Chemistry Reference
In-Depth Information
glance, it seemed simpler to load molecules inside commercial or tailor-made
dendrimers. After all, many efforts were put forward to simplify the synthesis of
dendrimers in the quest for future applications, with a need for a larger scale
production. The (bio)degradation or the covalent cleavage of dendrimers was not
seen as a priority until the beginning of the twenty-first century.
From a historical perspective, the field of degradable dendrimers followed a period
after some major studies were achieved in the polymer field, including degradable
polymer therapeutics. Such a degradable model for polymers was originally proposed
by Ringsdorf in 1975 [45]. Other important reviews on that topics are available [46-
48]. The cleavage of dendrimers started during their early days when the scientific
community requested more structural evidences of the dendritic structures. The
involvement of modern mass spectrometry techniques (such as MALDI-TOF, ESI,
etc.) often present a major parent dendritic molecular ion. However, in a few cases, it
could fragment to a smaller ion. It remained a pure analytical observation of a
degradation. It was also found during the synthesis of PAMAM dendrimers that a
retro-Michael addition could lead to methyl acrylate and an amine [49]. Similar
observations of dendrimer defects can be observed during the synthesis of PPI
dendrimers, as indicated by some MALDI-TOF [50] or ESI [51] studies. An
interesting analytical study using
1
H,
13
C NMR, and GC, with a G0.5 PAMAM
(EDA-core) dendrimer in methanol at various temperatures from
15 to 50
C
concluded for an equilibrium between a Michael, and a retro-Michael addition in
solution starting even at 4
C (Scheme 13.1) [52]. Higher temperatures shifted this
equilibrium toward the retro-Michael products and an increased degradation. It is a
demonstration that care must be taken against a degradation upon PAMAM storage
for a long period of time in order to avoid some changes in properties, such as for
vectorization. All in all, the degradability of dendrimers was clearly noticed many
years ago but it was not until the mid-1990s that some defined applications suggested
that their degradation could offer new perspectives in dendrimer chemistry.
In 1993, an early report mentioned the degradation of a hyperbranched polyester
dendrimer in the quest for a better characterization under a strongly basic conditions
(NaOH, THF, EtOH, H
2
O, reflux) [53]. After protecting the chain ends by stable
methoxy functions, the quantification of the recovered units permitted to evaluate the
degree of branching. However, the uncontrolled and irregular nature of the poly-
merization provided a polydispersity of 2.1, which is not representative of a
monodisperse, discrete, macromolecule (Scheme 13.2).
The first enzymatic degradations of dendrimers were disclosed in 1996, after a
depolymerization of a chiral polyester dendrimer made from (R)-3-hydroxy-butanoic
SCHEME 13.1
Degradation of PAMAM dendrimers at temperatures above 4
C by a retro-
Michael reaction [52].
