Ultrasound-Mediated Cavitation-Enhanced Extravasation of Mesoporous Silica Nanoparticles for Controlled-Release Drug Delivery

Mesoporous silica nanoparticles have been reported as suitable drug carriers, but their successful delivery to target tissues following systemic administration remains a challenge. In the present work, ultrasound-induced inertial cavitation was evaluated as a mechanism to promote their extravasation in a flow-through tissue mimicking agarose phantom. Two different ultrasound frequencies, 0.5 or 1.6 MHz, with pressures in the range 0.5-4 MPa were used to drive cavitation activity which was detected in real time. The optimal ultrasound conditions identified were employed to deliver dye-loaded nanoparticles as a model for drug-loaded nanocarriers, with the level of extravasation evaluated by fluorescence microscopy. The same nanoparticles were then co-injected with submicrometric polymeric cavitation nuclei as a means to promote cavitation activity and decrease the required in-situ acoustic pressure required to attain extravasation. The overall cavitation energy and penetration of the combination was compared to mesoporous silica nanoparticles alone. The results of the present work suggest that combining mesoporous silica nanocarriers and submcrometric cavitation nuclei may help enhance the extravasation of the nanocarrier, thus enabling subsequent sustained drug release to happen from those particles already embedded in the tumour tissue

Doxorubicin liposome-loaded microbubbles for contrast imaging and ultrasound-triggered drug delivery

International audienceTargeted drug delivery under image guidance is gaining more interest in the drug-delivery field. The use of microbubbles as contrast agents in diagnostic ultrasound provides new opportunities in noninvasive image-guided drug delivery. In the present study, the imaging and therapeutic properties of novel doxorubicin liposome-loaded microbubbles are evaluated. The results showed that at scanning settings (1.7 MHz and mechanical index 0.2), these microbubbles scatter sufficient signal for nonlinear ultrasound imaging and can thus be imaged in real time and be tracked in vivo. In vitro therapeutic evaluation showed that ultrasound at 1 MHz and pressures up to 600 kPa in combination with the doxorubicin liposomeloaded microbubbles induced 4-fold decrease of cell viability compared with treatment with free doxorubicin or doxorubicin liposome-loaded microbubbles alone. The therapeutic effectiveness is correlated to an ultrasound-triggered release of doxorubicin from the liposomes and an enhanced uptake of the free doxorubicin by glioblastoma cells. The results obtained demonstrate that the combination of ultrasound and the doxorubicin liposome-loaded microbubbles can provide a new method of noninvasive image-guided drug delivery

Role of thermal and mechanical effects on drug release from thermosensitive nanocarriers

The combination of focused ultrasound (FUS) with thermosensitive liposomes (TSL) is a promising method for drug delivery since it allows a localized release upon moderate heating with ultrasound. Besides thermal effects, FUS also induces mechanical stresses on drug nanocarriers. We propose in this study to examine the influence of both effects (thermal and mechanical) on drug release. For this, an in-vitro setup allowing liposomal drug delivery using FUS was first evaluated. Calcein was used as a model drug. FUS experiments were performed in water at 37°C using a 1 MHz transducer focused at 48 mm, at 1 kHz PRF and 40% duty cycle. The driving pressure and the insonation duration were varied from 1 to 2 MPa and from 0 to 30 min, respectively. Thermal heating using a water-bath was also performed with temperatures from 37 to 49°C. For TSL, the release reaches a plateau above 42°C (45%) after 10 min heating while no release is observed for non-thermosensitive liposomes (NTSL). Using FUS, a rapid calcein release is observed for pressures from 1 to 1.5 MPa (from 0% to 49%) for TSL. Above 1.5 MPa, the release increases slightly (59% at 2 MPa). For NTSL, a weak calcein release is measured for acoustic pressures higher than 1.5 MPa. This release is attributed to the mechanical stress generated by FUS which is sufficient to destabilize the liposomal membrane. Mechanical stress alone can enhance the calcein release by up to 17% for pressures higher than 1.75 MPa

Acoustically responsive polydopamine nanodroplets: A novel theranostic agent

Ultrasound-induced cavitation has been used as a tool of enhancing extravasation and tissue penetration of anticancer agents in tumours. Initiating cavitation in tissue however, requires high acoustic intensities that are neither safe nor easy to achieve with current clinical systems. The use of cavitation nuclei can however lower the acoustic intensities required to initiate cavitation and the resulting bio-effects in situ. Microbubbles, solid gas-trapping nanoparticles, and phase shift nanodroplets are some examples in a growing list of proposed cavitation nuclei. Besides the ability to lower the cavitation threshold, stability, long circulation times, biocompatibility and biodegradability, are some of the desirable characteristics that a clinically applicable cavitation agent should possess. In this study, we present a novel formulation of ultrasound-triggered phase transition sub-micrometer sized nanodroplets (~400 nm) stabilised with a biocompatible polymer, polydopamine (PDA). PDA offers some important benefits: (1) facile fabrication, as dopamine monomers are directly polymerised on the nanodroplets, (2) high polymer biocompatibility, and (3) ease of functionalisation with other molecules such as drugs or targeting species. We demonstrate that the acoustic intensities required to initiate inertial cavitation can all be achieved with existing clinical ultrasound systems. Cell viability and haemolysis studies show that nanodroplets are biocompatible. Our results demonstrate the great potential of PDA nanodroplets as an acoustically active nanodevice, which is highly valuable for biomedical applications including drug delivery and treatment monitoring

High-intensity focused ultrasound-mediated doxorubicin delivery with thermosensitive liposomes

Local drug delivery of doxorubicin holds promise to improve the therapeutic efficacy and to reduce toxicity profiles. Here, we investigated the release of doxorubicin from thermosensitive liposomes (Dox-TSL) into human glioblastoma (U-87MG) cells. Using Dox-TSL, experiments were carried out in a water bath and showed that 15 min incubation of TSL at 43°C induced the release of 80% doxorubicin loaded TSL compared to the release at 37°C. The cytotoxicity of a range of concentrations of Dox-TSL was also evaluated on U-87MG cells. At 37°C, no cytotoxicity was observed, whereas at 43°C the results showed that the cytotoxicity is dose dependent. At maximal dose of doxorubicin (30 ȝg/mL), the cell viability was less than 20%. Application of 15 min of HIFU at 1 MHz, 1.5 MPa and 50% duty cycle induced the release of 100% of doxorubicin from Dox-TSL. In the same experimental condition, the cell viability decreased to 40% and 20% at 12h and 48h, respectively, in comparison to that obtained during the incubation of cells with Dox-TSL alone without HIFU. In conclusion, a significant release of doxorubicin from temperature-sensitive liposomes can be achieved leading to an efficient treatment and cell death of tumor cells using HIFU

Investigation of the acoustic vaporization threshold of lipid-coated perfluorobutane nanodroplets using both high-speed optical imaging and acoustic methods

A combination of ultrahigh-speed optical imaging (5 × 106 frames/s), B-mode ultrasound and passive cavitation detection was used to study the vaporization process and determine both the acoustic droplet vaporization (ADV) and inertial cavitation (IC) thresholds of phospholipid-coated perfluorobutane nanodroplets (PFB NDs, diameter = 237 ± 16 nm). PFB NDs have not previously been studied with ultrahigh-speed imaging and were observed to form individual microbubbles (1-10 μm) within two to three cycles and subsequently larger bubble clusters (10-50 μm). The ADV and IC thresholds did not statistically significantly differ and decreased with increasing pulse length (20-20,000 cycles), pulse repetition frequency (1-100 Hz), concentration (108-1010 NDs/mL), temperature (20°C-45°C) and decreasing frequency (1.5-0.5 MHz). Overall, the results indicate that at frequencies of 0.5, 1.0 and 1.5 MHz, PFB NDs can be vaporized at moderate peak negative pressures (&lt;2.0 MPa), pulse lengths and pulse repetition frequencies. This finding is encouraging for the use of PFB NDs as cavitation agents, as these conditions are comparable to those required to achieve therapeutic effects with microbubbles, unlike those reported for higher-boiling-point NDs. The differences between the optically and acoustically determined ADV thresholds, however, suggest that application-specific thresholds should be defined according to the biological/therapeutic effect of interest.</p

Improved therapeutic antibody delivery to xenograft tumors using cavitation nucleated by gas-entrapping nanoparticles

Aims: Testing ultrasound-mediated cavitation for enhanced delivery of the therapeutic antibody cetuximab to tumors in a mouse model. Methods: Tumors with strong EGF receptor expression were grown bilaterally. Cetuximab was coadministered intravenously with cavitation nuclei, consisting of either the ultrasound contrast agent Sonovue or gas-stabilizing nanoscale SonoTran Particles. One of the two tumors was exposed to focused ultrasound. Passive acoustic mapping localized and monitored cavitation activity. Both tumors were then excised and cetuximab concentration was quantified. Results: Cavitation increased tumoral cetuximab concentration. When nucleated by Sonovue, a 2.1-fold increase (95% CI 1.3- to 3.4-fold) was measured, whereas SonoTran Particles gave a 3.6-fold increase (95% CI 2.3- to 5.8-fold). Conclusions: Ultrasound-mediated cavitation, especially when nucleated by nanoscale gas-entrapping particles, can noninvasively increase site-specific delivery of therapeutic antibodies to solid tumors

Layered acoustofluidic resonators for the simultaneous optical and acoustic characterisation of cavitation dynamics, microstreaming and biological effects

The study of the effects of ultrasound-induced acoustic cavitation on biological structures is an active field in biomedical research. Of particular interest for therapeutic applications is the ability of oscillating microbubbles to promote both cellular and tissue membrane permeabilisation and to improve the distribution of therapeutic agents in tissue through extravasation and convective transport. The mechanisms that underpin the interaction between cavitating agents and tissues are, however, still poorly understood. One challenge is the practical difficulty involved in performing optical microscopy and acoustic emissions monitoring simultaneously in a biologically compatible environment. Here we present and characterise a microfluidic layered acoustic resonator (μLAR) developed for simultaneous ultrasound exposure, acoustic emissions monitoring and microscopy of biological samples. The μLAR facilitates in vitro ultrasound experiments in which measurements of microbubble dynamics, microstreaming velocity fields, acoustic emissions and cell-microbubble interactions can be performed simultaneously. The device and analyses presented provide a means of performing mechanistic in vitro studies that may benefit the design of predictable and effective cavitation-based ultrasound treatments

(Toga/Coare Cruise) The Western equatorial Pacific ocean

航海番号: KH-92-5 ; 航海日程: October 28 - December 7, 199