Cell type-specific delivery of siRNAs with aptamer-siRNA chimeras.
Technologies that mediate targeted delivery of small interfering RNAs (siRNAs) are needed to improve their therapeutic efficacy and safety. Therefore, we have developed aptamer-siRNA chimeric RNAs capable of cell type-specific binding and delivery of functional siRNAs into cells. The aptamer portion of the chimeras mediates binding to PSMA, a cell-surface receptor overexpressed in prostate cancer cells and tumor vascular endothelium, whereas the siRNA portion targets the expression of survival genes. When applied to cells expressing PSMA, these RNAs are internalized and processed by Dicer, resulting in depletion of the siRNA target proteins and cell death. In contrast, the chimeras do not bind to or function in cells that do not express PSMA. These reagents also specifically inhibit tumor growth and mediate tumor regression in a xenograft model of prostate cancer. These studies demonstrate an approach for targeted delivery of siRNAs with numerous potential applications, including cancer therapeutics.
McNamara
James O
JO
Duke Center for Translational Research, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
Andrechek
Eran R
ER
Wang
Yong
Y
Viles
Kristi D
KD
Rempel
Rachel E
RE
Gilboa
Eli
E
Sullenger
Bruce A
BA
Giangrande
Paloma H
PH
D000818:Animals; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000235:genetics*; D045744:Cell Line, Tumor; D020868:Gene Silencing; D018390:Gene Targeting / Q000379:methods*; D018014:Gene Transfer Techniques; D006801:Humans; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*
D052157:Aptamers, Nucleotide; D034741:RNA, Small Interfering