In vitro study of magnetic nanoparticles as the implant for implant assisted magnetic drug targeting

Magnetic nanoparticle (MNP) seeds were studied in vitro for use as an implant in implant assisted-magnetic drug targeting (IA-MDT). The magnetite seeds were captured in a porous polymer, mimicking capillary tissue, with an external magnetic field (70 mT) and then used subsequently to capture magnetic drug carrier particles (MDCPs) (0.87 μm diameter) with the same magnetic field. The effects of the MNP seed diameter (10, 50 and 100 nm), MNP seed concentration (0.25-2.0 mg/mL), and fluid velocity (0.03-0.15 cm/s) on the capture efficiency (CE) of both the MNP seeds and the MDCPs were studied. The CE of the 10 nm MNP seeds was never more than 30%, while those of the 50 and 100 nm MNP seeds was always greater than 80% and in many cases exceeded 90%. Only the MNP seed concentration affected its CE. The 10 nm MNP seeds did not increase the MDCP CE over that obtained in the absence of the MNP seeds, while the 50 and 100 nm MNP seeds increased significantly, typically by more than a factor of two. The 50 and 100 nm MNP seeds also exhibited similar abilities to capture the MDCPs, with the MDCP CE always increasing with decreasing fluid velocity and generally increasing with increasing MNP seed concentration. The MNP seed size, magnetic properties, and capacity to self-agglomerate and form clusters were key properties that make them a viable implant in IA-MDT.     

Implant assisted-magnetic drug targeting: Comparison of in vitro experiments with theory

Implant assisted-magnetic drug targeting (IA-MDT) was studied both in vitro and theoretically, with extensive comparisons made between model and experiment. Magnetic drug carrier particles (MDCPs) comprised of magnetite encased in a polymer were collected magnetically using a ferromagnetic, coiled, wire stent as the implant and a NdFeB permanent magnet for the applied magnetic field. A 2-D mathematical model with no adjustable parameters was developed and compared to the 3-D experimental results. The effects of the fluid velocity, stent and MDCP properties, and magnetic field strength on the performance of the system were evaluated in terms of the capture efficiency (CE) of the MDCPs. In nearly all cases, the parametric trends predicted by the model were in good agreement with the experimental results: the CE always increased with decreasing velocity, increasing magnetic field strength, increasing MDCP size or magnetite content, or increasing wire size. The only exception was when experiments showed an increase in the CE with an increase in the number of loops in the wire, while the model showed no dependence. The discrepancies between experiment and theory were attributed to phenomena not accounted for by the model, such as 3-D to 2-D geometric and magnetic field orientation differences, and interparticle interactions between the MDCPs that lead to magnetic agglomeration and shearing force effects. Overall, this work showed the effectiveness of a stent-based IA-MDT system through both in vitro experimentation and corroborated theory, with the designs of the ferromagnetic wire and the MDCPs both being paramount to the CE.     

Biodegradable nanocomposite magnetite stent for implant-assisted magnetic drug targeting

This study shows, for the first time, the fabrication of a biodegradable polymer nanocomposite magnetic stent and the feasibility of its use in implant-assisted-magnetic drug targeting (IA-MDT). The nanocomposite magnetic stent was made from PLGA, a biodegradable copolymer, and iron oxide nanopowder via melt mixing and extrusion into fibers. Degradation and dynamic mechanical thermal analyses showed that the addition of the iron oxide nanopowder increased the polymer’s glass transition temperature (T_g) and its modulus but had no notable effect on its degradation rate in PBS buffer solution. IA-MDT in vitro experiments were carried out with the nanocomposite magnetic fiber molded into a stent coil. These stent prototypes were used in the presence of a homogeneous magnetic field of 0.3 T to capture 100 nm magnetic drug carrier particles (MDCPs) from an aqueous solution. Increasing the amount of magnetite in the stent nanocomposite (0, 10 and 40 w/w%) resulted in an increase in the MDCP capture efficiency (CE). Reducing the MDCP concentrations (0.75 and 1.5 mg/mL) in the flowing fluid and increasing the fluid velocities (20 and 40 mL/min) both resulted in decrease in the MDCP CE. These results show that the particle capture performance of PLGA-based, magnetic nanocomposite stents are similar to those exhibited by a variety of different non-polymeric magnetic stent materials studied previously.     

In vitro study of ferromagnetic stents for implant assisted-magnetic drug targeting

Implant-assisted-magnetic drug targeting (IA-MDT) was studied in vitro using a coiled ferromagnetic wire stent made from stainless steel 430 or 304, and magnetic drug carrier particle (MDCP) surrogates composed of poly(styrene/divinylbenzene) embedded with 20 wt% magnetite. The fluid velocity, particle concentration, magnetic field strength, and stent material all proved to be important for capturing the MDCP surrogates. Overall, this in vitro study further confirmed the important role of the ferromagnetic implant for attracting and retaining MDCPs at the target zone.     

In vitro study of magnetic particle seeding for implant-assisted-magnetic drug targeting: Seed and magnetic drug carrier particle capture

An implant-assisted-magnetic drug targeting system using seed particles as the implant to increase the capture of magnetic drug carrier particles (MDCPs) in capillary tissue was studied in vitro. Dextran-coated magnetite particles were used as seeds, polydivinylbenzene magnetite particles were used as MDCPs, and a polyethylene porous cylinder was used as surrogate capillary tissue. The results showed that seeds could be magnetically captured first and then used to magnetically capture the MDCPs, causing a significant increase in their collection compared to when the seeds were absent.     

Theoretical analysis of a transdermal ferromagnetic implant for retention of magnetic drug carrier particles

The use of a ferromagnetic wire implant placed near an artery to assist the collection of magnetic drug carrier particles (MDCPs) using an external magnet is theoretically studied. Three magnetic drug targeting (MDT) systems are evaluated in terms of their MDCP collection efficiency (CE): a permanent magnet and wire is better than a permanent magnet alone, which is better than a homogeneous magnetic field and wire.     

Application of high gradient magnetic separation principles to magnetic drug targeting

A hypothetical magnetic drug targeting system, utilizing high gradient magnetic separation (HGMS) principles, was studied theoretically using FEMLAB simulations. This new approach uses a ferromagnetic wire placed at a bifurcation point inside a blood vessel and an externally applied magnetic field, to magnetically guide magnetic drug carrier particles (MDCP) through the circulatory system and then to magnetically retain them at a target site. Wire collection (CE) and diversion (DE) efficiencies were defined and used to evaluate the system performance. CE and DE both increase as the strength of the applied magnetic field (0.3–2.0 T), the amount of ferromagnetic material (iron) in the MDCP (20–100%) and the size of the MDCP (1–10 μm radius) increase, and as the average inlet velocity (0.1–0.8 m s⁻¹), the size of the wire (50–250 μm radius) and the ratio (4–10) of the parent vessel radius (0.25–1.25 mm radius) to wire radius decrease. The effect of the applied magnetic field direction (0° and 90°) on CE and DE was minimal. Under these plausible conditions, CEs as high as 70% were obtained, with DEs reaching only 30%; however, when the MDCPs were allowed to agglomerate (4–10 μm radius), CEs and DEs of 100% were indeed achieved. These results reveal that this new magnetic drug targeting approach for magnetically collecting MDCPs at a target site, even in arteries with very high velocities, is feasible and very promising; this new approach for magnetically guiding MDCPs through the circulatory system is also feasible but more limited. Overall, this study shows that magnetic drug targeting, based on HGMS principles, has considerable promise as an effective drug targeting tool with many potential applications.     

Ferromagnetic seeding for the magnetic targeting of drugs and radiation in capillary beds

A new implant assisted-magnetic drug targeting approach is introduced and theoretically analyzed to demonstrate its feasibility. This approach uses ferromagnetic particles as seeds for collecting magnetic drug carrier particles at the desired site in the body, such as in a capillary bed near a tumor. Based on the capture cross section (λ_c) approach, a parametric study was carried out using a 2-D mathematical model to reveal the effects of the magnetic field strength (μ₀H₀=0.01–1.0 T), magnetic drug carrier particle radius (R_p=20–500 nm), magnetic drug carrier particle ferromagnetic material content (x_fm,p=20–80 wt%), average blood velocity (u_B=0.05–1.0 cm/s), seed radius (R_s=100–2000 nm), number of seeds (N_s=1–8), seed separation (h=0–8R_s), and magnetic drug carrier particle and seed ferromagnetic material saturation magnetizations (iron, SS 409, magnetite, and SS 304) on the performance of the system. Increasing the magnetic field strength, magnetic drug carrier particle size, seed size, magnetic drug carrier particle ferromagnetic material content, or magnetic drug carrier particle or seed saturation magnetization, all positively and significantly affected λ_c, while increasing the average blood velocity adversely affected it. Increasing the number of seeds or decreasing the seed separation, with both causing less significant increases in λ_c, verified that cooperative magnetic effects exist between the seeds that enhance the performance. Overall, these theoretical results were encouraging as they showed the viability of this minimally invasive, implant assisted-magnetic drug targeting approach for targeting drugs or radiation in capillary beds.     

Preparation and characterization of biodegradable magnetic carriers by single emulsion-solvent evaporation

This paper describes a single emulsion-solvent evaporation protocol to prepare PEGylated biodegradable/biocompatible magnetic carriers by utilizing hydrophobic magnetite and a mixture of poly(D,L lactide-co-glycolide) (PLGA) and poly(lactic acid-block-polyethylene glycol) (PLA-PEG) (26:1 by mass) polymers. We characterized the magnetic microspheres in terms of morphology, composite microstructure, size and size distribution, and magnetic properties. Results show that the preparation produces magnetic microspheres with a good spherical morphology, small size (mean diameter of 1.2–1.5 μm) by means of large size distributions, and magnetizations up to 20–30 emu/g of microspheres.     

Ferromagnetic resonance spectroscopic response of magnetite chains in a biological matrix

In this study ferromagnetic resonance (FMR) spectroscopy using different frequencies (4.02, 9.47, and 34.16 GHz) was applied to randomly distributed magnetotactic bacteria characterized by their alignment of equidimensional magnetite particles in a chain. Using this technique the coupling field between the aligned magnetite particles of 55 mT was determined. The non-linear frequency dependence of the spectral linewidth is interpreted by the strong influence of the anisotropy properties of the studied magnetic composite.     

Observation of large magnetic resistance in weak magnetic fields using CuPt/SiO2/Si/SiO2/CuPt structure

The magnetoresistive effect of CuPt(8 nm)/SiO₂(5 nm)/Si(50,000 nm)/SiO₂(5 nm)/CuPt(8 nm) structure made by e-beam evaporation technique is studied in this work. Variation in magnetoresistance obtained by I-V measurements at 77 K and in the presence of less than 5 mT magnetic field applied in parallel to the surface is investigated. We have found that this structure exhibit large magnetoresistance in low magnetic fields (i.e. <5 mT). Our results also indicate that the variation in magnetoresistance in the presence of external magnetic field has oscillatory behavior and has the maximum value of 3295%. This structure due to its high sensitivity to low magnetic fields can also be used as an active element in magnetic field sensor devices.     

Inclusion of magnetic dipole-dipole and hydrodynamic interactions in implant-assisted magnetic drug targeting

Mathematical modelling of the implant-assisted magnetic drug targeting system of Avilés, Ebner and Ritter is performed. In order to model the agglomeration of particles known to occur in this system, the magnetic dipole-dipole and hydrodynamic interactions are included. Such interactions were calculated previously by Mikkelsen et al. under low magnetic fields (~0.05 T) in microfluidic systems. Here, a higher magnetic field (0.7 T) is considered and the effect of interactions on two nanoparticles with a seed implant is calculated. The calculations were performed with the open-source software OpenFOAM. Different initial positions are considered and the system performance is assessed in terms of capture cross section. Inclusion of both interactions was seen to alter the capture cross section of the system by up to 7% in absolute terms.     

Magnetic and in vitro heating properties of implants formed in situ from injectable formulations and containing superparamagnetic iron oxide nanoparticles (SPIONs) embedded in silica microparticles for magnetically induced local hyperthermia

The biological and therapeutic responses to hyperthermia, when it is envisaged as an anti-tumor treatment modality, are complex and variable. Heat delivery plays a critical role and is counteracted by more or less efficient body cooling, which is largely mediated by blood flow. In the case of magnetically mediated modality, the delivery of the magnetic particles, most often superparamagnetic iron oxide nanoparticles (SPIONs), is also critically involved. We focus here on the magnetic characterization of two injectable formulations able to gel in situ and entrap silica microparticles embedding SPIONs. These formulations have previously shown suitable syringeability and intratumoral distribution in vivo. The first formulation is based on alginate, and the second on a poly(ethylene-co-vinyl alcohol) (EVAL). Here we investigated the magnetic properties and heating capacities in an alternating magnetic field (141 kHz, 12 mT) for implants with increasing concentrations of magnetic microparticles. We found that the magnetic properties of the magnetic microparticles were preserved using the formulation and in the wet implant at 37 °C, as in vivo. Using two orthogonal methods, a common SLP (20 W g⁻¹) was found after weighting by magnetic microparticle fraction, suggesting that both formulations are able to properly carry the magnetic microparticles in situ while preserving their magnetic properties and heating capacities.     

Optimal design of nanomagnets for targeted hyperthermia

We have numerically simulated the dynamic response of single-domain nanomagnets to alternating magnetic fields and discuss nanometer-sized thermal seeds suitable for selectively targeted magnetic hyperthermia. When we assign priority to the easy delivery and biological safety of these fields, the maximum heating power is obtained by the irradiation of a weak field at a medium frequency (∼1 MHz) on almost spherical magnetite nanomagnets with a diameter of approximately 20 nm. On the other hand, the irradiation of the amplified field at a low frequency (∼100 kHz) is more effective if the neural stimulation is allowable.     

Production of magnetic microspheres by ultrasonic atomisation

Magnetic microspheres, with mean particle sizes from 23 to 32 μm were produced by the ultrasonic atomisation of a suspension of magnetite particles, of approximately 200 nm diameter, in a solution of poly–l–lactic acid (PLLA). The mean particle diameter and the width of the particle diameter distribution both increased with increasing magnetite concentration. The particles appear to be suitable for magnetic hyperthermic treatment of liver cancers, with the hysteresis loop areas increasing linearly with nominal magnetite concentration up to 30 wt% magnetite.     

Synthesis of magnetite nanoparticles for AC magnetic heating

Magnetite particles with different average diameter (D_m) suitable for magnetic fluid hyperthermia (MFH) were synthesized by controlled coprecipitation technique. In this method, the reaction pH was stabilized using the pH buffer and the average particle diameter decreased with increasing reaction pH. The size-dependent magnetic behavior of the magnetite nanoparticles was studied and the optimum size range required for magnetic fluid hyperthermia (MFH) has been arrived at. Among the samples studied, the maximum specific absorption rate of 15.7 W/g was recorded for the magnetite sample with D_m of 13 nm, when exposed to an AC magnetic field strength of 3.2 kA/m and a frequency of 600 kHz. The AC magnetic properties suggested that the size distribution of the sample was bimodal with average particle size less than ∼13 nm.     

In situ hybridization to chitosan/magnetite nanocomposite induced by the magnetic field

Chitosan/magnetite nanocomposite was synthesized induced by magnetic field via in situ hybridization in ambient condition. Results of XRD patterns and TEM micrographs indicated that magnetite particles with 10–20 nm were dispersed in chitosan homogeneously. An interesting result is that magnetite nanoparticles were assembled to form chain-like structures under the influence of the external magnetic field, which mimics the magnetite chains inside of magnetotatic bacteria. The saturated magnetization (Ms) of nano-magnetite in chitosan was 50.54 emu/g, which is as high as 54% of bulk magnetite. The remanence (Mr) and coercivity (Hc) were 4 emu/g and14.8 Oe, respectively, which indicated that magnetite nanoparticles were superparamagnetic. The key of route is that a pre-precipitated chitosan hydrogel membrane, used as chemical reactor, which controlled the precipitation of chitosan precipitation and in situ transformation of magnetite from the precursor simultaneously in the magnetic field environment.     

Optimization of spin-valve parameters for magnetic bead trapping and manipulation

Magneto-optic Kerr effect (MOKE) and magnetoresistance (MR) measurements were used to measure the switching characteristics of spin-valve (SV) arrays currently being developed to trap and release superparamagnetic beads within a fluid medium. The effect of SV size on switching observed by MOKE showed that a 1 μm×8 μm SV element was found to have optimal switching characteristics. MR measurements on a single 1 μm×8 μm SV switched with either an external applied magnetic field or a local magnetic field generated by an integrated write wire (current density ranging from 10⁶ to 10⁷ A/cm²) confirmed the MOKE findings. The 1 μm×8 μm SV low field switching was observed to be +8 and −2 mT with two stable states at zero field; the high field switching was observed to be −18 mT. The low switching fields and the large magnetic moment of the SV trap along with our observation of minimal magnetostatic effects for dense arrays are necessary design characteristics for high-force, “switchable-magnet,” microfluidic bead trap applications.     

Magnetic,magnetoelectric and dielectric behavior of CoFe2O4–Pb(Fe1/2Nb1/2)O3 particulate and layered composites

Magnetic, magnetoelectric and dielectric properties of multiferroic CoFe₂O₄–Pb(Fe_1/2Nb_1/2)O₃ composites prepared as bulk ceramics were compared with those of tape cast and cofired laminates consisting of alternate ferrite and relaxor layers. X-ray diffraction analysis and Scanning Electron Microscope observations of ceramic samples revealed two-phase composition and fine grained microstructure with uniformly distributed ferrite and relaxor phases. High and broad maxima of dielectric permittivity attributed to dielectric relaxation were found for ceramic samples measured in a temperature range from −55 to 500 °C at frequencies 10 Hz–2 MHz. Magnetic hysteresis, zero-field cooled (ZFC) and field cooled (FC) curves, and dependencies of magnetization on temperature for both magnetoelectric composites were measured with a vibrating sample magnetometer in an applied magnetic field up to 80 kOe at 4–400 K. The hysteresis loops obtained for composites are typical of a mixture of the hard magnetic material with a significant amount of the paramagnet. The bifurcation of ZFC–FC magnetizations observed for both composites implies spin-glass behavior. Magnetoelectric properties at room temperature were investigated as a function of dc magnetic field (0.3–7.2 kOe) and frequency (10 Hz–10 kHz) of ac magnetic field. Both types of composites exhibit a distinct magnetoelectric effect. Maximum values of magnetoelectric coefficient attained for the layered composites exceed 200 mV/(cm Oe) and are almost three times higher than those for particulate composites.     

Analysis of magnetic drug carrier particle capture by a magnetizable intravascular stent—2: Parametric study with multi-wire two-dimensional model

A 2-D mathematical model was developed and used to examine the capture of magnetic drug carrier particles (MDCPs) by a magnetizable intravascular stent (MIS). The roles of both non-stent system parameters, i.e., the blood flow rate, magnetic field strength and direction and MDCP properties, and stent design parameters, i.e., the MIS radius, its wire radius, number of MIS loops, interwire loop spacing and MIS ferromagnetic material were evaluated over a wide range of plausible conditions. The results showed that the MIS could be a very effective magnetic drug targeting tool with many possible applications.