PMID- 20305636
OWN - NLM
STAT- MEDLINE
DCOM- 20100602
LR  - 20231120
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 464
IP  - 7291
DP  - 2010 Apr 15
TI  - Evidence of RNAi in humans from systemically administered siRNA via targeted 
      nanoparticles.
PG  - 1067-70
LID - 10.1038/nature08956 [doi]
AB  - Therapeutics that are designed to engage RNA interference (RNAi) pathways have 
      the potential to provide new, major ways of imparting therapy to patients. Long, 
      double-stranded RNAs were first shown to mediate RNAi in Caenorhabditis elegans, 
      and the potential use of RNAi for human therapy has been demonstrated by the 
      finding that small interfering RNAs (siRNAs; approximately 21-base-pair 
      double-stranded RNA) can elicit RNAi in mammalian cells without producing an 
      interferon response. We are at present conducting the first in-human phase I 
      clinical trial involving the systemic administration of siRNA to patients with 
      solid cancers using a targeted, nanoparticle delivery system. Here we provide 
      evidence of inducing an RNAi mechanism of action in a human from the delivered 
      siRNA. Tumour biopsies from melanoma patients obtained after treatment show the 
      presence of intracellularly localized nanoparticles in amounts that correlate 
      with dose levels of the nanoparticles administered (this is, to our knowledge, a 
      first for systemically delivered nanoparticles of any kind). Furthermore, a 
      reduction was found in both the specific messenger RNA (M2 subunit of 
      ribonucleotide reductase (RRM2)) and the protein (RRM2) levels when compared to 
      pre-dosing tissue. Most notably, we detect the presence of an mRNA fragment that 
      demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the site 
      predicted for an RNAi mechanism from a patient who received the highest dose of 
      the nanoparticles. Together, these data demonstrate that siRNA administered 
      systemically to a human can produce a specific gene inhibition (reduction in mRNA 
      and protein) by an RNAi mechanism of action.
FAU - Davis, Mark E
AU  - Davis ME
AD  - Chemical Engineering, California Institute of Technology, Pasadena, California 
      91125, USA. mdavis@cheme.caltech.edu
FAU - Zuckerman, Jonathan E
AU  - Zuckerman JE
FAU - Choi, Chung Hang J
AU  - Choi CH
FAU - Seligson, David
AU  - Seligson D
FAU - Tolcher, Anthony
AU  - Tolcher A
FAU - Alabi, Christopher A
AU  - Alabi CA
FAU - Yen, Yun
AU  - Yen Y
FAU - Heidel, Jeremy D
AU  - Heidel JD
FAU - Ribas, Antoni
AU  - Ribas A
LA  - eng
GR  - U54 CA119347/CA/NCI NIH HHS/United States
GR  - U54 CA119347-04/CA/NCI NIH HHS/United States
GR  - CA U54 119347/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100321
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Drug Carriers)
RN  - 0 (RNA, Messenger)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, Transferrin)
RN  - EC 1.17.4.- (ribonucleotide reductase M2)
RN  - EC 1.17.4.1 (Ribonucleoside Diphosphate Reductase)
SB  - IM
CIN - Cell Adh Migr. 2011 Jan-Feb;5(1):1-3. PMID: 20890128
MH  - Biopsy
MH  - *Clinical Trials, Phase I as Topic
MH  - *Drug Carriers/administration & dosage/pharmacokinetics
MH  - Drug Delivery Systems
MH  - Gene Knockdown Techniques/*methods
MH  - Humans
MH  - Injections, Intravenous
MH  - Melanoma/drug therapy/enzymology/genetics
MH  - *Nanoparticles/administration & dosage/analysis
MH  - RNA Interference/*drug effects
MH  - RNA, Messenger/analysis/genetics/metabolism
MH  - RNA, Small Interfering/*administration & 
      dosage/genetics/*pharmacology/therapeutic use
MH  - Receptors, Transferrin/metabolism
MH  - Ribonucleoside Diphosphate Reductase/biosynthesis/genetics
PMC - PMC2855406
MID - NIHMS183887
EDAT- 2010/03/23 06:00
MHDA- 2010/06/03 06:00
PMCR- 2010/10/15
CRDT- 2010/03/23 06:00
PHST- 2009/09/23 00:00 [received]
PHST- 2010/03/01 00:00 [accepted]
PHST- 2010/03/23 06:00 [entrez]
PHST- 2010/03/23 06:00 [pubmed]
PHST- 2010/06/03 06:00 [medline]
PHST- 2010/10/15 00:00 [pmc-release]
AID - nature08956 [pii]
AID - 10.1038/nature08956 [doi]
PST - ppublish
SO  - Nature. 2010 Apr 15;464(7291):1067-70. doi: 10.1038/nature08956. Epub 2010 Mar 
      21.