T HERMORESPONSIVE
DELIVERY
component. Several chitosan-based hydrogels
were derived using both kinds of cross-linking.
A majority of these utilize cross-linking agents,
such as pNIPA and ethylene glycol, which can
be a potential threat in terms of toxicity. A
cross-linking agent with low cytotoxicity helps
in quasi-linear drug release for up to 40 days;
however, the hydrogel loses its
thermoreversibility at 37°C. 24 Other
polysaccharide-based hydrogels, such as
Xyloglucan, Dextran, and Cellulose derivatives,
have also been extensively studied due to their
thermosensetive characteristics.
GELATIN: This is a bovine (usually) origin
biopolymer with thermoreversible properties.
At temperatures below 25°C, an aqueous
gelatin solution solidifies due to the formation
of triple helices and a rigid three-dimensional
network. When the temperature is raised above
approximately 30°C, the conformation changes
from a helix to the more flexible coil, rendering
the gel liquid again. It is by far the safest
thermosensetive biopolymer besides chitosan.
However, the challenge is to increase the gel-sol transition temperature above the
physiological temperature to use it as a
potential carrier for drug molecules.
PEO/PPO-BASED SYSTEMS: Triblock
copolymers poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide)
(PEO-PPO-PEO), known also as Pluronic® or
Poloxamers, are another important group of
synthetic polymers with a thermoreversible
behavior in aqueous solutions. It works through
a gelation mechanism, which has been
extensively investigated. This reversible
gelation can occur at physiological temperature
and pH through an adjustment of its
composition, molecular weight, and
concentration. 25 However, it has been reported
that Pluronic gel has an inadequate mechanical
integrity that makes it inappropriate for certain
biomedical applications. 26 Moreover,
carboplatin toxicity has been reported with the
use of three different kinds of Pluronic triblock
copolymers, such as F127, P85, and L61.27
OTHERS: Several other synthetic, nonsynthetic
polymers or combination of
synthetic/nonsynthetic polymers have been
used as possible candidates for this kind of
drug delivery platform. Examples are
PEG/biodegradable polyester copolymers,
poly(ethylene glycol)-b-poly(d,l-lactic acid-co-glycolic acid)-b-poly(ethylene glycol) (
PEG-PLGA-PEG) triblock copolymers, PLGA-PEG-PLGA-based systems, poly(ethylene
glycol)/poly(l-lactic acid) (PEG/PLLA),
methoxy poly(ethylene glycol) (mPEG) with
poly(propylene fumarate) (PPF), and
poly(organophosphazenes) grafted with amino
acids. However, in all cases, the fundamental
challenges are to modulate these
polymer/polymer combinations to get a
desirable LCST value close to a physiological
temperature.
MODIFICATION OF THE LCST &
ITS APPLICATION
TO DRUG DELIVERY
Once a possible thermoresponsive
polymeric candidate is identified, there are
several chemical ways to modulate its LCST.
Usually, the introduction of monomer units of
stronger amphiphilic character results in a
systematic decrease of the LCST. The LCST
modulation can be controlled by the choice of
the co-monomer as well as the co-monomer
ratio and can be tuned in the temperature range
from 46°C to 49°C. 28 However, in drug
delivery, the physical situation differs from a
pure polymer in solution because the polymer
is used as a coating (eg, drug coated
nano/micro spheres) or as a matrix to form
what is sometimes referred to as a
Thermoresponsive Drug Reservoir. Because
the formation of the gelatinous structure
associated with the hydration effects (as
discussed in the previous section) can still
occur, the potential for displaying
thermosensitive behavior still exists. However,
because of drug loading, there will be less
configurational freedom for the polymer, and
thus less ability to coil and/or uncoil.
Therefore, the actual transition temperatures
for coated/loaded nano/microparticles may
differ from the actual LCST of the free
polymer.
Drug-loaded nano/microparticles cannot
form a true solution. Therefore, the actual
behavior change associated with the
temperature may appear to be different for
these particles than for free polymer molecules.
Still, the effects will be associated with a
hydrophilic/hydrophobic transition, which
could result in aggregation or sticking to local
tissues (in vivo), either of which would be
expected to result in some type of localization
effect in vivo.
Another transition effect could be
differences in the release of drugs from the
coated nanoparticles. For hydrophobic drugs,
the hydrated gelatinous structure would likely
act as an effect barrier to drug release. In that
case, the release of drugs would be increased
above the LCST. For hydrophilic drugs, this
layer might also act to slow down release,
although perhaps not as effectively as would be
the case for hydrophobic drugs. For either
effect, the factor controlling the transitions in
surface properties and drug release from a
thermoresponsive drug reservoir is the critical
solution temperature. 29
CONCLUSION
Based on the above discussion,
mechanism, and citation of some examples, it
is indeed very promising that we do have some
successful thermosensetive platform that can
be further evaluated/developed as a possible
drug-reservior candidate. They may also serve
as a potential carrier for oral use whereby
swelling/de-swelling kinetics can be utilized for
the control of drug release. However, the
ultimate folllowing three questions remain:
