Biomedical Engineering Reference
In-Depth Information
3.5.5
Cationic Polyphosphazenes
Polyphosphazenes (PPPs) are an important family of hybrid inorganic-organic
polymers with organic side groups attached onto inorganic backbone with alterna-
tive phosphorus-nitrogen connected with alternative single and double bonds.
Linear polyphosphazenes were initially synthesized via ring-opening polymeriza-
tion of hexachlorocyclotriphosphazene (Allcock and Kugel
1965
). Hennink et al.
firstly explored the use of cationic polyphosphazene polymers for gene delivery,
and they synthesized PPPs with either 2-dimethylaminoethanol (DMAE) (PPP-
DMAE) or 2-dimethylaminoethylamine (DMAEA) (PPP-DMAEA) as side groups
(Fig.
4f
) (Luten et al.
2003
). These polymers exhibited slow degradation at pH 7.5
and 37°C with half-lives of 7 and 24 days for PPP-DMAE and PPP-DMAEA,
respectively.
In vitro
transfection in COS-7 cells suggested that these polymers
showed a transfection efficiency rivaling a well-known transfectant PDMAEMA.
The toxicity of both PPP-DMAE and PPP-DMAEA was lower than PDMAEMA.
Further study in tumor bearing mice suggested that PPP-DMAEA/DNA polyplexes
could preferentially mediate gene expression in tumor tissue (de Wolf et al.
2005
).
By co-substitution of PPP with DMAEA and diaminobutane (BA), in combination
with PEGylation using folate functionalized PEG, Hennink and coworkers also
synthesized a polycationic vector with improved compatibility and targeting capa-
bility for
in vivo
gene delivery (Luten et al.
2008
). Yang et al. have found that
cationic PPP with both DMAEA and histidyl groups could effectively mediate
DNA transfer, and the efficiency at a polymer/DNA ratio of 10:1 was much higher
than that of PPP-DMAEA and PEI25 (Yang et al.
2008a
). Also, imidazole and
DMAEA co-substituted PPP showed less toxicity and superior transfection activity
over PEI25 (Yang et al.
2008b
). Tetra(L-lysine)-grafted poly(organophosphazene)
with PEG as hydrophilic substituent has also been synthesized and its
in vitro
cyto-
toxicity was examined (Jun et al.
2007
). However, no transfection results have been
reported for this polymer.
3.6
Dendrimers Based Vectors
Dendrimers comprise a central core molecule which acts as the root from which a
number of tree-like arms emanated in an ordered and symmetric fashion. Since their
discovery in late 1970s, dendrimers have been widely used for drug delivery, gene
therapy and diagnostics as well as biomedical imaging (Tomalia and Frechet
2002
).
Polyamidoamine dendrimers (PAMAM) are probably the most frequently inves-
tigated dendrimers-based vectors for gene delivery (Fig.
5a
). The use of PAMAM
for gene transfection was originally reported by Haensler and Szoka (Haensler and
Szoka
1993
). The sixth-generation PAMAM was found to have the highest trans-
fection. In addition, expression was not affected by lysomotrophic agents such as
chloroquine and only mildly influenced by the presence of 10% serum in the
medium. When a membrane-destabilizing peptide was covalently attached to
Search WWH ::
Custom Search