Magnetically Activated Glass Transition (Tg) Switch Nanocomposites for On-demand Drug Delivery

Scott Campbell (Department of Chemical Engineering, McMaster University, Hamilton, Ontario, Canada)
Somiraa Said (Department of Chemical Engineering, McMaster University)
Angus Lam (Department of Chemical Engineering, McMaster University)
Nahieli Preciado (Department of Chemical Engineering, McMaster University)
Niels Smeets (Department of Chemical Engineering, McMaster University)
Todd Hoare (Department of Chemical Engineering, McMaster University)

Introduction

On-demand drug release has great potential in post-surgical pain control, infection treatment, hormonal therapy, and chemotherapy. Magnetically-activated drug release vehicles, based on the hysteresis heating of superparamagnetic iron oxide nanoparticles (SPIONs) in the presence of an alternating magnetic field (AMF), hold promise in this regard given that magnetic triggering is highly penetrative, non-invasive, and can be conducted using cytocompatible SPIONs. However, most reported magnetically-activated vehicles combining SPIONs with thermoresponsive hydrogels exhibit relatively low resolution between on- and off-states due to the high drug leakage in the off-state, reducing the shelf-life of the delivery system. In this project, SPIONs and drug-loaded polymeric nanoparticles with a glass transition temperature (Tg) just above physiological temperature were co-incorporated into an injectable hydrogel to produce an on-demand drug release delivery system. Our hypothesis was that the externally applied AMF will result in localized heating within the hydrogel due to the presence of SPIONs, driving a glass transition in the Tg nanoparticles to accelerate drug diffusion from the nanoparticles and out of the nanocomposite. When the AMF is removed, the system cools down to below its glass transition temperature and the nanoparticles will return to their glassy (off) state of minimal drug release, as illustrated in Figure 1.

Materials and Methods

Injectable hydrogels were prepared by mixing hydrazide-functionalized carboxymethyl cellulose (CMC) with aldehyde-functionalized dextran. The SPIONs were synthesized by co-precipitating iron (III) and iron (II) chloride salts, followed by coating with polyethylene glycol (PEG). The Tg switch nanoparticles were synthesized through mini-emulsion polymerization of butyl and methyl methacrylate (BMA, MMA). PEG-coated SPIONs were analyzed using transmission electron microscopy, while dynamic light scattering was used for detecting the particle size of the Tg nanoparticles. Temperature- and pulsed AMF-based drug release studies of rhodamine B-loaded nanocomposite hydrogel system were carried out and the amount of released drug was analyzed using a fluorescence microplate reader. The cytocompatibility of the nanocomposite hydrogel system components was examined using MTT assay.

Results

Differential scanning calorimetry results showed that the unloaded p(MMA-co-BMA) and rhodamine B loaded-nanoparticles had a Tg of ~39°C. Temperature-based drug release experiments indicated a 4.2:1 rhodamine release ratio between on- and off-states when the nanocomposites were maintained at 45°C relative to 37°C (Figure 2). Pulsed AMF-based release studies showed enhancement of rhodamine B release, although with decreased resolution between on- and off-states relative to the temperature-only triggering result (1.8:1) (Figure 3). However, the off-state release was significantly lower than that observed with hydrogel-SPION composites without the Tg nanoparticles; as a result, a similar triggered release profile could be attained when a pulsed AMF was applied after one week. In vitro metabolic activity studies using 3T3 fibroblasts showed that all the nanocomposite hydrogel system components were cytocompatible.

Discussion and Conclusion

Remote magnetic triggering of Tg switching nanocomposite hydrogels by the application of a pulsed AMF could provide localized drug delivery using a minimally invasive approach and good resolution between on- and off-states. Furthermore, in contrast to all-hydrogel systems, on-demand release of the model drug from the nanocomposite hydrogel system could be maintained over prolonged time periods. This magnetic multicomponent hydrogel system offers promising potential for on-demand drug delivery for a wide range of treatments requiring low doses of hydrophobic therapeutics over extended periods of time.


Figure 1: Preparation of the nanocomposite system with rhodamine B-loaded Tg nanoparticles and SPIONs embedded in the hydrogel using a double-barrel syringe equipped with a mixer for in situ gelation. AMF application induces a glass transition switch of the Tg nanoparticles accelerating drug release

Figure 2: Temperature-based release study of rhodamine B-loaded Tg nanoparticles incorporated in an injectable hydrogel of CMC and dextran with 5 wt% SPION content: (a) short term release over 6 hours; (b) longer term release over 6 days. * indicates statistical significance (p < 0.05).

Figure 3: AMF-based release study of rhodamine B-loaded Tg nanocomposites. (a) Release rate of rhodamine B with and without 30 min AMF pulses at 1, 3, and 5 h, (b) cumulative release of rhodamine B with pulsed AMF, constant applied AMF, and without an applied AMF.

Acknowledgements

The authors acknowledge the financial support from the J.P. Bickell Foundation (Medical Research Grant Program), the Vanier Scholarship program, and the Natural Sciences and Engineering Research Council of Canada.

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