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Biomaterials. 2016 Jan;77:98-110. doi: 10.1016/j.biomaterials.2015.11.004. Epub 2015 Nov 5.

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

Author information

1
Department of Pharmacy and Center for NanoScience, Ludwig-Maximilians-Universität München, Munich, Germany; Nanosystems Initiative Munich, Germany.
2
Department of Pharmacy and Center for NanoScience, Ludwig-Maximilians-Universität München, Munich, Germany.
3
Department of Chemistry and Center for NanoScience, Ludwig-Maximilians-Universität München, Munich, Germany.
4
Department of Chemistry and Center for NanoScience, Ludwig-Maximilians-Universität München, Munich, Germany; Nanosystems Initiative Munich, Germany.
5
Department of Pharmacy and Center for NanoScience, Ludwig-Maximilians-Universität München, Munich, Germany; Nanosystems Initiative Munich, Germany. Electronic address: ernst.wagner@cup.uni-muenchen.de.

Abstract

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 in vitro. Impressively, in the in vivo 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.

KEYWORDS:

Drug delivery; Methotrexate; Polyplexes; Tumor targeting; siRNA

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