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Magnetically induced localized on-demand drug delivery

Authors :
Rovers, S.A.
Keurentjes, Jos T.F.
Hoogenboom, Richard
Publication Year :
2010
Publisher :
Technische Universiteit Eindhoven, 2010.

Abstract

Externally triggered on-demand drug release from an implant can significantly improve the efficiency of the drug therapy since it enables the patient or physician to control the dosing to the patient’s needs and releases the drug only at the required location in the human body. Therefore, patient compliance and efficacy will increase and toxic side effects decrease as untargeted locations are not exposed to significant drug levels as is often the case in systemic drug administration. In this work, the externally triggered drug delivery system is a thermoresponsive polymeric implant triggered using an alternating magnetic field. The thermal switch is based on a significant change in diffusivity of a solute around the glass transition temperature (Tg) of a polymer. At a temperature below the glass transition temperature of the polymer (TTg), the polymer becomes rubbery. This significantly increases the flexibility and free volume of the polymer resulting in release of the active. Since the glass transition is a reversible transition, subsequent lowering of the temperature significantly decreases the drug release rate from the implant, enabling pulsatile drug administration. The temperature of the implant is increased using an externally applied alternating magnetic field. In order to increase the temperature of the implant using a magnetic field, the use of superparamagnetic iron oxide nanoparticles (SPION) is explored. These nanoparticles are used as MRI contrast agents and to locally increase the temperature in hyperthermia treatment, the destruction of tumors by elevated temperature. The particles have no remanent magnetization, are biocompatible and are able to generate thermal energy using an alternating magnetic field because of N´eel and Brown relaxation. N´eel relaxation is the reorientation of the magnetic moment within the particles, generating thermal energy by crossing an anisotropy barrier, and Brown relaxation the reorientation of the magnetic particles itself, generating thermal energy by viscous friction with the carrier fluid. Since the nanoparticles are used for heating a polymer implant, different preparation methods for an iron oxide - polymer nanocomposite have been investigated. Freeze drying a mixture of a ferrofluid with a poly(methyl methacrylate) (p(MMA)) latex and subsequent compounding, results in an optimal distribution of the particles. It is expected that the particles do not agglomerate because of the combination of stabilization of both the iron oxide particles and polymer latex by surfactants, and the lack of mobility during freeze drying. Other methods used, e.g. solvent casting and direct injection of the ferrofluid into the compounder, result in significant agglomeration of the particles. Subsequently, the particle distribution has been shown to have a significant effect on the heating of the particle. An optimal distribution of the particles results in the highest specific absorption rate (SAR), the amount of thermal energy generated per gram of iron oxide, because of a minimum in interparticle interactions. Since the nanoparticles incorporated in a polymer are immobilized, the particles are not able to generate thermal energy by Brown relaxation. By a direct comparison of the specific absorption rate of particles suspended in liquid and incorporated in p(MMA) using the optimal freeze drying method, the contribution of both N´eel and Brown relaxation to the heating of SPION has been investigated. Since the observed SAR is identical in both situations, it is concluded that at the frequency used (745 kHz), N´eel relaxation is the only relaxation process that contributes to the heating of the particles in ferrofluid, because of the significantly shorter relaxation time for N´eel relaxation. Using a cylindrical core of iron oxide - p(MMA) nanocomposite, coated with a thermoresponsive poly(butyl methacrylate-stat -methyl methacrylate) (p(BMAMMA)) layer, externally triggered on-demand drug release has been investigated. A model drug, ibuprofen, has been incorporated in the thermoresponsive p(BMAMMA) coating. Upon exposure of the sample to an alternating magnetic field (on situation), the drug release rate is significantly increased compared to the release rate without the magnetic field (off situation). After the magnetic field is removed, the release rate decreases back to the rate prior to the exposure, demonstrating the reversibility of the system. Multiple consecutive exposures to the external trigger result in similar increases of the release rate. Increasing the iron oxide concentration in the core of the device increases the release rate upon exposure, whereas the release rate without exposure is not influenced, therefore increasing the on/off ratio, because of a higher temperature increase upon exposure. Even though externally triggered pulsatile drug release has been shown, the maximum on/off ratio obtained is only 16.5. This relatively low ratio is primarily due to the suboptimal nature of the used commercially available iron oxide and the relative high off release rate of ibuprofen from p(BMA-MMA). In order to increase the on/off ratio, a cylindrical iron core has been used, coated with an ibuprofen incorporated poly(styrene-stat -butyl methacrylate) (p(S-BMA)) layer. The heat generated in the iron core upon exposure to the magnetic field is due to induction heating. Externally triggered pulsatile drug release has been shown using this concept with on/off ratios exceeding 2000, where both the on/off ratio and the release rate are affected by the concentration of ibuprofen. Generally, decreasing the base temperature of the release experiments from 37 to 25 ¿C significantly increases the on/off ratio. The effect of the orientation of the cylindrical iron rod with respect to the direction of the magnetic field on the heating of the device has been investigated using a Comsol model. Even though the effect of orientation is limited at small angles, a significantly lower surface temperature has been shown for larger angles, up to ~20 ¿C. This can result in a several orders of magnitude difference for the diffusion coefficient of ibuprofen in the polymer. Subsequently, the requirement of alignment between the sample and the magnetic field has been circumvented by the use of a macroscopic spherical iron core, coated with ibuprofen incorporated p(S-BMA). The absence of an alignment effect has been shown using 1 sample and 2 samples in line with the magnetic field, as this does not influence the release rate and on/off ratio, normalized to the surface area available for release in on-demand release experiments. Therefore, it is possible to use multiple samples to increase the attainable drug dose. Increasing the size of the spherical iron core and, therefore, decreasing the polymer thickness, only increases the release rate upon exposure, resulting in higher on/off ratios. In the case of a thinner polymer layer, the distance between the heating core and the outer surface of the polymer is smaller, resulting in a higher temperature of the outer layer. The solubility of a solute in a polymer is predominantly important for the release characteristics of that solute from the polymer. Therefore, the solubility of ibuprofen in p(S-BMA) has been investigated. Even though samples of p(S-BMA) with an ibuprofen concentration above 31 wt% show a clear phase separation, indicating maximum solubility at 31 wt% ibuprofen, measurement of the glass transition temperature of composites show that the system of p(S-BMA) with ibuprofen concentrations below 31 wt% is in a meta-stable state. In conclusion, repetitive on-demand drug release from a polymeric implant can be externally triggered using an alternating magnetic field. Due to their biocompatibility and the absence of an alignment effect, superparamagnetic iron oxide nanoparticles are preferable for the required heat generation. However, more optimal nanoparticles are required for high on/off ratios, as has been shown using another material for heat generation.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.narcis........96fbdec47b73a33bea7c3974906224f1