title: A Glu-urea-Lys Ligand-conjugated Lipid Nanoparticle/siRNA System Inhibits Androgen Receptor Expression In Vivo.
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 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.
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Justin B
authors.initials: JB
authors.lastname: Lee
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Kaixin
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yuen Yi C
authors.initials: YY
authors.lastname: Tam
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Joslyn
authors.initials: J
authors.lastname: Quick
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ying K
authors.initials: YK
authors.lastname: Tam
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Paulo Jc
authors.initials: PJ
authors.lastname: Lin
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sam
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Drug Discovery, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Jayaprakash K
authors.initials: JK
authors.lastname: Nair
authors.affiliation: Department of Drug Discovery, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Zlatev
authors.affiliation: Department of Drug Discovery, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Kallanthottathil G
authors.initials: KG
authors.lastname: Rajeev
authors.affiliation: Department of Drug Discovery, Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA.
authors.forename: Muthiah
authors.initials: M
authors.lastname: Manoharan
authors.affiliation: Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Rennie
authors.affiliation: Department of Biochemistry and Molecular Biology at the University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: pieterc@mail.ubc.ca.
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Cullis
keywords: androgen receptor; lipid nanoparticles; liposomes; prostate cancer; prostate specific membrane antigen; siRNA