Biomedical Engineering Reference
In-Depth Information
3.2.1.2 Approaches to Increase Carrier Stability to Prevent
Premature Release
A thermodynamically unstable carrier (an unstable carrier for short) may
dissociate before reaching its target and thus prematurely release the drug.
Such an unstable carrier may dissociate fast or slowly, referred to as micelle
dissociation kinetics (some authors
25
use ''kinetic stability''). We always prefer
carriers that are thermodynamically stable until they reach their target. At a
given temperature, micelles form at the polymer concentrations above the
critical micelle concentration (CMC):
40
d
n
4
y
3
n
g
|
2
C
CMC
&exp {ne
h
=
k
b
T
ð
Þ
where k
b
T is the thermal energy and e
h
is the monomer effective interaction
energy with the bulk solution (related to x in polymer physics). Polymers with
a low CMC suggest a high thermodynamic stability, and vice versa. Usually,
the longer the hydrophobic blocks, the more stable the micelles they form.
41
Thermodynamic stability is particularly important because locally, in
circulation, micelles may dissociate if the block copolymer concentration falls
below the CMC. It seems intuitive that a drug-loaded micelle may have a CMC
that is different from its virgin drug-free analog, but, to a first approximation,
it is common to neglect this difference.
Once the copolymer concentration falls below its CMC, the micelle
dissociation rate can vary, depending on cohesive forces among the core-
forming blocks. Chain insertion/expulsion and micellar fusion/splitting are two
mechanisms that can explain the overall dynamic exchange between monomers
and micelles.
41
Monte Carlo simulation indicated that chain insertion/expulsion
played a major role when the polymer concentration was low.
42
Because chain
mobility plays a crucial role, the hydrophobic blocks with a relatively high glass
transition temperature (T
g
) make the micelles dissociate much more slowly than
those with a low T
g
.
43
Furthermore, the size of the hydrophobic block and the
hydrophilic-to-hydrophobic block mass ratio were found to affect the rate of
micelle dissociation, from size-exclusion chromatography (SEC) experiments.
For simple PEG-PCL copolymers, micelles formed from PEG-PCL (5000:4000
and 5000:2500) dissociated slowly; however, micelles formed from the PEG-PCL
(5000:1000) dissociated quickly into monomers.
44
Even though there is evidence that some polymeric micelles can be stable in
serum even in vivo,
45
the stability of micelles in the blood is far from understood.
Quite different from carriers tested in water or in buffer solutions, micelles in
blood circulation can be extremely diluted and encounter various blood
components which may promote micelle dissociation. Burt et al. prepared
radiolabeled PTX-loaded PEG-PDLLA micelles and found that PTX was rapidly
released from the micelles, and the diblock copolymer was cleaved into its two
polymer components in the blood.
46,47
Maysinger et al. conjugated fluorescein-5-
carbonyl azide diacetate to PEG-PCL micelles and noticed that they were stable in
buffer solutions but unstable in serum-containing culture media with or without
