A Glu-urea-Lys Ligand-Conjugated Lipid Nanoparticle/siRNA System Inhibits Androgen Receptor Expression In Vivo


Authors: Lee JB, Zhang K, Tam YY, Quick J, Tam YK, Lin PJ, Chen S, Liu Y, Nair JK, Zlatev I, Rajeev KG

Journal: Nucleic Acids

DOI: 10.1038/mtna.2016.43

Publication - Abstract

April 03, 2016

Abstract:

The androgen receptor plays a critical role in the progression of prostate cancer. Here, we describe targeting the prostate-specific membrane antigen using a lipid nanoparticle (LNP) formulation containing small interfering RNA (siRNA) designed to silence expression of the messenger RNA 9mRNA) encoding the androgen receptor. Specifically, a Glu-urea-Lys PSMA-targeting ligand was incorporated into the lipid nanoparticle system formulated with a long alkyl chain polyethylene glycol-lipid to enhance accumulation at tumor sites and facilitate intracellular uptake into tumor cells following systemic administration. Through these features, and by using a structurally refined cationic lipid and an optimized small interfering RNA payload, a lipid nanoparticle system with improved potency and significant therapeutic potential against prostate cancer and potentially other solid tumors was developed. Decreases in serum prostate-specific antigen, tumor cellular proliferation, and androgen receptor levels were observed in a mouse xenograft model following intravenous injection. These results support the potential clinical utility of a prostate-specific membrane antigen–targeted lipid nanoparticle system to silence the androgen receptor in advanced prostate cancer.

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