Targeted renal therapies through microbubbles and ultrasound

Abstract

Microbubbles and ultrasound enhance the cellular uptake of drugs (including gene constructs) into the kidney. Microbubble induced modifications to the size selectivity of the filtration capacity of the kidney may enable drugs to enter previously inaccessible compartments of the kidney. So far, negative renal side-effects such as capillary bleeding have been reported only in rats, with no apparent damage in larger models such as pigs and rabbits. Although local delivery is accomplished by applying ultrasound only to the target area, efficient delivery using conventional microbubbles has depended on the combined injection of both drugs and microbubbles directly into the renal artery. Conjugation of antibodies to the shell of microbubbles allows for the specific accumulation of microbubbles in the target tissue after intravenous injection. This exciting approach opens new possibilities for both drug delivery and diagnostic ultrasound imaging in the kidney.

Fig. 1

Structure and appearance of microbubbles. A) Schematic of a phospholipid microbubble. B) Photograph of Sonovue microbubbles (Bracco, Milan) in close proximity to cultured bovine endothelial cells (phase contrast, 400* magnification). Note that the microbubbles are not uniform in size.

Fig. 2

Schematic diagram demonstrating local delivery of drugs to the kidney using microbubbles and ultrasound. Drug bearing microbubbles are injected intravenously into the circulation. Subsequent local exposure of the microbubbles to high intensity ultrasound releases the drug (✩) in the kidney.

Fig. 3

Diagram of a targeted microbubble. The gas phase is encapsulated by a lipid shell, which is stabilized by a polymer layer. Targeting ligands are immobilized on the distal surface of the polymer using various conjugation strategies, including biotin/avidin coupling, thioether, amide, and disulfide bonding.

Fig. 4

Representative images of accumulated microbubbles in diabetic mice 10 minutes after microbubble injection. Organ positions were outlined from B-mode images: liver is outlined in green and kidney is outlined in red. Specific accumulation of TGF-beta and P-selectin targeted microbubbles was observed in the diabetic kidney.