(536f) Controlling Drug Release Kinetics From Soft Nanocomposite Hydrogels
AIChE Annual Meeting
2012
2012 AIChE Annual Meeting
Materials Engineering and Sciences Division
Biomaterials for Drug Delivery
Wednesday, October 31, 2012 - 4:45pm to 5:03pm
Controlling Drug
Release Kinetics from Soft Nanocomposite Hydrogels
Daryl
Sivakumaran, Thomas Oszustowicz, Danielle Maitland, and Todd
Hoare 1
1Department
of Chemical Engineering, McMaster University, Hamilton, Ontario, L8S 4L8,
Canada
sivakudn@mcmaster.ca, oszusttl@mcmaster.ca, maitladm@mcmaster.ca, hoaretr@mcmaster.ca
Introduction
Hydrogels have found
widespread applications in the area of controlled release of bioactives since
they can be typically be loaded with high fractions of drugs (due to their high
internal free volume) and can be fabricated to have similar physical,
mechanical, and chemical properties to native extracellular matrix, generally
promoting high biocompatibility[1]. However,
conventional, single-phase hydrogels suffer from two key limitations from a
drug delivery perspective: (1) their high elasticity coupled with their
macroscopic dimensions make them difficult to administer via injection and (2)
the highly hydrated microstructure results in poor hydrophobic drug uptake[2] and rapid release of
hydrophilic drugs[1,
3],
limiting both the types and the rates of drug release that can be achieved.
While a range of physical and chemical in situ gelation approaches compatible
with physiological conditions have been reported to address the issue of
hydrogel administration in vivo, long-term release of hydrophilic drugs
remains a challenge, with few formulations reported to achieve release
durations for greater than one month.[3]
In
order to address this problem, a range of multi-phase hydrogels has been
developed in which a variety of nano or micron-sized drug carriers (for
example, liposomes[4], polymer
nanoparticles[5] or polymer
microparticles[6]) are physically
entrapped inside hydrogels. Relative
to single phase hydrogels, the incorporation of a second (and, in most cases,
significantly different) embedded discrete phase can introduce affinity sites
that facilitate increased loading of a target drug as well as additional
diffusive and/or partitioning barriers to tune the release of that drug through
the bulk hydrogel phase, leading to longer-term release.
In
our work, we aim to fabricate very well-defined multi-phase hydrogel-microgel
systems and investigate how both the magnitude of burst release (typically
observed for hydrogel-based systems) as well as the duration of effective
release can be tuned by rational engineering of the chemistry and morphology of
each individual phase. Specifically, we investigate
the effects of tuning the degree of anionic functionalization, the cross-link
density of the microgel, the concentration of reactive groups in the microgel
or hydrogel, and the degree of cross-linking observed between the microgel and
bulk hydrogel phases on drug delivery, using bupivacaine, a cationic
local anesthetic, as a model drug. The embedded phase chosen was copolymer
microgels based on N-isopropylacrylamide (NIPAM) and acrylic acid (AA); such
microgels exhibit thermosensitive swelling responses (~32oC) and have both ionic and hydrophobic affinity for
promoting bupivacaine binding. The microgels were
immobilized within a hydrogel network which is liquid outside the body but gels
via covalent cross-linking (using hydrazide-aldehyde chemistry) inside the body
by simple co-injection to form in situ gellable hydrogel-microgel
networks. Microgels can be simply physically entrapped within a bulk hydrogel
or they can be covalently cross-linked into the hydrogel matrix by
functionalizing the microgels with hydrazide groups to allow them to
participate in the cross-linking reaction.
Materials
and Methods
Acrylic acid functionalized poly(NIPAM) microgels were synthesized via a
mixed precipitation-emulsion polymerization according to methods by Pelton[7]. Varying amounts of acrylic acid (6mol% - 20 mol%) and N,N'-methylenebisacrylamide
cross-linker ranging from 1 to 9 mol% total monomer were incorporated into the
microgels to determine the effect of microgel functionalization and
cross-linking on bupivacaine release from the nanocomposites.
Hydrogels were fabricated from carboxymethyl cellulose
(CMC) and dextran modified with hydrazide (CMC-A) and aldehyde (Dex-B)
functional groups, via previously reported methods[8]. Hydrazide attachment to CMC was facilitated via EDC/NHS
chemistry, whereas aldehyde modified dextran was synthesized via sodium
periodate oxidation. When mixed via co-injection through a needle, these two
polymers rapidly form a hydrazone-cross-linked hydrogel network that physically
entraps AA-NIPAM microgels inside the hydrogel network. Incorporating microgels
into the hydrogel mixture prior to gelation created the nanocomposites.
Hydrazide-functionalized AA-NIPAM microgels were synthesized using a similar
protocol to determine the effects of covalent microgel attachment to the
hydrogel matrix on drug release from the nanocomposites.
Drug release from the composite hydrogels was analyzed
using a transwell plate technique and quantified using UV/VIS
spectrophotometry. The mechanical properties of the nanocomposite was assessed
through parallel plate rheometry. Cytotoxicity was assayed with the MTT assay,
using fibroblasts and myoblasts as model cells.
Results
The release of bupivacaine can be sustained for up to 60 days
using these nanocomposite hydrogels, significantly longer than that achievable
using the constituent hydrogel or microgels alone (less than one week in either
case, Figure 1)[9].
Figure
1:
Comparison of release profiles from (a) AA-20% microgel alone; (b) CMC-A/Dex-B hydrogel
alone; and (c) nanocomposite of AA-20% microgel and CMC-A/Dex-B hydrogel
Drug release kinetics from the nanocomposites were primarily
governed by the charge of the microgel; increasing the acrylic acid content
within the microgel allows for more prolonged drug release from the
nanocomposite system, owing to the higher anionic charge density (and thus
higher electrostatic affinity for cationic bupivacaine) in these microgels
(Figure 2).
Figure 2: Bupivacaine release from AA-NIPAM microgel-hydrogel nanocomposite
containing various AA functionalized microgels.
However, the magnitude
of microgel deswelling relative to the hydrogel at physiological temperature
also has a strong impact on drug release. When varying amounts of cross-linker were
incorporated into the microgels, microgels with higher cross-linker contents
facilitated slower drug release from the nanocomposite system. Of particular
interest, when hydrazide-functionalized microgels were used to covalently cross-link
the microgels to the hydrogel phase, significantly slower drug release was
observed (Figure 3).
Figure 3: Bupivacaine release from hydrazide functionalized 6mol% AA-NIPAM
microgel-hydrogel nanocomposite
In this case,
increased network elasticity restricts or eliminates the microgel phase
transition, resulting in lower convective transport of drug from the
nanocomposite hydrogel and slower overall release rates. Additional control of
drug release from the nanocomposites can be afforded by altering the cross-link density of
the bulk hydrogel phase, which regulates both drug diffusion and hydrogel
degradation; however, this effect was less significant than that provided by
manipulation of the embedded phase.
Rheological
tests were performed to determine the impact of microgel entrapment and
cross-linking on the mechanical properties of the hydrogels. The elastic
modulus of the hydrogels increases as a function of the degree of hydrazide
functionalization of the CMC-A polymer, consistent with more highly
functionalized pre-polymers creating more highly cross-linked hydrogels. In this way, hydrogels
with different cross-link densities (and thus pore sizes) can be generated via
simple co-injection of CMC-A polymers with different hydrazide contents. The
incorporation of microgels into the hydrogels does not significantly alter the
mechanical properties of the nanocomposite. However, when the microgels are
functionalized with hydrazide groups, the elastic modulus of the nanocomposites
significantly increases with degree of microgel functionalization, with G'
values doubling relative to those measured with the same bulk hydrogel that
contained only entrapped microgels. This indicates that the microgel actively
react with aldehyde functionalized polymers and participate in the
cross-linking of the hydrogel phase.
The
composite hydrogels, hydrogel pre-polymers, and microgels all showed no
significant cytotoxicity to fibroblasts or myoblasts at concentrations up to
2mg/mL according to the MTT assay.
Conclusions
Drug
release from microgel-hydrogel nanocomposite systems can be precisely tuned
through the modification of microgel characteristics such as net charge,
overall cross-linker content or covalent attachment of the microgel to the
hydrogel phase. In both cases, changes in microgel swelling/ deswelling
behavior lead to tunable changes in the observed drug release kinetics,
significantly prolonging release versus other hydrogel systems previously
reported. In particular, by regulating the relative swelling of the bulk and
entrapped gel phases via molecular design (composition and cross-link density),
both burst releases of drug as well as overall release rates of drug can be
significantly slowed. The results of this work could in principle be applied
to any drug to achieve similar prolongations in release, provided that a
drug-microgel affinity pair can be identified.
Acknowledgements:
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.
References
[1]
T.R. Hoare and D.S. Kohane, Polymer. 49 (2008) 1993.
[3]
G.D. Kang, S.H. Cheon and S.-C. Song, Int. J. Pharm. 319 (2006) 29.
[5]
M.D. Baumann, C.E. Kang, C.H. Tator and M.S. Shoichet, Biomaterials. 31 (2010)
7631.
[7]
T. Hoare and R. Pelton, Macromolecules. 37 (2004) 2544.
[8]
S.P. Hudson, R. Langer, G.R. Fink and D.S. Kohane, Biomaterials. 31 (2010)
1444.
[9]
D. Sivakumaran, D. Maitland and T. Hoare, Biomacromolecules. 12 (2011) 4112.
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