Biomedical Engineering Reference
In-Depth Information
d n 4 y 3 n g | 3
Scheme 4.1
Synthesis of (A) PEI-g-PEG and (B) PEI-co-PEG copolymers.
siRNA was mediated by these vectors and transfected to T lymphocytes. 10
They found that PEI-g-PEG (20 kDa)/siRNA polyplexes had low toxicity and
could knockdown GAPDH expression and inhibit HIV replication. However,
siRNA gene knockdown was less effective when a high density of shorter PEG
chains (2 kDa) was conjugated to PEI, as they hindered uptake or release of
active siRNA from internal vesicles.
Tsai et al. synthesized a single-monomer-derived linear-like PEI-co-PEG for
efficient siRNA delivery and silencing in vitro and in vivo (Scheme 4.1B). 11
This copolymer was only synthesized from a single monomer by intensive
synchrotron X-ray irradiation in the absence of catalyst and organic solvent.
They found that the incorporation of PEG segments into the copolymer not
only solved the cytotoxicity problems, but also improved the efficiency of
siRNA release compared to either linear PEI or Lipofectamine 2,000.
Besides PEGylation, several other modifications to PEI molecules have been
developed to reduce toxicity. Natural glucose polymers [e.g. dextran, b-
cyclodextrin (b-CD)] are a series of natural cyclic oligosaccharides which have
low immunogenicity and toxicity in humans. These natural polymers can
enhance the absorption and resistance to nucleases through binding and
interacting with oligonucleotides; thus, they have been incorporated into
cationic polymers as new gene delivery vectors. 12 Liu et al. employed b-CD to
crosslink LMW PEI (600 Da) and then coupled the product with ligand YC21
(epidermal growth factor receptor targeted oligopeptide) to form tumor-
targeted gene vectors (Scheme 4.2A). 13 The results showed that these vectors
possessed lower cytotoxicity and higher efficient gene delivery ability to the
EGFR-positive liver cancer cells in vitro and achieved favorable therapeutic
effects in the inhibition of tumor growth in vivo. Tang's group also reported a
series of b-CD crosslinked PEIs, grafted with folic acid, TAT-R8, or NLS
peptide. 14-16
These compounds exhibited higher targeting and transfection
 
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