Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications.
RNA interference (RNAi) has great potential to treat human disease. However, in vivo delivery of short interfering RNAs (siRNAs), which are negatively charged double-stranded RNA macromolecules, remains a major hurdle. Current siRNA delivery has begun to move away from large lipid and synthetic nanoparticles to more defined molecular conjugates. Here we address this issue by synthesis of short interfering ribonucleic neutrals (siRNNs) whose phosphate backbone contains neutral phosphotriester groups, allowing for delivery into cells. Once inside cells, siRNNs are converted by cytoplasmic thioesterases into native, charged phosphodiester-backbone siRNAs, which induce robust RNAi responses. siRNNs have favorable drug-like properties, including high synthetic yields, serum stability and absence of innate immune responses. Unlike siRNAs, siRNNs avidly bind serum albumin to positively influence pharmacokinetic properties. Systemic delivery of siRNNs conjugated to a hepatocyte-specific targeting domain induced extended dose-dependent in vivo RNAi responses in mice. We believe that siRNNs represent a technology that will open new avenues for development of RNAi therapeutics.
1] Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA. [2].
Bryan R
BR
Meade
1] Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA. [2].
Khirud
K
Gogoi
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Alexander S
AS
Hamil
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Caroline
C
Palm-Apergi
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Arjen
A
van den Berg
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Jonathan C
JC
Hagopian
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Aaron D
AD
Springer
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Akiko
A
Eguchi
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Apollo D
AD
Kacsinta
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Connor F
CF
Dowdy
1] Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA. [2] Department of Medicine, Division of Pulmonary and Critical Care, UCSD School of Medicine, La Jolla, California, USA.
Asaf
A
Presente
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Peter
P
Lönn
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Manuel
M
Kaulich
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Naohisa
N
Yoshioka
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Edwige
E
Gros
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Xian-Shu
XS
Cui
Department of Cellular &Molecular Medicine, UCSD School of Medicine, La Jolla, California, USA.
Steven F
SF
Dowdy
D000818:Animals; D016503:Drug Delivery Systems; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D012709:Serum Albumin / Q000737:chemistry
D011355:Prodrugs; D034741:RNA, Small Interfering; D012709:Serum Albumin