Magnetic Microbubbles Research Articles

Interventional Removal of Travelling Microthrombi Using Targeted Magnetic Microbubble.

Microthrombus is one of the major causes of the sequelae of Corona Virus Disease 2019 (COVID-19 and leads to subsequent embolism and necrosis. Due to their small size and irregular movements, the early detection and efficient removal of microthrombi in vivo remain a great challenge. In this work, an interventional method is developed to identify and remove the traveling microthrombi using targeted-magnetic-microbubbles (TMMBs) and an interventional magnetic catheter. The thrombus-targeted drugs are coated on the TMMBs and magnetic nanoparticles are shelled inside, which allow not only targeted adhesion onto the traveling microthrombi, but also the effective capture by the magnetic catheter in the vessel. In the proof-of-concept experiments in the rat models, the concentration of microthrombus is reduced by more than 60% in 3 min, without damaging the organs. It is a promising method for treating microthrombus issues.

Ultrasound imaging guided targeted sonodynamic therapy enhanced by magnetophoretically controlled magnetic microbubbles

Sonodynamic therapy (SDT) utilizes ultrasonic excitation of a sensitizer to generate reactive oxygen species (ROS) to destroy tumor. Two dimensional (2D) black phosphorus (BP) is an emerging sonosensitizer that can promote ROS production to be used in SDT but it alone lacks active targeting effect and showed low therapy efficiency. In this study, a stable dispersion of integrated micro-nanoplatform consisting of BP nanosheets loaded and Fe3O4 nanoparticles (NPs) connected microbubbles was introduced for ultrasound imaging guided and magnetic field directed precision SDT of breast cancer. The targeted ultrasound imaging at 18 MHz and efficient SDT effects at 1 MHz were demonstrated both in-vitro and in-vivo on the breast cancer. The magnetic microbubbles targeted deliver BP nanosheets to the tumor site under magnetic navigation and increased the uptake of BP nanosheets by inducing cavitation effect for increased cell membrane permeability via ultrasound targeted microbubble destruction (UTMD). The mechanism of SDT by magnetic black phosphorus microbubbles was proposed to be originated from the ROS triggered mitochondria mediated apoptosis by up-regulating the pro-apoptotic proteins while down-regulating the anti-apoptotic proteins. In conclusion, the ultrasound theranostic was realized via the magnetic black phosphorus microbubbles, which could realize targeting and catalytic sonodynamic therapy.

Magnetically navigated microbubbles coated with albumin/polyarginine and superparamagnetic iron oxide nanoparticles

While microbubbles (MB) are routinely used for ultrasound (US) imaging, magnetic MB are increasingly explored as they can be guided to specific sites of interest by applied magnetic field gradient. This requires the MB shell composition tuning to prolong MB stability and provide functionalization capabilities with magnetic nanoparticles. Hence, we developed air-filled MB stabilized by a protein–polymer complex of bovine serum albumin (BSA) and poly-L-arginine (pArg) of different molecular weights, showing that pArg of moderate molecular weight distribution (15–70 kDa) enabled MB with greater stability and acoustic response while preserving MB narrow diameters and the relative viability of THP-1 cells after 48 h of incubation. After MB functionalization with superparamagnetic iron oxide nanoparticles (SPION), magnetic moment values provided by single MB confirmed the sufficient SPION deposition onto BSA + pArg MB shells. During MB magnetic navigation in a blood vessel mimicking phantom with magnetic tweezers and in a Petri dish with adherent mouse renal carcinoma cell line, we demonstrated the effectiveness of magnetic MB localization in the desired area by magnetic field gradient. Magnetic MB co-localization with cells was further exploited for effective doxorubicin delivery with drug-loaded MB. Taken together, these findings open new avenues in control over albumin MB properties and magnetic navigation of SPION-loaded MB, which can envisage their applications in diagnostic and therapeutic needs.

Local control of magnetic microbubble behavior by magnetic field and pulsed ultrasound

The localization of magnetic microbubbles (MMBs) to a target site has been shown to be essential to their efficacy in therapeutic applications such as targeted drug delivery and gene therapy. In this work, the MMBs’ dynamic equations of vibration, horizontal and vertical motion in a fluid-filled tube, subject to a magneto-acoustic complex field, are established by Lagrange method. The responses and capture efficiency under three ultrasonic pulses waveform in a magnetic field are numerically analyzed. The regulation effects of the external field are observed by experiments. The results show that the transport behavior is influenced by bubble size, original position, liquid flow rate, tube diameter, parameters of acoustic and magnetic field. For the same acoustic parameters, square wave pulse can make stronger vibrate compared with cosine wave and sawtooth wave, which pushes MMBs closer to the magnet. In addition, high frequency and large amplitude pulse are benefit to translation, and increasing the cycle number in a single pulse can also promote translation. In practical applications, variable parameters such as bubble speed and magnet length can be used to improve the capture efficiency. The observations of high-speed camera are consistent with the prediction of theoretical model, which indicates the model is mostly correct.

Ultrasound-mediated multifunctional magnetic microbubbles for drug delivery of celastrol in VX2 liver transplant tumors.

Celastrol (CST) has positive pharmacological effects on various cancers, but clinical application is limited because of poor water solubility and systemic toxicity. Ferric oxide (Fe3O4) has a large specific surface area and can be functionalized by inorganic modification to form complex magnetic drug delivery systems. Herein, Fe3O4 was surface-modified with citric acid and polyethylene glycol (PEG) (via) the Mitsunobu reaction and then covalently bound to CST. Finally, magnetic microbubbles (MMBs) containing perfluoropropane (C3F8) and Fe3O4-PEG2K-CST particles were constructed with poly(lactic-co-glycolic acid) (PLGA) as the shell membrane. In vitro studies showed that ultrasound-mediated MMBs exhibited improved inhibition of VX2 cell proliferation compared to inhibition achieved using MMBs without ultrasound mediation, blank MMBs, or free CST. In ultrasound mode, MMBs have favorable imaging properties. After the application of a high mechanical index, MMBs collapse through the cavitation effect, releasing their internal Fe3O4-PEG2K-CST. The CST is then delivered to the tumor microenvironment under acidic conditions. In magnetic resonance imaging T2 mode, a specific hypointense signal was observed in the tumor area compared with that before treatment, whereas no significant change occurred in the signal intensity of the surrounding organs. After treatment, pathological examination of tumor-bearing rabbit tissues showed that iron elements accumulated in several apoptosis cells in the tumor area, with no apparent abnormalities found in other areas. Thus, ultrasound-mediated MMBs could significantly improve the drug uptake of solid tumors and inhibit tumor growth with favorable biological safety.

Effect of magnetic field on expansion of ferrofluid-encapsulated microbubble

Magnetic microbubbles (MMBs) have great potential applications in drug delivery and target therapy because they can be controlled by magnetic fields. In this paper, dynamic equations are derived by Lagrangian formalism and the behavior of MMBs subject to a combination field of magnetic and ultrasound field in an incompressible infinite fluid is analyzed numerically. The results show that the magnetic field can promote bubble expansion and hinder its translational motion, and both the enhancement and obstruction effects will weaken with the decrease of bubble size. The initial translational velocity has almost no effect on bubbles motion. Besides, the maximum expansion radius of MMBs increases with the ferrofluid shell thickness, while that of the common MBs is just the opposite. In addition, the periodic change of Levich viscous drag caused by the rebound leads to the step-like translational motion. Finally, the ferrofluid-shell model can be replaced by the model of non-magnetic microbubbles in magnetic liquid at high driving frequency.

Modeling dynamic behavior of two magnetic microbubbles in ultrasonic and magnetic fields

Magnetic microbubble (microbubble coated with magnetic nanoparticles) has the advantages of hybrid encapsulated shell, non-invasive fields manipulation and drug/gene delivery, which promotes a broad application prospects in both scientific research and clinic communities. In this work, the encapsulated shell coated with magnetic nanoparticles has been translated into the equivalent problem about bubble in the magnetic fluid. Behavior of two bubbles in the magnetic fluid are theoretically studied by using Lagrange formalism. We evaluate the manipulation of acoustic and magnetic fields on two bubbles dynamics. Magnetic pressure generated by magnetic field increases the pulsating amplitude of each bubble, affects bubbles translation and enhances the gas pressure and temperature inside bubble. Besides, bubbles attraction is caused by the competition between viscous drag and attractive secondary Bjerknes force related to bubble pulsation. In addition, the attractive force caused by magnetic field is useful at very close distance between bubbles, and its effect is quite small compared to the attraction driven by ultrasound. These findings may have implications for ultrasound guided drug delivery using microbubbles coated with magnetic nanoparticles, especial their manipulation in magnetic field.

Effect of pulse duty ratio on temperature rise induced by focused ultrasound combined with magnetic microbubbles

Development of acoustic/magnetic contrast agent microbubbles with various diagnostic and therapeutic functions has attracted more and more attention in medical ultrasound, biomedical engineering and clinical applications. Superparamagnetic iron oxide nanoparticles (SPIO) have unique magnetic characteristics and wonderful biocompatibility, so they can be used as MRI contrast agents to improve image contrast, spatial resolution and diagnostic accuracy. Our previous work shows that the multimodal diagnostic and therapeutic microbubble agents can be successfully constructed by embedding SPIO particles into the coating shell of conventional ultrasound contrast agent (UCA) microbubbles, which in turn changes the size distribution and shell properties of UCA microbubbles, thereby affecting their acoustic scattering, cavitation and thermal effects. However, previous studies only considered the influence factors such as acoustic pressure and microbubble concentration. The relevant investigation regarding the influence of ultrasound temporal characteristics on the dynamic response of magnetic microbubbles is still lacking. This work systematically measures the temperature enhancement effect of the SPIO-albumin microbubble solution flowing in the vascular gel phantom exposed to pulsed ultrasound with various temporal settings (e.g. duty cycle, PRF and single pulse length). Meanwhile, a two-dimensional finite element model is developed to simulate and verify the experimental observations. The results show that the increase of duty cycle of pulse signal should be the crucial factor affecting the temperature enhancement effect of flowing SPIO-albumin microbubble solution under the exposure to high-intensity focused ultrasound. The current results help us to better understand the influence of different acoustic setting parameters on the thermal effect of dual-modal magnetic UCA microbubbles, and provide useful guidance for ensuring the safety and effectiveness of the application of SPIO-albumin microbubbles in clinics.

Dynamics of magnetic microbubble transport in blood vessels

Magnetic microbubbles (MMBs) can be controlled and directed to the target site by a suitable external magnetic field, and thus have potential in therapeutic drug-delivery application. However, few studies focus on their dynamics in blood vessels under the action of magnetic and ultrasonic fields, giving little insight into the mechanism generated in diagnostic and therapeutic applications. In this study, equations of MMBs were established for simulating translation, radial pulsation and the coupled effect of both. Meanwhile, the acoustic streaming and shear stress on the vessel wall were also presented, which are associated with drug release. The results suggest that the magnetic pressure increases the bubble pulsation amplitude, and the translation coupled with pulsation is manipulated by the magnetic force, causing retention in the target area. As the bubbles approach the vessel wall, the acoustic streaming and shear stress increase with magnetic field enhancement. The responses of bubbles to a uniform and a gradient magnetic field were explored in this work. The mathematical models derived in this work could provide theoretical support for experimental phenomena in the literature and also agree with the reported models.

Thrombin‐Loaded Magnetic Microbubbles for the Treatment of Pseudoaneurysms

AbstractThe drive toward minimally invasive surgery has yielded multiple benefits for patients but has also increased the incidence of pseudoaneurysms (PSA). The current standard of care is ultrasound‐guided thrombin injection to coagulate blood in the PSA sac and seal the ruptured vessel. There is, however, a risk of downstream thrombosis if thrombin escapes into the communicating vessel and this limits patient eligibility for thrombin injection. In this study, the feasibility of using magnetic targeting to reduce the risk of distal thrombosis is investigated. Thrombin‐loaded magnetic microbubbles are formulated and injected into tissue‐mimicking phantoms of PSAs with different geometries using either saline or whole (equine) blood. Ultrasound imaging is used to quantify the concentration of bubbles remaining in the sac with and without application of a custom‐built magnetic array. An absorbance‐based assay is also used to quantify the concentration of thrombin escaping from the sac. Magnetic targeting enables a significant increase in thrombin retention in all femoral artery PSA models except one, with up to 97% ± 2.5% of the injected thrombin being retained. It is also confirmed that the enzymatic activity of thrombin is maintained, and that clot formation can be successfully achieved in whole blood.

A Hand-Held Magnetic Acoustic Device With Integrated Real-Time Monitoring for Targeted Drug Delivery.

Advances in magnetic materials have enabled the development of new therapeutic agents that can be localized by external magnetic fields. These agents offer a potential means of improving treatment targeting and reducing the toxicity-related side effects associated with systemic delivery. Achieving sufficiently high magnetic fields at clinically relevant depths in vivo, however, remains a challenge. Similarly, there is a need for techniques for real-time monitoring that do not rely on magnetic resonance imaging (MRI). Here, we present a hand-held device to meet these requirements, combining an array of permanent magnets and a thin 64-element capacitive micromachined ultrasonic transducer (CMUT) interfaced to a real-time imaging system. Drug carrier localization was assessed by measuring the terminal velocity of magnetic microbubbles in a column of fluid above the magnetic array. It was found that the magnetic pull force was sufficient to overcome buoyancy at equivalent tissue depths of at least 35 mm and that the median terminal velocity ranged from 0.7 to 20 [Formula: see text]/s over the distances measured. A Monte Carlo study was performed to estimate capture effectiveness in tumor microvessels over a range of different tissue depths and flow rates. Finally, B-mode and contrast-enhanced ultrasound (CEUS) imaging were demonstrated using a gel flow phantom containing a 1.6-mm diameter vessel. Real-time monitoring provided visual confirmation of retention of magnetic microbubbles along the vessel wall at a flow rate of 0.5 mL/min. These results indicate that the system can successfully retain and image magnetic microbubbles at tissue depths and flow rates relevant for clinical applications such as molecular ultrasound imaging of atherosclerosis, sonodynamic and antimetabolite cancer therapy, and clot dissolution via sonothrombolysis.

Contrast enhanced magneto-motive ultrasound in lymph nodes - modelling and pre-clinical imaging using magnetic microbubbles.

Despite advances in MRI, the detection and characterisation of lymph nodes in rectal cancer remains complex, especially when assessing the response to neo-adjuvant treatment. An alternative approach is functional imaging, previously shown to aid characterization of cancer tissues. We report proof-of-concept of the novel technique Contrast-Enhanced Magneto-Motive Ultrasound (CE-MMUS) to recover information relating to local perfusion and lymphatic drainage, and interrogate tissue mechanical properties through magnetically induced tissue deformations. The feasibility of the proposed application was explored using a combination of pre-clinical ultrasound imaging and finite element analysis. First, contrast enhanced ultrasound imaging on one wild type mouse recorded lymphatic drainage of magnetic microbubbles after bolus injection. Second, preliminary CE-MMUS data were acquired as a proof of concept. Third, the magneto-mechanical interactions of a magnetic microbubble with an elastic solid were simulated using finite element software. Accumulation of magnetic microbubbles in the inguinal lymph node was verified using contrast enhanced ultrasound, with peak enhancement occurring 3.7 s post-injection. Preliminary CE-MMUS indicates the presence of magnetic contrast agent in the lymph node. The finite element analysis explores how the magnetic force is transferred to motion of the solid, which depends on elasticity and bubble radius, indicating an inverse relation with displacement. Combining magnetic microbubbles with MMUS could harness the advantages of both techniques, to provide perfusion information, robust lymph node delineation and characterisation based on mechanical properties. Clinical Relevance- Robust detection and characterisation of lymph nodes could be aided by visualising lymphatic drainage of magnetic microbubbles using contrast enhanced ultrasound imaging and magneto-motion, which is dependent on tissue mechanical properties.

Modelling of magnetic microbubbles to evaluate contrast enhanced magnetomotive ultrasound in lymph nodes - a pre-clinical study.

Despite advances in MRI the detection and characterisation of lymph nodes in rectal cancer remains complex, especially when assessing the response to neoadjuvant treatment. An alternative approach is functional imaging, previously shown to aid characterisation of cancer tissues. We report proof of concept of the novel technique Contrast-Enhanced Magneto-Motive Ultrasound (CE-MMUS) to recover information relating to local perfusion and lymphatic drainage, and interrogate tissue mechanical properties through magnetically induced deformations. The feasibility of the proposed application was explored using a combination of experimental animal and phantom ultrasound imaging, along with finite element analysis. First, contrast-enhanced ultrasound imaging on one wild type mouse recorded lymphatic drainage of magnetic microbubbles after bolus injection. Second, tissue phantoms were imaged using MMUS to illustrate the force- and elasticity dependence of the magnetomotion. Third, the magnetomechanical interactions of a magnetic microbubble with an elastic solid were simulated using finite element software. Accumulation of magnetic microbubbles in the inguinal lymph node was verified using contrast enhanced ultrasound, with peak enhancement occurring 3.7 s post-injection. The magnetic microbubble gave rise to displacements depending on force, elasticity, and bubble radius, indicating an inverse relation between displacement and the latter two. Combining magnetic microbubbles with MMUS could harness the advantages of both techniques, to provide perfusion information, robust lymph node delineation and characterisation based on mechanical properties. (a) Lymphatic drainage of magnetic microbubbles visualised using contrast-enhanced ultrasound imaging and (b) magnetomechanical interactions between such bubbles and surrounding tissue could both contribute to (c) robust detection and characterisation of lymph nodes.

Low frequency (<1 MHz) transducers for intravenous sonothrombolysis

Venous embolism is a great challenge in the treatment of a wide range of diseases, including cardiovascular diseases and cancers. Ultrasound-mediated thrombolysis (sonothrombolysis) presents a promising treatment of venous embolism. In this paper, miniature ultrasound transducers with frequencies ranging from 250 kHz to 800 kHz were developed for microbubble/nanodroplet-mediated intravenous sonothrombolysis tests. Relative low frequency (e.g., <1 MHz) is preferred because of the findings that cavitation plays an important role in sonothrombolysis, and microbubble-associated cavitation events can be enhanced at low frequencies. Small aperture (e.g. <2 mm × 2 mm) low-frequency transducers are usually known with high electrical impedance (e.g., >1000 Ω), which is not preferred for efficient electromechanical transduction. To address this challenge, multilayer acoustic stacks were designed, fabricated, and characterized. The measured electrical impedance of these stacks is mostly closer to 50 Ω, and the peak negative pressure is higher than 1MPa. These small aperture transducers were then used in in vitro- thrombolysis tests with unretracted and retracted blood clots, showing promising lysis rates. Other techniques such as laser ultrasound transducers, vortex wave generation, and magnetic microbubbles were also investigated for thrombolysis tests.

Evaluation of Tumor Resection Effect of Color Doppler Ultrasound Positioning Guided Breast-Conserving Surgery Using Nano-Contrast Agent.

This study aimed to explore the clinical value of Fe3O4-based magnetic lipid nano-contrast agent in breast-conserving surgery for breast cancer using color doppler ultrasound positioning and to analyze the tumor resection effect of breast-conserving surgery. On account of Fe3O4 magnetic nanoparticles prepared by the chemical co-precipitation method, magnetic lipid ultrasonic microbubbles (MLU-MBs) were prepared by mechanical oscillation method after surface modification using polyethylene terephthalate (PET). Characterization and analysis of the prepared MLU-MBs were performed using scanning electron microscopy (SEM), energy spectrometer, transmission electron microscopy (TEM), and Fourier infrared spectroscopy (FIRS). A high-frequency alternating magnetic field was used to detect the heating of MLU-MBs and the color ultrasound machine was applied to observe the enhancement effect of the MLU-MBs on rabbit liver images. 92 patients undergoing breast-conserving surgery for breast cancer were taken as the research objects and were divided into a nano group (MLU-MB as contrast agent) and a control group (conventional contrast agent) according to the differences of intraoperative contrast agents, with 46 cases in each group. Before the surgery, both groups of patients were positioned and marked the tumor boundary under ultrasound. The differences in tumor volume (TV), amount of tissue removed, resection rate, and positive rate (PR) of resection margins were compared between the two groups. The results showed that the Fe3O4 magnetic nanoparticles were particles with an average particle size of about 15nm, and their iron and oxygen percentages were consistent with the content of Fe3O4. The MLU-MBs were spherical particles of about 1120nm, containing phosphorus (P), oxygen(O), and Ferrum (Fe). Under 30A and 220kHz of output current and frequency, the temperature rise of the MLU-MBs suspension with different concentrations was 10 ~ 60°C, and the temperature was constant after heating for 45 minutes. Compared with the rabbit liver parenchyma, the image was greatly enhanced. TV, the amount of tissue removed, the resection rate, and the PR of resection margins in the nano group were obviously lower than those in the control group (P<0.05). It showed that MLU-MBs with good image enhancement effect on account of Fe3O4 magnetic nanoparticles were successfully prepared and it could effectively reduce the PR of normal tissues and the positive margin of two-fold resection during breast-conserving surgery for breast cancer and showed good accuracy and stability.

Targeted drug delivery of magnetic microbubble for abdominal aortic aneurysm: an in silico study.

Targeted drug delivery (TDD) to abdominal aortic aneurysm (AAA) using a controlled and efficient approach has recently been a significant challenge. In this study, by using magnetic microbubbles (MMBs) under a magnetic field, we investigated the MMBs performance in TDD to AAA based on the amount of surface density of MMBs (SDMM) adhered to the AAA lumen. The results showed that among the types of MMBs studied in the presence of the magnetic field, micromarkers are the best type of microbubble with a -[Formula: see text] increase in SDMM adhered to the critical area of AAA. The results show that applying a magnetic field causes the amount of SDMM adhered to the whole area of AAA to increase -[Formula: see text] times compared to the condition in which the magnetic field is absent. This optimal and maximum value occurs for Definity MMBs with - 3.3 μm diameter. Applying a magnetic field also increases the adhesion surface density by - [Formula: see text], - [Formula: see text], and -[Formula: see text] times for the Micromarker, Optison, and Sonovue microbubbles, respectively, relative to the condition in which the magnetic field is absent. It was shown that using MBBs under magnetic field has the best performance in delivery to AAA for patients with negative inlet blood flow. Also, we have exposed that in an efficient TDD to AAA using MMBs, decreasing the density of MMBs increases drug delivery efficiency and performance. When density is - [Formula: see text], there is the highest difference (about - 75%) between the SDMM adhered to AAA in the presence of a magnetic field and in the absence of a magnetic field.

Acoustic scattering properties of multilayer membrane structured magnetic microbubbles

Normal ultrasound contrast agents (UCAs) loaded with magnetic nanoparticles are called magnetic microbubbles (MMBs), which can be used in multimodal imaging, thrombolytic therapy, and targeted drug delivery. The MMBs are often studied by &lt;i&gt;in situ&lt;/i&gt; measurement techniques, however scattering model is the basis of inversion techniques. Therefore, we develop a scattering model of multilayer structured MMBs with magnetic fluid inner layer and phospholipid outer layer, in which outer layer’s viscoelasticity and the effect of nanoparticles on inner layer’s density are considered, while scattered sound fields in each region are obtained by solving normal series. The MMB model is compared with other bubbles, and its acoustic scattering characteristics are analyzed numarically, including the effects of radius, magnetic nanoparticle volume fraction, inner layer thickness and outer layer characteristics parameters. The results show that when the volume fraction &lt;i&gt;α&lt;/i&gt; of magnetic nanoparticles in the inner layer does not exceed 0.1, magnetic nanoparticles have a two-sided effect on resonant scattering of MMBs, depending mainly on its radius, and the bubble has a critical radius value. If the radius of MMBs exceeds this critical value, the particles will enhance scattering, on the contrary, if the radius of MMBs is smaller than this critical value, the particles will reduce scattering; for a given microbubble radius, when &lt;i&gt;α&lt;/i&gt; is not more than 0.1, the larger the &lt;i&gt;α&lt;/i&gt; value&lt;i&gt;,&lt;/i&gt; the stronger the resonant scattering of MMBs will be; the smaller the thickness of the inner film layer and outer film layer or the Larmé constant, the stronger the scattering will be. This study provides a theoretical guidance for the optimal structural design of MMBs and its &lt;i&gt;in situ&lt;/i&gt; monitoring and therapeutic applications.

Monodisperse magnetic lecithin-PFP submicron bubbles as dual imaging contrast agents for ultrasound (US) and MRI.

Multimodal imaging is a recent idea of combining two or more imaging methods synergistically to overcome the weakness of individual imaging modalities and utilizing complementary benefits. Ultrasound (US) and magnetic resonance imaging (MRI) are widely used imaging techniques in healthcare and to fully utilize the potential of fusion imaging, dual-modal contrast agents are necessary to improve disease diagnosis by enhancing contrast resolution and reducing health risks associated with the dual dosage of contrast agents. In this study, magnetic microbubbles were synthesized by incorporating oleic acid stabilized superparamagnetic iron oxide nanoparticles (OA-SPIONs) into lecithin microbubbles, encapsulating the perfluoropentane (PFP) core. The magnetic microbubbles were characterized by FTIR, SEM, MFM, zeta potential, in vitro MRI, and ultrasound. Upon in vitro MRI, magnetic microbubbles showed a negative contrast effect by producing darker T2 weighted images. Magnetic microbubbles showed concentration-dependent response with a decrease in signal intensity with an increase in the concentration of OA-IONP in microbubbles. However, a decrease in acoustic enhancement was also observed with an increase in OA-IONP concentration, therefore concentration was optimized to achieve the best effect on both modalities. The magnetic lecithin microbubble with 10 mg SPIONs provided the best contrast on both US and MR imaging. The hemocompatibility testing resulted in hemolysis less than 7% with plasma recalcification time and thrombin time of 240 s and 6 s corresponding to excellent hemocompatibility. Thus the magnetic microbubbles with a phase convertible PFP core encapsulated by a lecithin shell loaded with OA-SPIONs can serve as a potential bimodal contrast agent for both US and MRI imaging.

Contrast-enhanced ultrasound imaging using long-circulating cationic magnetic microbubbles in vitro and in vivo validations

Traditional encapsulated microbubbles are recently used as delivery carriers for drugs and genes, but they have low efficiency. If the local microbubble concentration could be increased, this might be able to improve the therapeutic efficacy of diseases. In this study, we developed novel cationic magnetic microbubbles (MBM), which could simultaneously realize targeted aggregation under a magnetic field as well as ultrasonographic real-time visualization. Their physicochemical properties, biocompatibility, ultrasonography, magnetic response characteristics, and biodistribution were systematically evaluated. Here, the MBM were 2.55 ± 0.14 µm in size with a positive zeta potential, and had a good biocompatibility. They were able to enhance ultrasonographic contrast both in vitro and in vivo. MBM could be attracted by an external magnet for directional movement and aggregation in vitro. We confirmed that MBM also had a great magnetic response in vivo, by means of fluorescence imaging and contrast-enhanced ultrasound imaging. Following intravenous injection into tumor-bearing mice, MBM showed excellent stability in the internal circulation, and could accumulate in the tumor vasculature through magnetic targeting. With the excellent combination of magnetic response and acoustic properties, cationic magnetic microbubbles (MBM) have promising potential for use as a new kind of drug/gene carrier for theranostics in the future.

Nonlinear oscillation characteristics of magnetic microbubbles under acoustic and magnetic fields

Microbubbles loaded with magnetic nanoparticles (MMBs) have attracted increasing interests in multimode imaging and drug/gene delivery and targeted therapy. However, the dynamic behaviors generated in diagnostic and therapeutic applications are not clear. In the present work, a novel theoretical model of a single MMB was developed, and the dynamic responses in an infinite viscous fluid were investigated under simultaneous exposure to magnetic and acoustic fields. The results showed that the amplitude reduces and the resonant frequency increases with the strength of the applied steady magnetic field and the susceptibility of the magnetic shell. However, the magnetic field has a limited influence on the oscillating. It is also noticed that the responses of MMB to a time-varying magnetic field is different from a steady magnetic field. The subharmonic components increase firstly and then decrease with the frequency of the magnetic field and the enhanced effect is related to the acoustic driving frequency. It is indicated that there may be a coupling interaction effect between the acoustic and magnetic fields.