Superhydrophobic silica nanoparticles as ultrasound contrast agents

Highlights

• Nanoscale ultrasound contrast agents was proposed.

• Superhydrophobic porous silica nanoparicles are sensitive to ultrasound.

• Bubbles can be generated over 0.6 MI by superhydrophobic silica nanoparticle.

Abstract

Microbubbles have been widely studied as ultrasound contrast agents for diagnosis and as drug/gene carriers for therapy. However, their size and stability (lifetime of 5–12 min) limited their applications. The development of stable nanoscale ultrasound contrast agents would therefore benefit both. Generating bubbles persistently in situ would be one of the promising solutions to the problem of short lifetime. We hypothesized that bubbles could be generated in situ by providing stable air nuclei since it has been found that the interfacial nanobubbles on a hydrophobic surface have a much longer lifetime (orders of days). Mesoporous silica nanoparticles (MSNs) with large surface areas and different levels of hydrophobicity were prepared to test our hypothesis. It is clear that the superhydrophobic and porous nanoparticles exhibited a significant and strong contrast intensity compared with other nanoparticles. The bubbles generated from superhydrophobic nanoparticles sustained for at least 30 min at a MI of 1.0, while lipid microbubble lasted for about 5 min at the same settings. In summary MSNs have been transformed into reliable bubble precursors by making simple superhydrophobic modification, and made into a promising contrast agent with the potentials to serve as theranostic agents that are sensitive to ultrasound stimulation.

Introduction

Microbubbles (MBs) ranging in size from 1 to 10 μm have not only been explored extensively as contrast agents for use in ultrasound-based diagnosis but also shown to have substantial potentials in ultrasound molecular imaging [1], [2], [3], [4], ultrasound targeted drug/gene delivery [5], [6], thermal tissue ablation [7], [8], and sonothrombolysis [9], [10], [11] for therapeutic purposes. However, their micron size and poor stability have greatly hindered their application as theranostic agents. The development of stable nanoscale ultrasound contrast agents would therefore be hugely beneficial.

One possible strategy for addressing the issues mentioned above is to make smaller nanobubbles [12], [13], [14] or gas liposomes [15], [16], [17]. However, nanobubbles are not ideal ultrasound contrast agents because their contrast efficiency is lower and lifetime is shorter than those of MBs [18]. A second strategy is to design nanoscale bubble-precursors, which are usually metastable agents capable of being converted into MBs when exposed to a physical or chemical stimulus [19], [20]. Among the most promising candidates are phase-shift nanodroplets constructed from liquid perfluorocarbons, which could potentially overcome the size and stability issues simultaneously [21], [22], [23], [24]. Unfortunately, the Laplace pressure associated with their nanoscale size results in an extremely high vaporization threshold [25]. Although Sheeran et al. developed an ingenious condensation technique using low-boiling-point perfluoropropane and perfluorobutane and lowered the threshold to about 4 MPa [26], there is a trade-off between the acoustic vaporization threshold and stability. Another solution is to generate MBs in situ based on chemical reactions of solid nanoparticles (NPs) with a surrounding medium (e.g. tumor interstitial fluid) [27], [28]. However, it is very difficult to control the chemical reactions involved in the process of bubble production.

Recently, it has been found that the interfacial nanobubbles (INBs) on a hydrophobic surface have a much longer lifetime (orders of days) than the bulk nanobubbles (orders of microseconds) [29], [30], [31], [32], [33]. In addition, many studies found that these INBs can nucleate the formation of bubbles during ultrasound exposure [34], [35], [36]. Furthermore, the INBs trapped by superhydrophobic pits can nucleate cavitation hundreds of times and thereby greatly improve sonochemical productivity [37], [38]. However, there has been little research taking full advantage of the stability of INBs as gaseous bubble-precursors to develop a stable nanoscale ultrasound contrast agent. Yildirim et al. very recently applied mesoporous silica nanoparticles (MSNs) with a hydrophobic interior to produce bubbles for use as ultrasound contrast agents under an extremely high acoustic pressure (9.87 MPa at a frequency of 1.1 MHz) [39], corresponding to a mechanical index (MI) of 9.4, which far exceeds the FDA safety guidance (M ⩽ 1.9) for diagnosis purpose. Noted that MI can be used as an estimate for the degree of bio-effects.

Herein we propose producing MBs from INBs using a clinically available transducer to generate MBs in situ in a switchable manner, which is considered accessible when combining the characteristics of high surface area and superhydrophobicity. Therefore, MSNs were selected in this work due to their large surface areas, biocompatibility, and adjustable surface properties, which render various biomedical applications such as drug delivery [40], [41], [42], [43], cancer-targeting [44], [45], [46], and multimodality imaging [47], [48]. As schemed in Fig. 1, superhydrophobic MSNs are designed to adsorb INBs on their surfaces and in their mesopores, since such bubble-precursors could remain stable until being converted into MBs under exposure to acoustic pressure above a certain MI. MSNs (MCM-48 type) with different levels of hydrophobicity were prepared to demonstrate our idea.