Journal
INTERNATIONAL JOURNAL OF PHARMACEUTICS
Volume 499, Issue 1-2, Pages 131-145Publisher
ELSEVIER
DOI: 10.1016/j.ijpharm.2015.12.055
Keywords
Gene delivery; Prostate cancer; Anisamide targeted cyclodextrin; Targeted nanoparticle; Sigma receptor; Inclusion complex formation
Categories
Funding
- Irish Cancer Society [PCI110DR]
- Irish Research Council [GOIPD/2014/151]
- FRSQ postdoctoral fellowship
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Prostate cancer is a leading cause of cancer-related death in men and RNA interference (RNAi) has emerged as a potential therapeutic option. However, the absence of a safe and specific delivery vector remains a major obstacle to the clinical application of RNAi. Cyclodextrin derivatives are known to be efficient delivery systems with low toxicity in a variety of cell types. In this study, a cationic cyclodextrin derivative was synthesized to complex siRNA. The nanoparticle was then further modified by exploiting the ability of the beta-cyclodextrin cavity to form an inclusion complex with the hydrophobic molecule adamantane. PEGylated adamantane derivatives were synthesized with and without the anisamide-targeting ligand on the terminal end of the PEG chain. Anisamide is known to bind specifically to the sigma receptor which is overexpressed on the surface of prostate cancer cells. The resulting nanocomplexes were slightly cationic and less than 300 nm in size. They successfully protected siRNA from serum-induced nuclease degradation and were non-toxic to prostate cancer cells. In addition, the targeted nanoparticles mediated high levels of siRNA cellular uptake and corresponding PLK1 gene knockdown in prostate cancer cells in vitro. To our knowledge, this is the first time that the ability of cyclodextrins to form inclusion complexes with adamantane derivatives has been exploited for the targeted delivery of siRNA to prostate cancer cells via the sigma receptor. (C) 2015 Elsevier B.V. All rights reserved.
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