

来源：

PHARMACEUTICS | 2021年 / 13卷 / 05期

关键词：

targeted siRNA delivery; maltose-modified poly(propylene imine); Survivin; prostate stem cell antigen; STEM-CELL ANTIGEN; IN-VITRO; SURVIVIN; GENE; CANCER; EXPRESSION; PROTEINS; THERAPY; SIRNA; VIVO;

D O I：

10.3390/pharmaceutics13050676

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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(PSCA/ffLuc) and PC3(PSCA) cells and caused knockdown of reporter gene firefly luciferase and Survivin expression, respectively. In a therapeutic study in PC3(PSCA) 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.

引用

页数：15