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).