Dual antitumoral potency of EG5 siRNA nanoplexes armed with cytotoxic bifunctional glutamyl-methotrexate targeting ligand

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• 作者：Dian-Jang Lee^a ; ^c ; Eva Kessel^a ; ^c ; Daniel Edinger^a ; Dongsheng He^a ; ^c ; Philipp M. Klein^a ; Lena Voith von Voithenberg^b ; Don C. Lamb^b ; ^c ; Ulrich Lä ; chelt^a ; ^c ; Taavi Lehto^a ; Ernst Wagner^a ; ^c ; ^{ernst.wagner@cup.uni-muenchen.de" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Methotrexate ; Drug delivery ; Tumor targeting ; Polyplexes ; siRNA
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：77
• 期：Complete
• 页码：98-110
• 全文大小：2166 K

文摘

Synthetic small interfering RNA (siRNA) is a class of therapeutic entities that allow for specific silencing of target genes via RNA interference (RNAi) and comprise an enormous clinical potential for a variety of diseases, including cancer. However, efficient tissue-specific delivery of siRNA remains the major limitation in the development of RNAi-based cancer therapeutics. To achieve this, we have synthesized a series of sequence-defined oligomers, which include a cationic (oligoethanamino)amide core (for nanoparticle formation with siRNA), cysteines (as bioreversible disulfide units), and a polyethylene glycol chain (for shielding of surface charges) coupled to a terminal targeting ligand. The antifolate drug methotrexate (MTX), a well-established chemotherapeutic agent, serves as both targeting ligand and anticancer agent. The oligomers form homogeneous spherical siRNA polyplexes with a hydrodynamic diameter of approximately 6 nm. These polyplexes access KB cells by binding to the folate receptor in a MTX-dependent manner and induce efficient gene silencing activity <em>in vitroem>. Impressively, in the <em>in vivoem> studies, MTX-conjugated polyplexes significantly increase the intratumoral retention (168 h) of the siRNA, as compared to alanine-substituted non-targeted control polyplexes (48 h). The combination of MTX-conjugated polyplexes and eglin 5 (EG5) siRNA provides enhanced antitumoral potency with 50% of recurrence-free survival of KB tumor-bearing mice. The design of such siRNA carrier systems with a dual-functional ligand for cellular delivery and augmented tumor suppression could be a valuable strategy for translating RNAi-based cancer therapeutics to the clinics.