Chemistry Reference
In-Depth Information
often put forward. The reader is referred to some excellent reviews [106,173,174].
That implies a profound surface functionalization of the dendrimers with some
functional units toward a “refinement” of the dendritic structures for a better
structure/activity relationship, cellular uptake, biocompatibility, targeting, imaging,
and bioactivity. Among many examples, the work of Schl
uter and coworkers used
a new type of poly(amidoamine) dendrimers decorated by amines, ammoniums,
t-Boc, carbobenzyloxy groups, natural amino acids, ethylene diamine, or dansyl
fluorescent labels [175]. They concluded that the surface functionalization grossly
influences the dendrimer toxicity and that the internal structure does not seem to play
a major role despite the fact that the interior of low generation dendrimers is
accessible. Another interesting nanodevice for cancer therapy was from Baker, Jr.
and coworkers using PAMAM as a template for introducing units such as metho-
trexate (MTX—anticancer drug), fluorescein isothiocyanate (FITC—fluorescent
unit), and folic acid [176].
In spite of many newcomplex dendritic structures, further studies will be necessary
to better understand their in vitro hydrolysis and their in vivo degradation. Some
general trends are proposed. For instance, a surface functionalization by a PEGylation
of PAMAM [177,178] poly(
L
-lysine) [137], or triazine dendrimers [179] could have a
drastic consequence on water-solubility, steric stabilization for preventing aggrega-
tion, cellular uptake (internalization) [180], targeting tissues, targeting organs, or
dendrimer-drug persistence in the blood. In short, it could provide a positive effect
while modifying the pharmacodynamics and the pharmacokinetics [181]. However, a
good balance between hydrophilicity and hydrophobicity of the surface is often
needed for many enzymes. All of those factors will directly affect the rate of release of
a drug in vivo and in vitro.
In general, a dendrimer surface modification by a PEGylation or an esterification
with long aliphatic chains usually provides a protective shell to the dendrimer and
prevent the hydrolytic enzymes to work efficiently. In the recent years, the
expression “core-shell dendrimers” was used in the literature to describe such
architectures.
Another example of such degradable dendrimers was recently reported. They had a
Boltorn
-type polyester core and were covered by a mixed shell of PEG chains and
amino acids. The latter provided the anchoring points to PEG chains and for new
functions at the surface (such as doxorubicin) [182]. The hydrolysis of that dendrimer
was tested in a buffer at pH 7.4 and in human plasma at 37
C. Even if a degradation
occurred, the results and conditions were not optimized (a reconstituted plasma at
about pH9). Another example is given by using
€
-chymotrypsin for cleaving a peptide
dendrimer [93]. A recent work from PEGylated poly(
L
-lysine) dendrimers was
previously mentioned, albeit under hydrolytic conditions, without the addition of
enzymes [136].
a
13.2.3.6 Hydrophilicity and Charges It is reported that hydrophilic biomaterials
are quickly degraded compared to biomaterials containing hydrophobic units. For
instance, a glycolic acid-based dendrimer is known to degrade faster than a caproic
acid-based dendrimer [112]. Hydration and charge effects also play a role in
