Stable Encapsulation of Air in Mesoporous Silica Nanoparticles: Fluorocarbon‐Free Nanoscale Ultrasound Contrast Agents

Abstract

While gas-filled micrometer-sized ultrasound contrast agents vastly improve signal-to-noise ratios, microbubbles have short circulation lifetimes and poor extravasation from the blood. Previously reported fluorocarbon-based nanoscale contrast agents are more stable but their contrast is generally lower owing to their size and dispersity. The contrast agents reported here are composed of silica nanoparticles of ≈100 nm diameter that are filled with ≈3 nm columnar mesopores. Functionalization of the silica surface with octyl groups and resuspension with Pluronic F127 create particles with pores that remain filled with air but are stable in buffer and serum. Administration of high intensity focused ultrasound (HIFU) allows sensitive imaging of the silica nanoparticles down to 10 10 particles mL −1, with continuous imaging for at least 20 min. Control experiments with different silica particles supported the hypothesis that entrapped air could be pulled into bubble nuclei, which can then in turn act as acoustic scatterers. This process results in very little hemolysis in whole blood, indicating potential for nontoxic blood pool imaging. Finally, the particles are lyophilized and reconstituted or stored in PBS (phosphate-buffered saline, at least for four months) with no loss in contrast, indicating stability to storage and reformulation.

Understanding Acoustic Cavitation Initiation by Porous Nanoparticles: Toward Nanoscale Agents for Ultrasound Imaging and Therapy

“…It was observed that responsivities of the particles stored for 3 d or 14 d were almost same with the fresh particles (see the Supporting Information, Figure S6) suggesting that the nanobubbles are stable for at least two weeks, which is in accordance with our previous findings with Pluronic F127 stabilized hydrophobic MCM-41 MSNs. 29 …”

“…More recently, we showed that acoustic cavitation initiated by Pluronic polymer stabilized hydrophobic MSN, when exposed to HIFU, can be observed by using a conventional imaging transducer. 29 In these studies it was assumed that the air encapsulated inside the mesopores of silica nanoparticles initiates acoustic cavitation. Later, it was shown that the air stabilized inside the cavities of nanocups 30, 33 or even at the surface of solid hydrophobic particles 31 can also initiate acoustic cavitation.…”

“…The nanobubbles remain stable on the particle surface but grow when exposed to sufficient negative acoustic pressures by externally applied ultrasound. 35–38 Recently, we and others showed that acoustic cavitation can be induced at clinically relevant acoustic pressures via the interaction of sound with hydrophobic mesoporous silica nanoparticles, 28, 29 polystyrene nanocups, 30, 33 and solid polytetrafluoroethylene (PTFE) nanoparticles. 31 These generated bubbles can not only be imaged using conventional ultrasound, 29 but the shock waves emitted by the acoustic cavitation process can kill cancer cells 28, 32 and facilitate drug delivery in vivo.…”

Superhydrophobic materials for biomedical applications

“…Ahmad Nor et al prepared similar particles, with varying degrees of hydrophobicity, and demonstrated that the particles which were both rough and hydrophobic released their drug loadings slowest [224]. Yildrim et al reported that mesoporous silica nanoparticles are effective ultrasound contrast agents, by releasing or nucleating microbubbles in response to focused ultrasound [225]. Finally, Chen et al synthesized mesoporous silica nanoparticles with grafted fluorocarbons and photoresponsive spiropyran [226].…”

Covalent nano delivery systems for selective imaging and treatment of brain tumors

“…Due to these limitations, perfluorocarbon-based nanodroplets have been developed, which are capable of entering tumors [164]. However, these nanodroplets have poorer contrast than the more traditional microbubbles, which is a major deterrent for use in tumor imaging [182]. Luke et al recently reported “super-resolution ultrasound imaging” of a new generation of nano-sized contrast agents, laser-activated nanodroplets (LANDs), which seem to hold future promise for deep tissue molecular imaging [183].…”