Full length articleSelf-assembled microbubbles as contrast agents for ultrasound/magnetic resonance dual-modality imaging
Graphical abstract
Microbubbles bearing “Poly(acrylic acid)-Iron oxide nanoparticles-Polyamine” sandwich-like shells were fabricated by a self-assembly approach for MR/US dual-modal imaging applications.
Introduction
Iron oxide nanoparticles (IONPs) act as T2-weighted magnetic resonance imaging (MRI) contrast agents based on their superparamagnetic properties and have great potential in biomedical applications [1], [2]. The contrast enhancement provided by IONPs contrast agents is due to the acceleration on the transverse relaxation of the water protons, caused by their interaction with the neighboring contrast agents. This results in a T2 and shortening. Previous studies have revealed that the relaxivity, , strongly depends on the volume magnetization of the particle and the radius of the particle [3], [4], [5], [6]. Hence, embedding IONPs into microcapsules will essentially affect T2 and which are related to the spherical structure of the cluster and to the magnetic field distribution around it. Based on the IONP-conjugated microcapsule structure, microbubbles have been proven to endow the composites with unique sonic properties [7]. For better visualization of specific tissues, microbubbles and perfluorocarbon emulsions of various formulations have been developed and applied clinically as US contrast agents. However, they have suffered from instability due to ultrasonic pressures, broad size distributions, and poor circulating acoustic contrast properties [8], [9]. Inorganic nanoparticle/polymer composites and inorganic-material based US contrast agents have recently attracted great attention due to their tunable particle diameters, good compatibility and superior stability over that provided by traditional organic microbubbles under US exposure [10], [11], [12]. Meanwhile, IONP-conjugated microbubbles behave as MRI/US dual-modal contrast agents, thus providing more precise diagnostic molecular imaging that combines the susceptibility of US imaging and the exquisite soft tissue contrast provided by the MRI modality [13], [14].
Dual-modal contrast agents for T2-weighted MR and US imaging can be categorized into two general classes, including IONP-conjugated microbubbles bearing lipid shells [13] and polymer shells [7], [10], [15], [16], [17], [18]. IONP-conjugated microbubbles bearing lipid shells have certain limitations that arise not only due to the tedious synthetic procedure via the thin film hydration method required for their preparation, but also because of their instability that causes them to be potentially toxic [13]. In comparison with magnetic lipid microbubbles, IONP-conjugated microbubbles bearing biodegradable polymer shells are provided with physical rigidity and may be loaded with drugs or other cargos. The biocompatible outer coating provides a biological interface and a potential “scaffold” for targeting species. The only reported method to fabricate IONP-conjugated polymer microbubbles is through the double emulsion method, which builds a platform for dual-mode MRI/US contrast agents [7], [10], [15], [16], [17], [18]. However, only hydrophobic polymers can be selected to form the bubble’s shell during the double emulsion process, and the removal of the residual emulsifier is another concern during the synthesis. Hence, it remains a challenge to develop a facile method to fabricate a multifunctional contrast agent for dual MR/US imaging.
The self-assembly approach is a widely used method to fabricate nanoparticle/polymer composite microcapsules with diverse compositions and sizes [19], [20], [21], [22]. The self-assembly method can be divided into template-based self-assembly and template-free self-assembly strategies. In particular, the layer-by-layer (LBL) self-assembly method is a well-established template-based method for constructing superparamagnetic IONP-based microcapsules [5]. However, the LBL self-assembly method involves a time-consuming process to form a template with a fixed size and also requires the subsequent removal of the template to generate hollow capsules. Recently, a novel self-assembly method known as the polyamine–salt aggregate (PSA) assembly method was proposed by Wong et al. [23]. This self-assembly route involves the formation of polymer aggregates and the subsequent deposition of particles around these aggregates to form microcapsules. The entire process is based on electrostatic interactions between oppositely charged components. In addition to providing a simplified procedure compared to the LBL method, the PSA approach can also be applied to encapsulate various agents and the shell thickness can be conveniently tuned [3], [24], [25], [26], [27], [28], [29]. These features provide the PSA assembly strategy with advantages in fabricating nanoparticle-conjugated microbubbles.
In this study, we developed a novel self-assembly approach to fabricate a multifunctional iron oxide nanoparticle-conjugated microbubble as a contrast agent for dual-modality MR/US imaging. The self-assembled microbubble has a unique triple layered shell constructed by “Poly(acrylic acid)-IONPs-Polyamine” composites. The MR and US imaging properties of self-assembled microbubbles were investigated both in vitro and in vivo. Additionally, metabolic investigations and histological evaluations were performed to characterize the biocompatibility of the microbubbles.
Section snippets
Materials
Anhydrous ferric chloride, anhydrous ethanol, N,-N-dimethyl formamide (DMF), sodium oleate, n-hexane, acetone, 1,2-dichlorobenzene, toluene, dimethyl sulfoxide (DMSO), citric acid monohydrate, trisodium citrate dehydrate, fluorescein sodium salt and glacial acetic acid (AR) were purchased from Sinopharm Chemical Reagent Co., Ltd. Oleic acid (OA, 90%), 1-octadecene (ODE) (90%), a poly(allylamine) solution (Mw = 65000, 20 wt.% in water), poly(acrylic acid) (PAA, Mw = 1800), tetradecafluorohexane (C6F14
Fabrication and characterization of self-assembled microbubble (SAMB)
Scheme 1 shows the approach used to prepare the self-assembled MR/US dual imaging microbubbles with a “sandwich-like” structure. The fabrication of SAMB initially involves the self-assembly of the precursors to form self-assembled microcapsule (SAMC). A gas-filling process is subsequently employed to obtain SAMB. During this overall procedure, the fabrication of SAMC involves three steps. Firstly, cationic polyamines undergo complexation with sodium citrate (Cit) to form polyamine–citrate
Conclusions
A novel self-assembly approach has been developed to fabricate magnetic self-assembled microbubbles bearing “PAA-IONP-Polyamine” sandwich-like shells. The structures, sizes and the magnetic properties of the SAMBs were investigated. It was found that the sizes of SAMBs could be easily tuned by changing the ratio of the polyamine within the precursors, while the different SAMBs contained almost identical magnetite contents. The superparamagnetic SAMBs exhibited MR/US dual imaging contrast
Acknowledgments
The authors thank the financial support of the National Natural Science Foundation of China (Nos. 21174082, 21374061, 81100295), the SJTU SMC-Chen Xing Young Scholars Award, Program of New Century Excellent Talent in University (NCET-13-0360), International Science and Technology Cooperation Project of the Science and Technology Commission of Shanghai Municipality (No. 14520710300) and the Instrumental Analysis Center of the SJTU.
References (37)
- et al.
Iron/iron oxide core/shell nanoparticles for magnetic targeting MRI and near-infrared photothermal therapy
Biomaterials
(2014) - et al.
MRI of iron oxide nanoparticle-labeled ADSCs in a model of hindlimb ischemia
Biomaterials
(2013) - et al.
Superparamagnetic colloid suspensions: water magnetic relaxation and clustering
J. Magn. Magn. Mater.
(2005) - et al.
Monte Carlo simulation and theory of proton NMR transverse relaxation induced by aggregation of magnetic particles used as MRI contrast agents
J. Magn. Reson.
(2011) - et al.
Iron oxide nanoparticle-containing microbubble composites as contrast agents for MR and ultrasound dual-modality imaging
Biomaterials
(2011) - et al.
Prostate stem cell antigen antibody-conjugated multiwalled carbon nanotubes for targeted ultrasound imaging and drug delivery
Biomaterials
(2014) - et al.
SPIO-conjugated, doxorubicin-loaded microbubbles for concurrent MRI and focused-ultrasound enhanced brain-tumor drug delivery
Biomaterials
(2013) - et al.
Superparamagnetic iron oxide nanoparticle-embedded encapsulated microbubbles as dual contrast agents of magnetic resonance and ultrasound imaging
Biomaterials
(2009) - et al.
Superparamagnetic PLGA-iron oxide microcapsules for dual-modality US/MR imaging and high intensity focused US breast cancer ablation
Biomaterials
(2012) - et al.
Doxorubicin loaded superparamagnetic PLGA-iron oxide multifunctional microbubbles for dual-mode US/MR imaging and therapy of metastasis in lymph nodes
Biomaterials
(2013)
Clinical use of ultrasound tissue harmonic imaging
Ultrasound Med. Biol.
A universal scaling law to predict the efficiency of magnetic nanoparticles as MRI T2-contrast agents
Adv. Healthcare Mater.
Relaxation times of colloidal iron platinum in polymer matrixes
J. Mater. Chem.
Nanoparticles as contrast agents for in-vivo bioimaging: current status and future perspectives
Anal. Bioanal. Chem.
Ultrasound microbubbles for molecular diagnosis, therapy, and theranostics
J. Nucl. Med.
“Two-in-one” fabrication of Fe3O4/MePEG-PLA composite nanocapsules as a potential ultrasonic/MRI dual contrast agent
Langmuir
Functionalized multiwalled carbon nanotubes as ultrasound contrast agents
Proc. Natl. Acad. Sci.
Molecular imaging in the clinical arena
JAMA
Cited by (15)
Application of dual modality contrast agent combined with multi-scale representation in ultrasound-magnetic resonance imaging registration scheme
2020, MCB Molecular and Cellular BiomechanicsEnhancing cancer therapeutic efficacy through ultrasound-mediated micro-to-nano conversion
2020, Wiley Interdisciplinary Reviews: Nanomedicine and NanobiotechnologyNovel Hybrid Dextran-Gadolinium Nanoparticles as High-relaxivity T1 Magnetic Resonance Imaging Contrast Agent for Mapping the Sentinel Lymph Node
2019, Journal of Computer Assisted Tomography