Biomedical Engineering Reference
In-Depth Information
et al., 2007). First, in what form can the iRNA be injected, so that it is not
degraded and has a chance to reach tumor cells intact? Possible forms include
free, cyclodextrin polymer-conjugated, carbohydrate-modified, liposomal
nanopeptide carrier, biologic nanopeptide vehicle (ENGeneICDeliver Vehicle),
and lentivirus or adenovirus constructs. Obviously, such a long list implies that
no single approach has worked well, and much work needs to be done to devise
a successful and general mode of delivery. Also, the route of injection may be
critical. For example, free iRNA would not be expected to survive to reach the
cancer unless it is injected directly into the tumor. The various routes of delivery
proposed, besides direct injection into the tumor, include systemic, nasal,
intraperitoneal, and intrahepatic. Nanoimmunoliposome complexes of iRNA
against HER-2 mRNA, encapsulated by a cationic liposome and decorated
with anti-TfR single-chain antibody fragments, have been targeted at primary
and metastatic lesions in SCID mice transplanted with human breast and
pancreatic cancers (Pirollo et al., 2007).
3.4 Molecular Inhibitors
Molecular inhibitors for major stem cell signaling pathways are listed in
Table 2, and the full names of these inhibitors appear in Table 3. Again,
most of these agents have been shown to have some inhibitory effect on cancer
cells in vitro, but how this information can be applied in vivo and whether or
not the agents will have deleterious effects on normal tissue stem cells remain
to be determined. Even if some of these approaches eventually do work out, a
word of caution is needed because of the tendency of cancer stem cells to
mutate and change characteristics, usually to a more malignant form (Nowell,
1976). This property makes the cancer stem cell a moving target for specific
therapy.
Table 2 Some inhibitors of major stem cell signaling pathways
Signaling pathway
Inhibitor
JAK-STAT
APS
Notch
g-secretase inhibitor (DAPT)
MAPK/ERK
RAF kinase inhibitors/U0126
PI3K/Akt
Rapamycin (LY294002)
NF-kB
I-kB, PTDC, Velcade
Wnt/b-catenin
NSAID, GSK-3, sFRPs, DKK, Axin
TGF-b (BMP)
SMAD6,7; Lefty1,2; Gremlin; SM16, etc.
Sonic hedgehog (sHH)
Cyclopamine
Oct-4/Sox2/Nanog
Tcf3
Adapted from Sell (2007a)
