Increasing the sonoporation efficiency of targeted polydisperse microbubble populations using chirp excitation

Abstract

Abstract-The therapeutic use of microbubbles for targeted drug or gene delivery is a highly active area of research. Phospholipid-encapsulated microbubbles typically have a polydisperse size distribution over the 1-10 µm range and can be functionalised for molecular targeting as well as loaded with drug-carrying liposomes. Sonoporation through the generation of shear stress on the cell membrane by microbubble oscillations is one mechanism that results in pore formation in the cell membrane and can improve drug delivery. A microbubble oscillating at its resonant frequency would generate maximum shear stress on a membrane. However, due to the polydisperse nature of phospholipid microbubbles, a range of resonant frequencies would exist in a single population. In this study, the use of linear chirp excitations was compared with equivalent duration and acoustic pressure tone excitations when measuring the sonoporation efficiency of targeted-microbubbles on human colorectal cancer cells. A 3-7 MHz chirp had the greatest sonoporation efficiency of 26.9 ±5.6 %, compared with 16.4 ±1.1 % for the 1.32-3.08 MHz chirp. The equivalent 2.2 and 5 MHz tone excitations have efficiencies of 12.8 ±2.1 % and 15.6 ±1.1 %, respectively, which were all above the efficiency of 4.1 ±3.1 % from the control exposure.

Targeted ultrasound contrast agents for ultrasound molecular imaging and therapy

“…Since then, several other studies reported tUCAs for drug delivery by either co-administering the drug with the tUCAs or loading the drug in/on the tUCAs. Another co-administration in vitro study using PI showed that sonoporation of cancer cells by a v b 6 -tUCAs was higher with chirp pulses from 3-7 MHz than with chirp pulses between 1.3 and 3.1 MHz or single frequency insonification at 2.2 or 5 MHz (110 kPa, 10 ms burst, pulse repetition frequency (PRF) 1 kHz, 2 min treatment) [182]. This can be explained by the fact that chirp pulses cover a broader range of resonance frequencies, as MBs with various sizes have different resonance frequencies; chirp pulses are therefore more efficient than single frequency pulses.…”

“…tUCA vs. non-tUCA for enhanced drug delivery Strikingly, when tUCAs for drug delivery are directly compared with their non-targeted UCA counterparts, tUCAs are more efficient both in vitro [184,185,188,189,192] (up to 7.7-fold higher [189]) and in vivo [186,187,190,191] (up to 5-fold higher [186]), regardless of whether the drug was coadministered with the tUCAs or whether the drug was loaded on/in the tUCAs. Although the reasons for this higher efficiency have not yet been investigated, several could be possible.…”

Membrane blebbing as a recovery manoeuvre in site-specific sonoporation mediated by targeted microbubbles

“…Doing so would render new insight on why the use of bubble-to-cell ratios greater than unity for sonoporation purposes has been shown to increase the chances of cell death [45]. Note that the recovery dynamics of sonoporation may be different when using nontone-burst ultrasound pulsing waveforms, such as chirps [46]. It would be relevant to survey this issue as well.…”

The effect of amplitude modulation on subharmonic imaging with chirp excitation

“…The vial was shaken for 45 seconds by a CapMix mechanical shaker (3M ESPE, St. Paul, MN). After producing the microbubbles, their size distribution and concentration were optically measured by Nikon Eclipse Ti-U inverted microscope (Nikon Corp, Tokyo, Japan) [42] as shown in Figure 4. The average diameter and the concentration of the manufactured microbubbles were 1.9 ± 1 µm and 1 × 10 10 MB/ml, respectively.…”