Bursting microbubbles: How nanobubble contrast agents can enable the future of medical ultrasound molecular imaging and image-guided therapy

The field of medical ultrasound has undergone a significant evolution since the development of microbubbles as contrast agents. However, because of their size, microbubbles remain in the vasculature and therefore have limited clinical applications. Building a better—and smaller—bubble can expand the applications of contrast-enhanced ultrasound by allowing bubbles to extravasate from blood vessels—creating new opportunities. In this review, we summarize recent research on the formulation and use of nanobubbles (NBs) as imaging agents and as therapeutic vehicles. We discuss the ongoing debates in the field and reluctance to accepting NBs as an acoustically active construct and a potentially impactful clinical tool that can help shape the future of medical ultrasound. We hope that the overview of key experimental and theoretical findings in the NB field presented in this article provides a fundamental framework that will help clarify NB–ultrasound interactions and inspire engagement in the field.     

Formulation and acoustic studies of a new phase-shift agent for diagnostic and therapeutic ultrasound

Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications.     

Polymeric nano/microcapsules of liquid perfluorocarbons for ultrasonic imaging: physical characterization

Ultrasonic imaging is a widely available, noninvasive, and cost-effective diagnostic modality, but vessels smaller than 200 mum in diameter are impossible to visualize. Commercial ultrasound contrast agents (UCAs), consisting of encapsulated gas microbubbles injected intravenously, enable only a qualitative visualization of the microvascularization for a short period of time since they are rather unstable. In a strategy to develop more stable UCAs, we designed a process to obtain nano/microcapsules with a single core of liquid perfluorocarbons within a biodegradable polymeric shell of homogeneous thickness. The polymer shell should improve the stability of the capsules as compared to UCAs stabilized by a monomolecular layer, while the acoustic impedance of the perfluorocarbons should ensure their echogenicity. These capsules have been optimized to encapsulate several liquid perfluorocarbons: perfluorohexane, perfluorodecalin, and perfluorooctyl bromide. The system is rather versatile: the mean size of the capsules can be adjusted between 70 nm and 25 microm and the thickness-to-radius ratio (T/R) can be easily modulated by simply modifying the polymer-to-perfluorocarbon ratio. T/R does not depend on the size of the capsules and is between 0.2 and 0.6. The dependence of the echogenic properties of the capsules with their size and their T/R has yet to be studied experimentally before this system can be evaluated in vivo.     

Cyclodextrin-Based Contrast Agents for Medical Imaging

Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits. CDs are widely used in host–guest chemistry and biochemistry due to their structural advantages, biocompatibility, and ability to form inclusion complexes. Recently, CDs have become of high interest in the field of medical imaging as a potential scaffold for the development of a large variety of the contrast agents suitable for magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, positron emission tomography, single photon emission computed tomography, and computed tomography. The aim of this review is to summarize and highlight the achievements in the field of cyclodextrin-based contrast agents for medical imaging.     

On-chip generation of microbubbles as a practical technology for manufacturing contrast agents for ultrasonic imaging

This paper presents a new manufacturing method to generate monodisperse microbubble contrast agents with polydispersity index (sigma) values of <2% through microfluidic flow-focusing. Micron-sized lipid shell-based perfluorocarbon (PFC) gas microbubbles for use as ultrasound contrast agents were produced using this method. The poly(dimethylsiloxane) (PDMS)-based devices feature expanding nozzle geometry with a 7 microm orifice width, and are robust enough for consistent production of microbubbles with runtimes lasting several hours. With high-speed imaging, we characterized relationships between channel geometry, liquid flow rate Q, and gas pressure P in controlling bubble sizes. By a simple optimization of the channel geometry and Q and P, bubbles with a mean diameter of <5 microm can be obtained, ideal for various ultrasonic imaging applications. This method demonstrates the potential of microfluidics as an efficient means for custom-designing ultrasound contrast agents with precise size distributions, different gas compositions and new shell materials for stabilization, and for future targeted imaging and therapeutic applications.     

纳米级造影剂在肿瘤影像学诊疗中的基础应用进展

肿瘤的早期诊断对其生存率及预后有极大的意义,医学成像造影剂的应用可极大地提高肿瘤的早期诊断水平。通过新兴纳米技术开发无毒、成像能力更强、循环时间更长的纳米级造影剂是目前研究的热点。本文综述了纳米级造影剂在MRI、CT、US、PET和SPECT等生物医学成像技术中,对于肿瘤诊疗的基础应用,并列举了部分研究实例。纳米级造影剂具有广阔的临床应用前景,未来的研究重点将会是开发集诊断、治疗于一体的多功能的纳米平台。     

Towards highly efficient,intelligent and bimodal imaging probes: Novel approaches provided by lanthanide coordination chemistry

Gd³⁺ complexes are widely used as contrast enhancing agents in medical magnetic resonance imaging (MRI). In recent years, new fields have emerged in their development. The general tendency of using higher magnetic fields in biomedical and clinical MRI for a better signal to noise ratio calls for new contrast agents specifically optimized for such high field applications. Molecular imaging, aiming at the non-invasive visualisation of expression and function of bioactive molecules, requires imaging probes that provide a specific magnetic response to a particular molecular event. Finally, bimodal imaging may allow for combining the excellent resolution of MRI with a good sensitivity of other imaging modalities, such as optical methods. It requires bimodal imaging probes that satisfy requirements for both modalities within a single molecule. Here we review our latest efforts to develop novel lanthanide-based contrast agents in these specific fields and demonstrate the possibilities offered by lanthanide coordination chemistry.     

Recent advances of non-lamellar lyotropic liquid crystalline nanoparticles in nanomedicine

Non-lamellar lyotropic liquid crystalline nanocarriers such as hexosomes and cubosomes are relatively unexplored lipid-based nanoparticles in nanomedicine that can be specifically formulated to match specific medical applications, thus exploiting the majority of the possible routes of administrations. A growing number of papers demonstrate intriguing features that make them good candidates as nanocarriers for therapeutically active molecules or imaging probes. Yet, important aspects, including pharmacokinetics, hemocompatibility, toxicity, and delivery properties, are not completely clarified, so that their full potential as nanomedicines remains to be assessed.This article reviews recent advances in the field and suggests possible new routes forward.     

Functional micro/nanobubbles for ultrasound medicine and visualizable guidance

Chemically functionalized gas-filled bubbles with a versatile micro/nano-sized scale have witnessed a long history of developments and emerging applications in disease diagnosis and treatments. In combination with ultrasound and image-guidance,micro/nanobubbles have been endowed with the capabilities of biomedical imaging, drug delivery, gene transfection and diseaseoriented therapy. As an external stimulus, ultrasound(US)-mediated targeting treatments have been achieving unprecedented efficiency. Nowadays, US is playing a crucial role in visualizing biological/pathological changes in lives as a reliable imaging technique and a powerful therapeutic tool. This review retrospects the history of ultrasound, the chemistry of functionalized agents and summarizes recent advancements of functional micro/nanobubbles as US contrast agents in preclinical and transclinical research. Latest ultrasound-based treatment modalities in association with functional micro/nanobubbles have been highlighted as their great potentials for disease precision therapy. It is believed that these state-of-the-art micro/nanobubbles will become a booster for ultrasound medicine and visualizable guidance to serve future human healthcare in a more comprehensive and practical manner.     

High-Field MRI Contrast Agents and their Synergy with Optical Imaging: the Evolution from Single Molecule Probes towards Nano-architectures

Contrast agents for magnetic resonance imaging have historically been based on paramagnetic metal complexes, particularly Gd³⁺ chelates, which tend to lose their contrast enhancement ability with increasing magnetic field strength. Emerging high-field MRI applications require the development of novel contrast agents that exhibit high relaxation enhancement as a function of magnetic field strength. Paramagnetic ions such as Dy³⁺, Tb³⁺ or Ho³⁺ incorporated into supramolecular or inorganic nano-architectures represent promising platforms for the development of high field MRI contrast agents. Furthermore, such platforms allow facile inclusion of multiple imaging modalities, therapeutic loading, and targeting vectors. This Minireview examines the application of contrast agents for high-field MRI, which range from single molecules to nanoparticles. Approaches to create multimodal agents by combining high-field MRI contrast properties with another imaging modality are also discussed.     

无机溶致液晶研究进展

目前发现的液晶多数为有机液晶,无机液晶非常少见。非球形无机胶体(棒状或盘状)体系在排斥体积熵的作用下可形成液晶相,即无机溶致液晶。由于其具有的理论意义和潜在的应用价值,无机液晶近年来引起了人们的关注。本文综述了无机溶致液晶的研究历史和最新进展。     

激活型有机光声造影剂的应用

光声(PA)成像作为一种结合了光学和声学成像优势的新型成像方式,具有深层组织穿透和高空间分辨率等优点,在重大疾病的早期影像诊断方面有着巨大的应用前景.然而传统的PA造影剂依然存在信噪比低、选择性及特异性差等不足,容易产生假阳性诊断结果.激活型PA造影剂可以有效的降低背景噪声,并提升成像的灵敏度和特异性,是目前PA造影剂...     

生物医用氟碳胶体的研究进展

全氟碳化物(PFCs)胶体的生物医学应用由最初的血液代用品逐渐发展成为多种需氧治疗的辅助剂,例如用于心血管系统、肺部疾患的治疗,肿瘤化疗与放疗的辅助、移植器官的保存及细胞培养技术等,还可作为造影剂和药物释放载体,以及充当生物医用的诊断探针。     

Palladium: a future key player in the nanomedical field?

Metal nanostructures offer invaluable possibilities for targeted drug delivery, detection/diagnosis and imaging. Whereas iron, gold, silver and platinum nanoarchitectures have largely dominated this field to date, several hurdles impede the widespread application of those nanopharmaceuticals in a clinical context. Therefore, technologies based on alternative metals are now being evaluated for their potential in medical applications. Palladium nanostructures are characterized by remarkable catalytic and optical properties. However, until recently, very few studies have taken advantage of these unique characteristics for applications in the biomedical field. Very recently, palladium nanostructures have been reported as prodrug activator, as photothermal agents and for anti-cancer/anti-microbial therapy. With only a handful of reports available, the pharmaceutical applications of palladium nanostructures reviewed here are in their infancy. Yet their interesting performance and toxicity profiles may qualify them as future key players in the nanomedical field.     

Magnetic nanoparticles for the manipulation of proteins and cells

In the rapidly developing areas of nanobiotechnology, magnetic nanoparticles (MNPs) are one type of the most well-established nanomaterials because of their biocompatibility and the potential applications as alternative contrast enhancing agents for magnetic resonance imaging (MRI). While the development of MNPs as alternative contrast agents for MRI application has moved quickly to testing in animal models and clinical trials, other applications of biofunctional MNPs have been explored extensively at the stage of qualitative or conceptual demonstration. In this critical review, we summarize the development of two straightforward applications of biofunctional MNPs--manipulating proteins and manipulating cells--in the last five years or so and hope to provide a relatively comprehensive assessment that may help the future developments. Specifically, we start with the examination of the strategy for the surface functionalization of MNPs because the applications of MNPs essentially depend on the molecular interactions between the functional molecules on the MNPs and the intended biological targets. Then, we discuss the use of MNPs for manipulating proteins since protein interactions are critical for biological functions. Afterwards, we evaluate the development of the use of MNPs to manipulate cells because the response of MNPs to a magnetic field offers a unique way to modulate cellular behavior in a non-contact or "remote" mode (i.e. the magnet exerts force on the cells without direct contact). Finally, we provide a perspective on the future directions and challenges in the development of MNPs for these two applications. By reviewing the examples of the design and applications of biofunctional MNPs, we hope that this article will provide a reference point for the future development of MNPs that address the present challenges and lead to new opportunities in nanomedicine and nanobiotechnology (137 references).     

Acoustic nanodrops for biomedical applications

Acoustic nanodrops are designed to vaporize into ultrasound-responsive microbubbles, which present certain challenges nonexistent for conventional nanoemulsions. The requirements of biocompatibility, vaporizability, and colloidal stability have focused research on perfluorocarbons. Shorter perfluorocarbons yield better vaporizability via their lower critical temperature, but they also dissolve more easily owing to their higher vapor pressure and solubility. Thus, acoustic nanodrops have required a trade-off between vaporizability and colloidal stability in vivo. The recent advent of vaporizable endoskeletal droplets, which are both colloidally stable and vaporizable, may have solved this problem. The purpose of this review is to justify this premise by pointing out the beneficial properties of acoustic nanodrops, providing an analysis of vaporization and dissolution mechanisms, and reviewing current biomedical applications.     

Diagnostic prospects and preclinical development of optical technologies using gold nanostructure contrast agents to boost endogenous tissue contrast

Numerous developments in optical biomedical imaging research utilizing gold nanostructures as contrast agents have advanced beyond basic research towards demonstrating potential as diagnostic tools; some of which are translating into clinical applications. Recent advances in optics, lasers and detection instrumentation along with the extensive, yet developing, knowledge-base in tailoring the optical properties of gold nanostructures has significantly improved the prospect of near-infrared (NIR) optical detection technologies. Of particular interest are optical coherence tomography (OCT), photoacoustic imaging (PAI), multispectral optoacoustic tomography (MSOT), Raman spectroscopy (RS) and surface enhanced spatially offset Raman spectroscopy (SESORS), due to their respective advancements. Here we discuss recent technological developments, as well as provide a prediction of their potential to impact on clinical diagnostics. A brief summary of each techniques'' capability to distinguish abnormal (disease sites) from normal tissues, using endogenous signals alone is presented. We then elaborate on the use of exogenous gold nanostructures as contrast agents providing enhanced performance in the above-mentioned techniques. Finally, we consider the potential of these approaches to further catalyse advances in pre-clinical and clinical optical diagnostic technologies.

Optical biomedical imaging research utilising gold nanostructures as contrast agents has advanced beyond basic science, demonstrating potential in various optical diagnostic tools; some of which are currently translating into clinical applications.     

Biohybrid fluorescent nanodiamonds as dual‐contrast markers for light and electron microscopies

Cathodoluminescence (CL) and correlative light‐electron microscopy (CLEM) are two useful analytical tools in diverse research areas. Recently, fluorescent nanodiamonds (FNDs) have emerged as promising imaging agents for both CL and CLEM owing to their exceptional photophysical and chemical properties. However, to realize their practical applications in the life sciences, surface modification and functionalization of the nanomaterials with bioactive molecules are critical and essential. Here we provide a comprehensive review on the methods of synthesizing biohybrid FNDs as well as recent advances of CL and CLEM imaging of cells with these carbon nanoparticles as dual‐contrast markers.