**7. Mechanism by cavitation of the bubbles**

It is characterized by rapid destruction of contrast agents due to a hydrodynamic instability during large amplitude oscillations, and is directly dependent on the transmission pressure [43]. Cavitation of the microbubbles increases capillary permeability and delivery of material to the interstitial tissue. When cavitation occurs, this may impart a ballistic effect to drive the drug from the vasculature into or through the vessel wall. Cavitation events will be intimately associated with the drugs themselves (**Figure 4**) [34]. There are two mechanisms for drug delivery in microbubbles that are incorporation of drug and drug release from these microbubbles.

#### **Figure 4.**

*Different ways microbubbles can transport drugs. Drugs may be attached to the membrane surrounding the microbubble. (a) Drugs may might also be formulated to load the interior with drug and gas, or be imbedded within the membrane itself. (b) Materials, e.g. DNA, may be bound noncovalently to the surface of the microbubbles. (c) Microbubbles hydrophobic drugs can be incorporated into a layer of oily material that forms a film around the microbubble, which is then surrounded by a stabilizing membrane. (e) In this example a targeting ligand is incorporated on the membrane allowing targeted delivery of the drug. Note that although in these examples the stabilizing materials are shown as lipids, but could also be polymeric materials [33].*

**Figure 5.** *Drug release from microbubbles by cavitation.*

1.**Drug incorporation into microbubbles:** incorporation of drug molecule in the microbubbles in a following way (1) incorporation of drug molecule only within bubble, (2) incorporation of drug molecule within cell membrane, (3) attachment of drug molecule to microbubbles by covalent bonds, (4) attachment of drug molecule to microbubbles by ligand (ex avidin-biotin complex), and (5) incorporation of drug molecule in multiple layer of microbubbles. Microbubbles are able to cross the BBB through above process.

In **Figure 3** by attaching a targeted ligand such as monoclonal antibody a targeted microbubbles are developed. These are specific for endothelial marker as microbubbles. To assess vascular pathology targeted ultrasound contrast agent are used ex: P-selectin, ICAM-1, GpIIb/IIIa, the αv integrins.

2.**Release of drug from microbubbles:** microbubbles on application of ultrasound undergo a process known as cavitation. Ultrasound causes the microbubble to burst or break. The body fluids begin to insonate on cavitation to create acoustic cavitation. After oscillating microbubbles produces increase small eddy, this increases the permeability of cell membrane and drug passes across the membrane. Microbubbles also release the drug by phagocytosis mechanism. **Figure 5** describe the delivery of drug through fusion mechanism in which the phospholipid microbubble fuse with phospholipid bilayer of cell membrane and releasing of drug or gene into the cytoplasm of cell membrane. By this mechanism the gene get directly transfer to the nucleus of the cell [44–47].
