The Impact of Surface Drug Distribution on the Acoustic Behavior of DOX-Loaded Microbubbles

Abstract

Previous studies have reported substantial improvement of microbubble (MB)-mediated drug delivery with ultrasound when drugs are loaded onto the MB shell compared with a physical mixture. However, drug loading may affect shell properties that determine the acoustic responsiveness of MBs, producing unpredictable outcomes. The aim of this study is to reveal how the surface loaded drug (doxorubicin, DOX) affects the acoustic properties of MBs. A suitable formulation of MBs for DOX loading was first identified by regulating the proportion of two lipid materials (1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol sodium salt (DSPG)) with distinct electrostatic properties. We found that the DOX loading capacity of MBs was determined by the proportion of DSPG, since there was an electrostatic interaction with DOX. The DOX payload reduced the lipid fluidity of MBs, although this effect was dependent on the spatial uniformity of DOX on the MB shell surface. Loading DOX onto MBs enhanced acoustic stability 1.5-fold, decreased the resonance frequency from 12–14 MHz to 5–7 MHz, and reduced stable cavitation dose by 1.5-fold, but did not affect the stable cavitation threshold (300 kPa). Our study demonstrated that the DOX reduces lipid fluidity and decreases the elasticity of the MB shell, thereby influencing the acoustic properties of MBs.

Oxygen-loaded microbubble-mediated sonoperfusion and oxygenation for neuroprotection after ischemic stroke reperfusion

“…The improvement of blood perfusion signals at the peripheral microcirculation of ACArb after OMB treatment was visualized in the laser speckle images (Figure S4). Since MB cavitation can activate release of the vasodilator nitric oxide (NO), sonoperfusion might promote effective reperfusion in the microcirculation to protect neurons [18,22]. In addition, the local release of O 2 during OMB treatment promoted a 10.3 ± 3.1% increase in pO 2 level relative to the S/R group, allowing reoxygenation of the hypoxic brain.…”

The relationship between surface drug distribution of Dox-loaded microbubbles and drug release/cavitation behaviors with ultrasound

“…This study employed the thin film hydration method to synthesize MBs following previous publication [2] , using three types of lipids: 1,2-distearoyl- sn -glycero-3-phosphocholine (DSPC, Avanti Polar Lipids, AL, USA), 1,2-distearoyl- sn -glycero-3-phospho- rac -glycerol sodium salt (DSPG, Avanti Polar Lipids, AL, USA), and 1,2-distearoyl- sn -glycero-3-phosphoethanolamine-N-[methoxy(poly(ethylene glycol))-2000] (DSPE-PEG2000, Avanti Polar Lipids, AL, USA). DSPC, DSPG, and DSPE-PEG2000 were dissolved in chloroform with a mole ratio of 42:63:2.…”

“…Moreover, cavitation serves as a trigger for the controlled release of drug payloads from these microbubbles in response to US sonication. It is essential to acknowledge that most reported studies have indicated that the composition of the payload significantly influences the acoustic properties of drug-loaded MBs onto the shell of the MBs [1] , [2] . Leveraging these distinctive acoustic properties and drug release behaviors associated with drug-loaded MBs containing various types of surface drug distribution holds the potential to enable precise control over their behavior, thus expanding their utility in the realm of medical applications.…”

“…Integrating Dox into MBs, along with US excitation, offers the prospect of significantly reducing the associated side effects of Dox, thereby enhancing its therapeutic efficacy. In our previous study, we successfully developed a novel MB formulation that permits the direct loading of Dox onto MBs through precise modulation of the lipid components within the MB shell, obviating the need for further modifications to the Dox molecule itself [2] . While it is possible to increase the Dox payload, limited information is available regarding the relationship between the Dox payload and the cavitation behavior exhibited by the MBs.…”

Nanotechnology-enabled sonodynamic therapy against malignant tumors

“… 101 Moreover, US microvesicles can also be used as gene and drug delivery carriers, providing a dual advantage in the diagnosis and treatment of tumors. Lin et al 102 found that new DOX-loaded MBs could be safely applied in rats, resulting in a corresponding increase in the local drug concentration and inhibition of tumor growth. In clinical case studies of patients with locally advanced and inoperable pancreatic cancer, it was found that the combination of US, MBs and chemotherapy significantly increased the treatment cycle and extended the quality of life of patients with pancreatic adenocarcinoma compared with chemotherapy alone.…”