**5. Mechanisms for target drug delivery using microbubbles**

Based on the cavitation of microbubbles, two possible strategies for delivering drugs and genes with microbubbles are emerging: the first consists on the ultrasound-mediated microbubble destruction and the second is the direct delivery

**107**

**Figure 4.**

*Using Microbubbles as Targeted Drug Delivery to Improve AIDS*

of substances bound to microbubbles in the absence of ultrasound. Different drugs and genes can be integrated into the ultrasound contrast agent such as perfluorocarbon-filled albumin microbubbles which actively bind proteins and synthetic oligonucleotides [43]. Microbubbles can directly take up genetic material, such as plasmids, adenovirus, and phospholipid-coated microbubbles as these have high

**6. Mechanism by ultrasound-mediated microbubble destruction**

Ultrasound facilitates the delivery of drugs and genes. In the insonified field, the presence of microbubbles reduces the peak negative pressure which is necessary to enhance drug delivery. This happened because microbubbles acting as nuclei for cavitations decrease the threshold of ultrasound energy. Microbubble gets destroyed by ultrasound due to the gradual diffusion of gas at low acoustic power, formation of a shell defect with diffusion of gas, immediate expulsion of the microbubble shell at high acoustic power, and dispersion of microbubbles into several smaller 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

*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].*

incorporation of drug and drug release from these microbubbles.

*DOI: http://dx.doi.org/10.5772/intechopen.87157*

affinity for chemotherapeutic drugs.

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

*Using Microbubbles as Targeted Drug Delivery to Improve AIDS DOI: http://dx.doi.org/10.5772/intechopen.87157*

*Pharmaceutical Formulation Design - Recent Practices*

platelet aggregation.

*Liquid perfluorocarbon gene carrier.*

**Figure 3.**

peptides, directed to the activated GP2B3A receptor of platelets, were evaluated for affinity to bind to activated platelets by testing for the inhibition of

In **Figure 3** the outer surface is stabilized by amphipathic lipid. Targeting ligands have been incorporated onto the head groups of the lipids. The genetic material is stabilized by cationic lipids. Electron microscopy studies have shown that the DNA is condensed as an electron-dense granule within the center of the nanoparticle. The diameter of these particles is about 100–200 nm [37]. There are several advantages to lipid shells. At the air-Space minimized, the phopspholipid's hydrophobic acyl chains face the phopspholipid's gas, and hydrophilic head groups face the water. Thus the monolayer will form around a newly trained gas bubble. Saturated diacyl phospholipids have very low surface tension below phase transition temperature. This is essential as surface tension at the curved interface induces a Laplace overpressure, thus forcing the gas core to dissolve [8]. The microbubble stabilizes at low tension which is achieved by the lipid monolayer [38]. Monolayers of lipids are highly cohesive and form solid-like character because of the attractive hydrophobic interaction between the tightly packed acyl chains and van der Waals [39]. These effect can be effective because the stability of microbubbles during sonication is not dependent on superoxide formation to facilitate disulfide bridging, as is the case with proteins. Therefore, as recently described by Stride and Edirisinghe, lipids are suitable for a variety of manufacturing techniques apart from sonication [40]. In the absence of ultrasound, if the adenovirus was administered with microbubbles using the same model, the author confirmed that plasmid transgene expression can be directed to the heart, with an even higher specificity than viral vectors and that this expression can be regulated by repeated treatments [41]. Lu et al. [42] have also shown that albumin-coated microbubbles significantly improved transgene

expression in skeletal muscle of mice, even in the absence of ultrasound.

Based on the cavitation of microbubbles, two possible strategies for delivering drugs and genes with microbubbles are emerging: the first consists on the ultrasound-mediated microbubble destruction and the second is the direct delivery

**5. Mechanisms for target drug delivery using microbubbles**

**106**

of substances bound to microbubbles in the absence of ultrasound. Different drugs and genes can be integrated into the ultrasound contrast agent such as perfluorocarbon-filled albumin microbubbles which actively bind proteins and synthetic oligonucleotides [43]. Microbubbles can directly take up genetic material, such as plasmids, adenovirus, and phospholipid-coated microbubbles as these have high affinity for chemotherapeutic drugs.
