(351c) Injectable Modular Hydrogels for Drug Delivery

Injectable Modular Hydrogels
for Drug Delivery

Mathew Patenaude and Todd Hoare

Department of Chemical Engineering, McMaster
University, Hamilton, Ontario, L8S 4L7

Introduction

           
The development of novel drug delivery systems is an essential step toward
controlled site-specific administration of therapeutics within the body. It is
desirable for delivery vehicles to be introduced into the body through
minimally invasive means and, once present at their desired site, these
vehicles should be capable of releasing drug to their intended location at a
controlled rate. Furthermore, it is desirable to develop drug delivery vehicles
that are capable of in vivo degradation once delivery of the drug is
complete, avoiding the need to surgically remove the vehicle at the end of its
useful lifetime. Hydrogels are of particular interest
for drug delivery drug delivery applications due to their ability to address
these needs in addition to their generally good biocompatibility, tunable
network structure to control the diffusion of drug out of the network, and
tunable affinity for specific drugs¹. However, hydrogels
are limited for drug delivery applications due to the often quick elution of
drug from their highly swollen polymer matrices as well as the difficulty
inherent in injecting macroscopic hydrogels into the
body.

           
These challenges can in part be addressed by fabricating hydrogels
based on poly(N-isopropylacrylamide)
(polyNIPAM). These hydrogels
undergo a reversible thermal transition at ~32 °C, causing them to collapse and
subsequently expel water from their network when placed in vivo. Upon
introduction into the body, these vehicles are capable of entrapping drug
following their thermal collapse, allowing for the elution of a therapeutic
into the surrounding environment at a rate that depends on the diffusion
coefficient of the drug through the network and relative affinity of the drug
toward the hydrogel phase over its aqueous surroundings. To take advantage of
these thermoresponsive properties, hydrogels must be designed such that they form
spontaneously inside the body from liquid-like precursors outside the body.
Hydrazone cross-links between aldehyde and hydrazide-functionalized polymer precursors provide a means
of rapid in vivo hydrogel formation following their co-injection into
the body. The hydrazone bond offers the additional advantage of being slowly
hydrolyzed at normal physiological pH, allowing for the excretion of polymer
precursors following hydrogel degradation provided that their molecular weight
is kept below the renal cutoff (< 40 kDa)².
Hydrogel degradation, swelling, and thermosensitivity
can further be modified by cross-linking the polyNIPAM
oligomers with natural polysaccharides,
functionalized to contain the same hydrazide and aldehyde groups.  By mixing these synthetic and
natural polymer building blocks in any combination and at any ratio, ?modular? hydrogels
may be generated that possess targeted physical and biological properties as
well as finely tuned drug release characteristics. 

Materials and Methods

           
Hydrogels were fabricated from hydrazide-functionalized poly(NIPAM)
co-polymers and aldehyde-functionalized
polysaccharides, such as carboxymethyl cellulose
(CMC), hyaluronic acid (HA), and dextran
(dex). Hydrazide-functionalized
poly(NIPAM) was generated by copolymerizing NIPAM with
acrylic acid and subsequently grafting the resulting copolymer with adipic acid dihydrazide using
EDC/NHS chemistry. Aldehyde-functionalized
polysaccharides were generated using using periodate-mediated oxidation.

           
The molecular weight of precursor poly(NIPAM)
copolymers was determined using aqueous gel permeation chromatography. The
degree of hydrazide functionality of poly(NIPAM) copolymers was determined through conductometric titration.  Polysaccharide aldehyde functionality was quantified with a carbazate-based aldehyde
detection assay.

            Hydrazide and aldehyde-functionalized
polymers were mixed at various concentrations via co-injection through a needle
along with bupivacaine, a cationic local anesthetic. These polymers rapidly
form a hydrazone-crosslinked hydrogel network upon mixing. Hydrogel drug
release properties were determined using a transwell
plate technique and quantified using UV/VIS spectrophotometry.
Cytotoxicity was assayed using an MTT assay.

Results

           
 Poly(NIPAM)-only hydrogels were
successfully synthesized by mixing hydrazide and aldehyde-functionalized poly(NIPAM) oligomers,
exhibiting thermal deswelling on the order of 70 %
upon heating from 25 °C to 37 °C.  Such hydrogels also
exhibited the classical poly(NIPAM) burst drug release
profile, rapidly expelling 90 % of pre-loaded drug via convective mass transfer
following the rapid collapse of the hydrogel network. This is, to our
knowledge, the first demonstration of an injectable
and degradable poly(NIPAM)-based
hydrogel. The thermosensitivity, swelling, and
degradation of the hydrogels can be readily modulated
by replacing all or part of the aldehyde-functionalized
synthetic polymer with one or more aldehyde-functionalized
carbohydrates (see figures). The thermosensitivity of
these hydrogels is shown to increase by increasing
their dextran content, while it can be effectively
turned off by increasing their CMC content. Completely replacing poly(NIPAM)
with CMC resulted in a non-thermoresponsive hydrogel
that swelled by 75 % under physiological conditions (relative to 25 °C) while replacing poly(NIPAM) with dextran
resulted in a thermoresponsive hydrogel that
collapsed by 10 % more under physiological conditions than at room
temperature.  Similarly, while CMC-crosslinked hydrogels degraded within two days, dextran-crosslinked
hydrogels degraded over the period of several weeks,
providing tunable control over the lifetime of the hydrogel in
vivo. 
            By mixing CMC and dextran,
hydrogels with any lifetime, any degree of thermosensitivity, and any degree of
swelling (including zero swelling) can be generated by simple co-injection and
subsequent spontaneous gelation of multiple, off-the-shelf modular polymer
precursors.  Hydrogel composition and swelling can similarly be tuned
independently to generate hydrogels with more or less
affinity for a target drug or faster or slower drug release kinetics, allowing
control over the drug release profiles achieved using the modular hydrogels.

Conclusions

           
By mixing hydrazide and aldehyde-functionalized
polymeric oligomers with various chemistries, injectable hydrogels with
targeted degradation rates, thermoresponsivity,
swelling, and drug delivery properties can be generated by simple mixing. 
This ?modular? approach to the synthesis of degradable hydrogels,
by which hydrazide and aldehyde-functionalized
natural or synthetic polymers can be mixed in any combination and any ratio,
permits the facile preparation of any desired hydrogel composition.

References

            1 - Hoare,
T.; Kohane, D. Polymer, 49, 1993 (2008)

            2 - Lee, K.,
Macromolecules, 33, 97 (2000)

Acknowledgments: Funding from the Natural Sciences
and Engineering Research Council of Canada (NSERC) and the Ontario Ministry of
Research and Innovation (Early Researcher Award program) is gratefully
acknowledged.