(741d) On-Demand, Targeted Drug Delivery Using Magnetic Thermosensitive Nanocomposites

On-demand,
targeted drug delivery using magnetic thermosensitive nanocomposites

Scott Campbell, Elysia Jellema, and Todd Hoare

Department of Chemical Engineering, McMaster
University, Hamilton, ON, Canada

INTRODUCTION: Control
of both the site and rate of drug release is a persistent challenge in
medicine. Several polymer-based delivery systems have been able to achieve
constant or sustained drug release for up to several months, but devices
delivering drugs via pulsatile release have proven difficult to achieve.¹
Specifically, in cases where the disease progression is uncertain (e.g.
chemotherapy or chronic pain management) or pulsatile, on-off release of drug
is clinically required (e.g. insulin delivery), current treatments are largely
limited to external pumps that can be up or down-regulated or multiple,
sequential injections to provide bolus drug amounts. The development of a
device that can be externally and non-invasively triggered to deliver high/low
or on/off doses of a drug locally inside the body would address this challenge.
Such a delivery system would have the potential to improve drug safety, reduce
the risk of systemic side effects, reduce the cost and prolong the effective
duration of action of a given drug delivery vehicle. In order to effectively
provide for ?on-demand? or pulsatile delivery, a drug delivery vehicle must
contain materials with two key properties: a switching material that can
modulate drug diffusion in vivo by
changing its bulk size, pore size, or affinity for a target drug upon a
stimulus and a triggering material that can modulate an external trigger (e.g.
light or an electromagnetic field) into a stimulus recognized by the triggering
material. Recently, a composite membrane consisting of ethyl cellulose (the
matrix), thermoresponsive microgels based on
poly(N-isopropylacrylamide) (PNIPAM, the switching material), and magnetite
nanoparticles (the triggering material) was reported that demonstrated effective,
on-off pulsatile drug delivery upon the application of an oscillating magnetic
field.² While this membrane was highly effective for pulsatile
release, the macroscopic size of the membrane-based devices used requires
surgical implantation for their effective use. The development of injectable
materials that can provide similar release profiles would be highly beneficial
to expand the potential applications and patient convenience of such a device.  This research focuses on the development of
drug-loaded, injectable, ?smart? nanocomposites that can both repeatedly
deliver a drug ?on-demand? and have site-specific functionality.

EXPERIMENTAL: We
are have entrapped microgels and magnetite nanoparticles inside an in situ-injectable hydrogel prepared by
mixing hydrazide-functionalized PNIPAM and aldehyde-functionalized dextran. The
microgels consist of copolymers of poly(N-isopropylacrylamide) (PNIPAM) and
poly(N-isopropylmethacrylamide) (PNIPMAM); such
microgels are thermosensitive such that they reversibly decrease in size when
the temperature of their environment exceeds their volume phase transition
temperature (VPTT), which is designed to be just above physiological
temperature (~40°C).³ The magnetite nanoparticles can generate heat
when placed in an oscillating magnetic field (OMF) via hysteresis losses and
provide targeting functionality using an external permanent magnet.²
When microgels and magnetite nanoparticles are combined in the same
nanocomposite, heating of the nanoparticles induces a phase transition in the
microgels, creating free volume in the microgel-templated pores and thus
increased drug release.

Site-specificity
is achieved by injecting the composite at the desired site, where it quickly
gels in vivo.  The thermosensitive nature of the both the
microgels and the surrounding hydrogel can be adjusted, along with numerous
other parameters (ferrofluid and microgel concentration, functionalization and
concentration of hydrogel precursor polymers, etc.) to attempt to control the
rate of drug release and the on-demand control of drug release under the
presence of an OMF.

RESULTS: A
wide range microgel-magnetite-hydrogel nanocomposites, with variations in the
ratio and concentration of the two hydrogel polymeric components and microgel content,
have been characterized for their swelling, degradation and drug release
characteristics at 37°C and 43°C, as well as their drug release under the
presence of an OMF. Using a non-thermosensitive and non-swelling bulk phase to
encapsulate the microgels and the magnetite nanoparticles, a threefold increase
in drug release rate (assayed using sodium fluorescein as a model drug) can be
achieved in the presence of an oscillating magnetic field, illustrating the
utility of this approach as an injectable and externally controllable drug
delivery vehicle.  The composites have
high mechanical strength and can be programmed to degrade either at controlled
rates via hydrolysis of the bulk phase or catastrophically via magnetic
ablation.  MTT assays and live/dead
assays will also be discussed that assessed cell biocompatibility.

CONCLUSIONS: The
combination of thermosensitive polymers with magnetite nanoparticles is a
powerful tool for in the fabrication of composites for drug delivery. The
injectable and externally-triggerable drug delivery
nanocomposite offers significant advantages over current drug delivery
techniques in terms of facilitating triggered changes in drug release using a
patient-friendly and non-invasive triggering technology.

REFERENCES: (1)
Saltzman, W. M. (2001). Drug Delivery:
Engineering Principles for Drug Therapy. New York: Oxford University Press;
(2) Hoare, T.; Santamaria, J.; Goya, G.F.; Irusta, S.; Lin, D.; Lau, S.; Padera,
R.; Langer, R.; Kohane D.S. (2009). A Magnetically Triggered
Composite Membrane for On-Demand Drug Delivery. Nano Letters, 9(10), 3651-3657; (3) Pelton, R. (2000). Temperature-sensitive aqueous microgels. Advances in Colloid and Interface
Science, 85, 1-33.

ACKNOWLEDGEMENTS: This
research is funded by the Natural Sciences and Engineering Research Council of
Canada (NSERC) and the J.P. Bickell Foundation
(Medical Research Grant).