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

• Main Authors: Justin B Lee (Author), Kaixin Zhang (Author), Yuen Yi C Tam (Author), Joslyn Quick (Author), Ying K Tam (Author), Paulo JC Lin (Author), Sam Chen (Author), Yan Liu (Author), Jayaprakash K Nair (Author), Ivan Zlatev (Author), Kallanthottathil G Rajeev (Author), Muthiah Manoharan (Author), Paul S Rennie (Author), Pieter R Cullis (Author)
• Format: Book
• Published: Elsevier, 2016-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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 formulation containing small interfering RNA designed to silence expression of the messenger RNA 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.

Item Description

2162-2531
10.1038/mtna.2016.43