Magnetic Microbubbles Research Articles

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe2O3 magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l‐TRAIL@MMBs. Such RGD‐l‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.

Enhancement and Passive Acoustic Mapping of Cavitation from Fluorescently Tagged Magnetic Resonance-Visible Magnetic Microbubbles In Vivo

Previous work has indicated the potential of magnetically functionalized microbubbles to localize and enhance cavitation activity under focused ultrasound exposure in vitro. The aim of this study was to investigate magnetic targeting of microbubbles for promotion of cavitation in vivo. Fluorescently labelled magnetic microbubbles were administered intravenously in a murine xenograft model. Cavitation was induced using a 0.5-MHz focused ultrasound transducer at peak negative focal pressures of 1.2–2.0 MPa and monitored in real-time using B-mode imaging and passive acoustic mapping. Magnetic targeting was found to increase the amplitude of the cavitation signal by approximately 50% compared with untargeted bubbles. Post-exposure magnetic resonance imaging indicated deposition of magnetic nanoparticles in tumours. Magnetic targeting was similarly associated with increased fluorescence intensity in the tumours after the experiments. These results suggest that magnetic targeting could potentially be used to improve delivery of cavitation-mediated therapy and that passive acoustic mapping could be used for real-time monitoring of this process.

Structural regulation of self-assembled iron oxide/polymer microbubbles towards performance-tunable magnetic resonance/ultrasonic dual imaging agents

Fe3O4/polymer hybrid microcapsules were prepared via a template-free route which is based on polyamine-salt aggregates (PSAs) self-assembly approach. The measurements of transmission electron microscopy (TEM) indicated that the diameter and shell thickness of the microcapsules could be tuned by varying the experimental conditions, such as the concentration of reactants and evolution time employed during the PSA assembly. The results of vibrating sample magnetometer (VSM) demonstrated that the magnetic nanoparticles content of the synthesized microcapsules was tunable and all samples exhibited superparamagnetic behavior. After filling appropriate perfluorocarbon into the inner cavities of the microcapsules, the biomedical applications of the resultant microbubbles, including ultrasonic imaging (USI) and magnetic resonance imaging (MRI), were studied in vitro. It showed that the synthesized magnetic microbubbles possessed both strong ultrasound contrast enhancement capability and high relaxation rate. The excellent acoustic and magnetic properties of these self-assembled microbubbles ensure that the Fe3O4/polymer hybrid microbubbles have great potential as MRI/USI dual-modality contrast agents.

Controlled nanoparticle release from stable magnetic microbubble oscillations

Magnetic microbubbles (MMBs) are microbubbles (MBs) coated with magnetic nanoparticles (NPs). MMBs not only maintain the acoustic properties of MBs, but also serve as an important contrast agent for magnetic resonance imaging. Such dual-modality functionality makes MMBs particularly useful for a wide range of biomedical applications, such as localized drug/gene delivery. This article reports the ability of MMBs to release their particle cargo on demand under stable oscillation. When stimulated by ultrasound at resonant frequencies, MMBs of 450 nm to 200 μm oscillate in volume and surface modes. Above an oscillation threshold, NPs are released from the MMB shell and can travel hundreds of micrometers from the surface of the bubble. The migration of NPs from MMBs can be described with a force balance model. With this technology, we deliver doxorubicin-containing poly(lactic-co-glycolic acid) particles across a physiological barrier both in vitro and in vivo, with a 18-fold and 5-fold increase in NP delivery to the heart tissue of zebrafish and tumor tissue of mouse, respectively. The penetration of released NPs in tissues is also improved. The ability to remotely control the release of NPs from MMBs suggests opportunities for targeted drug delivery through/into tissues that are not easily diffused through or penetrated. Microsized gas bubbles containing magnetic nanoparticles and drug nanoparticles (nanodrugs) can eject nanodrugs across biobarriers in cell, tissue and animals. Drug-delivery technologies use triggers such as enzymes, shear stress or magnetic fields to deposit medicinal payloads directly to afflicted tissues and organs. Chenjie Xu at Nanyang Technological University reports non-invasive drug delivery can be realized by using ultrasonic triggers to ‘magnetic microbubbles’ — spherical complexes of iron oxide nanoparticles and nanodrugs. The team loaded magnetic microbubbles with doxorubicin-containing polymer nanoparticles and used ultrasound irradiation to make the microspheres shrink and expand at their resonant frequencies. The constant oscillation caused the doxorubicin–nanoparticle complexes to be expelled hundreds of micrometres from the bubbles. The on-demand delivery proved powerful enough to cross tricky physiological barriers such as zebrafish heart/brain tissue and the vasculature of solid tumor in mouse. Drug-encapsulated nanoparticles (NPs) are emerging as therapeutic agents to deliver DNA\drugs into cells. However, clinical applications demand a technique to concentrate NPs at the diseased cells that are beneath other tissues. We report a strategy to achieve this goal with magnetic- and therapeutic NP-coated microbubbles as carriers. Although external magnetic field concentrates them at the targeted tissue, moderate ultrasound irradiation at their resonance frequency drives stable oscillation and microstreaming flow. Consequently, the NP armor detaches, penetrates into tissues and is later internalized by the cells. This technique would greatly improve the on-target delivery of nanomedicine, thereby reduces cost and side effects.

Magnetic targeting of microbubbles against physiologically relevant flow conditions.

The localization of microbubbles to a treatment site has been shown to be essential to their effectiveness in therapeutic applications such as targeted drug delivery and gene therapy. A variety of different strategies for achieving localization has been investigated, including biochemical targeting, acoustic radiation force, and the incorporation of superparamagnetic nanoparticles into microbubbles to enable their manipulation using an externally applied magnetic field. The third of these strategies has the advantage of concentrating microbubbles in a target region without exposing them to ultrasound, and can be used in conjunction with biochemical targeting to achieve greater specificity. Magnetic microbubbles have been shown to be effective for therapeutic delivery in vitro and in vivo. Whether this technique can be successfully applied in humans however remains an open question. The aim of this study was to determine the range of flow conditions under which targeting could be achieved. In vitro results indicate that magnetic microbubbles can be retained using clinically acceptable magnetic fields, for both the high shear rates (approx. 104 s−1) found in human arterioles and capillaries, and the high flow rates (approx. 3.5 ml s−1) of human arteries. The potential for human in vivo microbubble retention was further demonstrated using a perfused porcine liver model.

In vivo biodistribution of fluorescently tagged magnetic microbubbles for cavitation enhancement with real time passive acoustic mapping

Previous work has demonstrated the potential of magnetically functionalized microbubbles to localize and enhance cavitation activity under focused ultrasound exposure in vitro. The aim of this study was investigate magnetic targeting of microbubbles for promotion of cavitation in vivo. Fluorescently labeled magnetic microbubbles were intravenously injected into a murine xenograft model. Cavitation was induced using a 0.5 MHz single element focused transducer at peak negative focal pressures of 0.1–1.0 MPa and monitored in real-time using simultaneous B-mode imaging and passive acoustic mapping. Magnetic targeting was found to increase the amplitude of the cavitation signal as compared with untargeted bubbles and a commercial ultrasound contrast agent. Post exposure magnetic resonance imaging indicated a correlation between cavitation activity and deposition of magnetic nanoparticles in the tumor volume. Magnetic targeting was similarly associated with an increase in the fluorescence intensity measured from the tumors following the experiments; the highest levels corresponding to the maximum cavitation signals. These results indicate a strong correlation between cavitation activity and increased uptake of both molecular species and nanoparticles in tumors; and that the effect can be enhanced by magnetic targeting.

Passive acoustic mapping of magnetic microbubbles for cavitation enhancement and localization

Magnetic targeting of microbubbles functionalized with superparamagnetic nanoparticles has been demonstrated previously for diagnostic (B-mode) ultrasound imaging and shown to enhance gene delivery in vitro and in vivo. In the present work, passive acoustic mapping (PAM) was used to investigate the potential of magnetic microbubbles for localizing and enhancing cavitation activity under focused ultrasound. Suspensions of magnetic microbubbles consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), air and 10 nm diameter iron oxide nanoparticles were injected into a tissue mimicking phantom at different flow velocities (from 0 to 50 mm s−1) with or without an applied magnetic field. Microbubbles were excited using a 500 kHz single element focused transducer at peak negative focal pressures of 0.1–1.0 MPa, while a 64 channel imaging array passively recorded their acoustic emissions. Magnetic localization of microbubble-induced cavitation activity was successfully achieved and could be resolved using PAM as a shift in the spatial distribution and increases in the intensity and sustainability of cavitation activity under the influence of a magnetic field. Under flow conditions at shear rates of up to 100 s−1 targeting efficacy was maintained. Application of a magnetic field was shown to consistently increase the energy of cavitation emissions by a factor of 2–5 times over the duration of exposures compared to the case without targeting, which was approximately equivalent to doubling the injected microbubble dose. These results suggest that magnetic targeting could be used to localize and increase the concentration of microbubbles and hence cavitation activity for a given systemic dose of microbubbles or ultrasound intensity.

Controlled assembly of magnetic nanoparticles on microbubbles for multimodal imaging

Magnetic microbubbles (MMBs) consisting of microbubbles (MBs) and magnetic nanoparticles (MNPs) were synthesized for use as novel markers for improving multifunctional biomedical imaging. The MMBs were fabricated by assembling MNPs in different concentrations on the surfaces of MBs. The relationships between the structure, magnetic properties, stability of the MMBs, and their use in magnetic resonance/ultrasound (MR/US) dual imaging applications were determined. The MNPs used were NPs of 3-aminopropyltriethoxysilane (APTS)-functionalized superparamagnetic iron oxide γ-Fe2O3 (SPIO). SPIO was assembled on the surfaces of polymer MBs using a "surface-coating" approach. An analysis of the underlying mechanism showed that the synergistic effects of covalent coupling, electrostatic adsorption, and aggregation of the MNPs allowed them to be unevenly assembled in large amounts on the surfaces of the MBs. With an increase in the MNP loading amount, the magnetic properties of the MMBs improved significantly; in this way, the shell structure and mechanical properties of the MMBs could be modified. For surface densities ranging from 2.45 × 10(-7) μg per MMB to 8.45 × 10(-7) μg per MMB, in vitro MR/US imaging experiments showed that, with an increase in the number of MNPs on the surfaces of the MBs, the MMBs exhibited better T2 MR imaging contrast, as well as an increase in the US contrast for longer durations. In vivo experiments also showed that, by optimizing the structure of the MMBs, enhanced MR/US dual-modality image signals could be obtained for mouse tumors. Therefore, by adjusting the shell composition of MBs through the assembly of MNPs in different concentrations, MMBs with good magnetic and acoustic properties for MR/US dual-modality imaging contrast agents could be obtained.

Magnetic microbubble-mediated ultrasound-MRI registration based on robust optical flow model.

BackgroundAs a dual-modality contrast agent, magnetic microbubbles (MMBs) can not only improve contrast of ultrasound (US) image, but can also serve as a contrast agent of magnetic resonance image (MRI). With the help of MMBs, a new registration method between US image and MRI is presented.MethodsIn this method, MMBs were used in both ultrasound and magnetic resonance imaging process to enhance the most important information of interest. In order to reduce the influence of the speckle noise to registration, semi-automatic segmentations of US image and MRI were carried out by using active contour model. After that, a robust optical flow model between US image segmentation (floating image) and MRI segmentation (reference image) was built, and the vector flow field was estimated by using the Coarse-to-fine Gaussian pyramid and graduated non-convexity (GNC) schemes.ResultsQualitative and quantitative analyses of multiple group comparison experiments showed that registration results using all methods tested in this paper without MMBs were unsatisfactory. On the contrary, the proposed method combined with MMBs led to the best registration results.ConclusionThe proposed algorithm combined with MMBs contends with larger deformation and performs well not only for local deformation but also for global deformation. The comparison experiments also demonstrated that ultrasound-MRI registration using the above-mentioned method might be a promising method for obtaining more accurate image information.

Mechanical and dynamic characteristics of encapsulated microbubbles coupled by magnetic nanoparticles as multifunctional imaging and drug delivery agents

Development of magnetic encapsulated microbubble agents that can integrate multiple diagnostic and therapeutic functions is a key focus in both biomedical engineering and nanotechnology and one which will have far-reaching impact on medical diagnosis and therapies. However, properly designing multifunctional agents that can satisfy particular diagnostic/therapeutic requirements has been recognized as rather challenging, because there is a lack of comprehensive understanding of how the integration of magnetic nanoparticles to microbubble encapsulating shells affects their mechanical properties and dynamic performance in ultrasound imaging and drug delivery. Here, a multifunctional imaging contrast and in-situ gene/drug delivery agent was synthesized by coupling super paramagnetic iron oxide nanoparticles (SPIOs) into albumin-shelled microbubbles. Systematical studies were performed to investigate the SPIO-concentration-dependence of microbubble mechanical properties, acoustic scattering response, inertial cavitation activity and ultrasound-facilitated gene transfection effect. These demonstrated that, with the increasing SPIO concentration, the microbubble mean diameter and shell stiffness increased and ultrasound scattering response and inertial cavitation activity could be significantly enhanced. However, an optimized ultrasound-facilitated vascular endothelial growth factor transfection outcome would be achieved by adopting magnetic albumin-shelled microbubbles with an appropriate SPIO concentration of 114.7 µg ml−1. The current results would provide helpful guidance for future development of multifunctional agents and further optimization of their diagnostic/therapeutic performance in clinic.

Magnetic nanoparticle and magnetic field assisted siRNA delivery in vitro.

This chapter describes how to design and conduct experiments to deliver siRNA to adherent cell cultures in vitro by magnetic force-assisted transfection using self-assembled complexes of small interfering RNA (siRNA) and cationic lipids or polymers that are associated with magnetic nanoparticles (MNPs). These magnetic complexes are targeted to the cell surface by the application of a gradient magnetic field. A further development of the magnetic drug-targeting concept is combining it with an ultrasound-triggered delivery using magnetic microbubbles as a carrier for gene or drug delivery. For this purpose, selected MNPs, phospholipids, and siRNAs are assembled in the presence of perfluorocarbon gas into flexible formulations of magnetic lipospheres (microbubbles). Methods are described how to accomplish the synthesis of magnetic nanoparticles for magnetofection and how to test the association of siRNA with the magnetic components of the transfection vector. A simple method is described to evaluate magnetic responsiveness of the magnetic siRNA transfection complexes and estimate the complex loading with magnetic nanoparticles. Procedures are provided for the preparation of magnetic lipoplexes and polyplexes of siRNA as well as magnetic microbubbles for magnetofection and downregulation of the target gene expression analysis with account for the toxicity determined using an MTT-based respiration activity test. A modification of the magnetic transfection triplexes with INF-7, fusogenic peptide, is described resulting in reporter gene silencing improvement in HeLa, Caco-2, and ARPE-19 cells. The methods described can also be useful for screening vector compositions and novel magnetic nanoparticle preparations for optimized siRNA transfection by magnetofection in any cell type.

On the dynamics of non-spherical magnetic microbubbles

Magnetic microbubbles are a relatively recent development with the potential to greatly improve the efficacy of the minimally invasive drug-delivery procedure sonoporation. However, very little is known about the dynamics of magnetic microbubbles, in general. In this paper, a novel mathematical model and numerical method are developed to simulate the dynamics of non-spherical magnetic microbubbles in vitro. The ambient fluid is assumed to be inviscid and the flow irrotational, enabling a generalized Bernoulli equation to be derived that includes surface tension effects and the effect of the applied magnetic field. The governing equations are solved using the boundary element method in which both the bubble surface and the velocity potential are represented by cubic splines. Results show that magnetic microbubble dynamics are highly dependent on the magnetic susceptibility difference, Δχ, between the bubble and the ambient fluid, with the sign and magnitude of Δχ dictating the direction and velocity of any formed liquid jets. Importantly, it is shown that the magnetic field can provide an additional means of flow control to the experimental investigator: in the presence of surface tension, weak magnetic fields do not generate jets. However, increasing the magnitude of the magnetic field can instigate jet formation, and increase the maximum and time-averaged jet velocities. Experimentally relevant parameter values are also considered, and results suggest that a combined application of magnetic and ultrasound fields is required to generate the high-speed bubble collapse events most likely to maximise cell poration and drug delivery.

On the interplay of shell structure with low- and high-frequency mechanics of multifunctional magnetic microbubbles

Polymer-shelled magnetic microbubbles have great potential as hybrid contrast agents for ultrasound and magnetic resonance imaging. In this work, we studied US/MRI contrast agents based on air-filled poly(vinyl alcohol)-shelled microbubbles combined with superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs are integrated either physically or chemically into the polymeric shell of the microbubbles (MBs). As a result, two different designs of a hybrid contrast agent are obtained. With the physical approach, SPIONs are embedded inside the polymeric shell and with the chemical approach SPIONs are covalently linked to the shell surface. The structural design of hybrid probes is important, because it strongly determines the contrast agent's response in the considered imaging methods. In particular, we were interested how structural differences affect the shell's mechanical properties, which play a key role for the MBs' US imaging performance. Therefore, we thoroughly characterized the MBs' geometric features and investigated low-frequency mechanics by using atomic force microscopy (AFM) and high-frequency mechanics by using acoustic tests. Thus, we were able to quantify the impact of the used SPIONs integration method on the shell's elastic modulus, shear modulus and shear viscosity. In summary, the suggested approach contributes to an improved understanding of structure-property relations in US-active hybrid contrast agents and thus provides the basis for their sustainable development and optimization.

Magnetic targeting of microbubbles at physiologically relevant flow rates

The localization of microbubbles to a target site has been shown to be essential to their effectiveness in ultrasound mediated drug delivery and gene therapy. The incorporation of super paramagnetic nanoparticles into the microbubble coating enables them to be manipulated using an externally applied magnetic field. Magnetic microbubbles have been shown to be effective in therapeutic delivery both in vitro and in vivo in a mouse model. The aim of this experiment was to determine under what conditions in the human body magnetic microbubbles can be successfully imaged and targeted. Different flow rates and shear rates were generated in a tissue mimicking phantom and targeting was observed using a 9.4 MHz ultrasound imaging probe. For the highest shear rates, targeting was also observed optically. Results indicate that magnetic microbubbles can be successfully targeted at shear rates found in the human capillary system (>1000/s) and at flow rates found in the veins and smaller arteries (~200 ml/s). Successful retention was also demonstrated in a perfused porcine liver model simulating conditions in vivo. This study provides further evidence for the potential of magnetic microbubbles for targeted therapeutic delivery.

Acoustic characterization and contrast imaging of microbubbles encapsulated by polymeric shells coated or filled with magnetic nanoparticles

The combination of superparamagnetic iron oxide nanoparticles with polymeric air-filled microbubbles is used to produce two types of multimodal contrast agents to enhance medical ultrasound and magnetic resonance imaging. The nanoparticles are either covalently linked to the shell or physically entrapped into the shell. In this paper, the characterization of the acoustic properties (backscattered power, fracturing pressure, attenuation and dispersion of the ultrasonic wave) and ultrasound imaging of the two types of magnetic microbubbles are presented. In vitro B-mode images are generated using a medical ultrasound scanner by applying a nonconventional signal processing technique that is suitable to detect polymeric bubbles and based on the combination of multipulse excitation and chirp coding. Even if both types of microbubbles can be considered to be effective ultrasound contrast agents, the different structure of the shell loaded with nanoparticles has a pronounced effect on the echogenicity and the detection sensitivity of the imaging technique. The best results are obtained using microbubbles that are externally coated with nanoparticles. A backscattered power of 20 dB was achieved at lower concentration, and an increment of 8 dB in the contrast-to-tissue ratio was observed with respect to the more rigid microbubbles with particles entrapped into the shell.

Ultrasound assessment of polymer-shelled magnetic microbubbles used as dual contrast agents

This letter describes an ultrasound imaging assessment of novel contrast agents that are detectable by both medical ultrasound and magnetic resonance imaging. Such agents are created by including superparamagnetic particles in polymer-shelled microbubbles through two different approaches. The reduced echogenicity and nonlinearity of the microbubbles are observed, depending on the strategy used to include the particles and the resulting density. The best results are obtained using imaging techniques that exploit the third-order nonlinear term, which is especially true when the microbubbles are excited by means of chirp pulses.

Passive acoustic mapping of magnetic microbubbles in an in vitro flow model

Magnetic microbubbles can be successfully retained near a vascular target and simultaneously imaged using conventional B-mode ultrasound. When further modified to carry a drug, they could enable significant enhancements in targeted drug delivery for applications such as sonothrombolysis, where stable cavitation has been shown to play a key role. However, the effect of the increased proximity of the microbubbles under the effect of the magnetic field on their acoustic response remains unknown. Passive acoustic mapping is a method that enables real-time spatiotemporal monitoring of cavitation dynamics in an arbitrary plane or volume within the field of view of the ultrasound probe, and classification of the type of cavitation activity on the basis of the spatial distribution of frequency-domain emissions. In the present work, PAM is used to investigate the effect of bubble proximity and flow rate on the type, sustainability, intensity, and spatial distribution of cavitation activity observed for both magnetic and non-magnetic microbubbles excited by 0.5 MHz therapeutic ultrasound in an in vitro flow model. It is hoped that this study will not only yield a new method for real-time monitoring of drug delivery using magnetically trapped microbubbles, but will also help elucidate complex bubble–bubble interactions in therapeutic ultrasound fields.

Fabrication and application of a magnetic-targeting and controlled-release system using ST68-based microbubbles

Objective To manufacture magnetic microbubbles with dual-response to ultrasound and magnetic fields.Methods Microbubbles of ultrasound contrast agent (ST68) based on a surfactant were prepared by the acoustic cavitation method.Fe3O4 magnetic nanoparticles with negative charge were synthesized using the polyol procedure.Magnetic microbubbles were generated by depositing polyethylenimine and Fe3O4 magnetic nanoparticles alternately onto the microbubbles using the layer-by-layer self-assembly.In vitro ultrasonography was performed on a silicone tube with/without magnetic microbubbles (3 × 108/ml) by a self-made device to observe the movement of magnetic microbubbles under the effects of magnetic field.In vivo imaging was performed on the kidney of New Zealand rabbits before and after the injection of magnetic microbubbles.Results The Fe3O4 nanoparticles carried a stable negative charge of (-24.6 ± 6.7) mV and more than 98％ of the particles were less than 8 μm in diameter,meeting the size requirement of an ultrasound contrast agent for intravenous administration.There was no echoic signal in the silicone tube before injection of magnetic microbubbles,but there were strong echoic signals after injection.After applying a magnetic field,the magnetic microbubbles moved along the direction of the magnetic flux.In vivo ultrasound imaging could not visualize the kidney before injection of magnetic microbubbles,but could remarkably visualize the kidney after injection.Conclusions The magnetic microbubbles exhibit favorable magnetic targeting and ultrasound contrast enhancement characteristics.Such properties may serve as the foundation to study their potential for simultaneous diagnosis and treatment in the future. Key words: Ultrasonography; Microbubbles ; Nanoparticles; Superparamagnetic iron oxides ; Contrast media

Multimodality imaging using SPECT/CT and MRI and ligand functionalized 99mTc-labeled magnetic microbubbles

BackgroundIn the present study, we used multimodal imaging to investigate biodistribution in rats after intravenous administration of a new 99mTc-labeled delivery system consisting of polymer-shelled microbubbles (MBs) functionalized with diethylenetriaminepentaacetic acid (DTPA), thiolated poly(methacrylic acid) (PMAA), chitosan, 1,4,7-triacyclononane-1,4,7-triacetic acid (NOTA), NOTA-super paramagnetic iron oxide nanoparticles (SPION), or DTPA-SPION.MethodsExaminations utilizing planar dynamic scintigraphy and hybrid imaging were performed using a commercially available single-photon emission computed tomography (SPECT)/computed tomography (CT) system. For SPION containing MBs, the biodistribution pattern of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs was investigated and co-registered using fusion SPECT/CT and magnetic resonance imaging (MRI). Moreover, to evaluate the biodistribution, organs were removed and radioactivity was measured and calculated as percentage of injected dose.ResultsSPECT/CT and MRI showed that the distribution of 99mTc-labeled ligand-functionalized MBs varied with the type of ligand as well as with the presence of SPION. The highest uptake was observed in the lungs 1 h post injection of 99mTc-labeled DTPA and chitosan MBs, while a similar distribution to the lungs and the liver was seen after the administration of PMAA MBs. The highest counts of 99mTc-labeled NOTA-SPION and DTPA-SPION MBs were observed in the lungs, liver, and kidneys 1 h post injection. The highest counts were observed in the liver, spleen, and kidneys as confirmed by MRI 24 h post injection. Furthermore, the results obtained from organ measurements were in good agreement with those obtained from SPECT/CT.ConclusionsIn conclusion, microbubbles functionalized by different ligands can be labeled with radiotracers and utilized for SPECT/CT imaging, while the incorporation of SPION in MB shells enables imaging using MR. Our investigation revealed that biodistribution may be modified using different ligands. Furthermore, using a single contrast agent with fusion SPECT/CT/MR multimodal imaging enables visualization of functional and anatomical information in one image, thus improving the diagnostic benefit for patients.

Polymeric theranostics: using polymer-based systems for simultaneous imaging and therapy.

Polymer-based nanomedicine is a large and fast growing field. Polymer-based systems have been extensively used as therapeutic carriers as well as bioimaging agents for example in tumour diagnosis. However, fewer polymeric systems have been able to combine both therapy and imaging in a new field that is called theranostics (theragnostics). This review aims to summarise the recent developments and trends on polymeric theranostics. Four different types of therapies/treatments are examined namely drug delivery, gene delivery, photodynamic therapy and hyperthermia treatment combined with different imaging moieties like magnetic resonance imaging agents, fluorescent agents and microbubbles for ultrasound imaging.