Magnetically induced localized on-demand drug delivery

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

Relaxation processes of superparamagnetic iron oxide nanoparticles in liquid and incorporated in poly(methyl methacrylate)

Commercially available superparamagnetic iron oxide nanoparticles (SPION) of 12 nm are investigated with respect to the contribution of both Neìel and Brown relaxation to the magnetic heating of these particles. For this purpose experiments have been performed to heat the particles, suspended in a liquid as well as incorporated in a poly(methyl methacrylate) (p(MMA)) matrix, using an alternating (ac) magnetic field of 745 kHz at three different field strengths up to 2850 A m−1. It is shown that the specific absorption rates (SAR) of the particles in the ferrofluid are identical within experimental error to the SAR of the particles incorporated in p(MMA) at all measured field strengths. As Brown relaxation is not possible if the SPION are incorporated in the polymer matrix, it can be concluded that Neìel relaxation is the only relaxation process that contributes to heating the ferrofluid at 745 kHz as well. This is confirmed by calculation of the relaxation times for Neìel and Brown relaxation. Furthermore, calculations suggest that Neìel relaxation is also the predominant relaxation process for small superparamagnetic particles at lower frequencies

On-demand drug delivery from polymeric implants by external triggering

In this contribution, a novel on demand drug delivery concept based on polymeric implants is presented. The simple combination of drug substance and polymer matrix was found to result in a robust and reproducible on demand drug delivery device that can be switched by temp. High switching ratios (several hundreds) were found in repetitive (up to 5) on demand drug dosing. In addn., the use of several other noninvasive triggers was explored. Finally, the potential of this novel drug delivery technol. will be demonstrated by in vivo on demand drug delivery

On-demand drug delivery from polymeric implants by external triggering

In this contribution, a novel on demand drug delivery concept based on polymeric implants is presented. The simple combination of drug substance and polymer matrix was found to result in a robust and reproducible on demand drug delivery device that can be switched by temp. High switching ratios (several hundreds) were found in repetitive (up to 5) on demand drug dosing. In addn., the use of several other noninvasive triggers was explored. Finally, the potential of this novel drug delivery technol. will be demonstrated by in vivo on demand drug delivery

Influence of distribution on the heating of superparamagnetic iron oxide nanoparticles in poly(methyl methacrylate) in an Alternating Magnetic Field

The effect of distribution on the heating of superparamagnetic iron oxide nanoparticles in a polymer matrix has been investigated in an alternating magnetic field. Commercially available particles have been distributed using 30 and 50 wt % loading in a poly(methyl methacrylate) (p(MMA)) matrix by different preparation methods, resulting in different distributions of the particles. Freeze-drying a mixture of ferrofluid and p(MMA) latex followed by compounding is found to diminish particle aggregation, leading to an optimal distribution. Subsequently, the heating of the particles in the nanocomposites has been investigated in an alternating magnetic field of 2850 A m-1 with a 745 kHz frequency. These heating experiments show significantly higher specific absorption rates (SARs) of the incorporated iron oxide particles in the case of the freeze-drying method due to the improved distribution of the particles when compared to direct compounding or solvent casting. Furthermore, the higher particle loading provides faster heating, although the SAR decreases due to the presence of larger aggregates

Characterization and magnetic heating of commercial superparamagnetic iron oxide nanoparticles

Commercially available superparamagnetic iron oxide nanoparticles (SPION) of 12 nm are characterized with respect to their physical, magnetic, and heating properties in an alternating magnetic field. For this purpose, a specialized magnetic field setup has been developed and characterized. Particles of the waterbased ferrofluid, EMG705, and particles coated for a hydrocarbon carrier have been investigated using several techniques, including transmission electron microscopy and superconducting quantum interference device magnetometry, showing the superparamagnetic behavior of the particles. The specific absorption rate of the particles has been confirmed to have square dependency on the magnetic field strength. The difference in heating of the two samples could be explained by the difference in particles size distribution

Externally triggered glass transition switch for localized on-demand drug delivery

want a new drug dose: External on-demand laser triggering is used in a drug-delivery concept, with on/off ratios in excess of 1000/1. The switching mechanism involves the glass transition of hydrophobic polymers with a large change in diffusivity. Formation of a glassy surface layer of the implant in the off state plays a key role, resulting in negligible off-release. (Picture: data points indicate ibuprofen concentration)

Testosterone, sex hormone-binding globulin and the metabolic syndrome in men: an individual participant data meta-analysis of observational studies

BACKGROUND: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably. OBJECTIVES: We aimed to investigate whether associations differ across specific subgroups (according to age and body mass index (BMI)) and individual MetS components. DATA SOURCES: Two previously published meta-analyses including an updated systematic search in PubMed and EMBASE. STUDY ELIGIBILITY CRITERIA: Cross-sectional or prospective observational studies with data on TT and/or SHBG concentrations in combination with MetS in men. METHODS: We conducted an individual participant data meta-analysis of 20 observational studies. Mixed effects models were used to assess cross-sectional and prospective associations of TT, SHBG and free testosterone (FT) with MetS and its individual components. Multivariable adjusted odds ratios (ORs) and hazard ratios (HRs) were calculated and effect modification by age and BMI was studied. RESULTS: Men with low concentrations of TT, SHBG or FT were more likely to have prevalent MetS (ORs per quartile decrease were 1.69 (95% CI 1.60-1.77), 1.73 (95% CI 1.62-1.85) and 1.46 (95% CI 1.36-1.57) for TT, SHBG and FT, respectively) and incident MetS (HRs per quartile decrease were 1.25 (95% CI 1.16-1.36), 1.44 (95% 1.30-1.60) and 1.14 (95% 1.01-1.28) for TT, SHBG and FT, respectively). Overall, the magnitude of associations was largest in non-overweight men and varied across individual components: stronger associations were observed with hypertriglyceridemia, abdominal obesity and hyperglycaemia and associations were weakest for hypertension. CONCLUSIONS: Associations of testosterone and SHBG with MetS vary according to BMI and individual MetS components. These findings provide further insights into the pathophysiological mechanisms linking low testosterone and SHBG concentrations to cardiometabolic risk