Lipid-coated microbubbles

E.C. Unger, T. Porter, W. Culp, R. Labell, T. Matsunaga, R. Zutshi, Therapeutic applications of lipid-coated microbubbles, Adv. Drug Deliv. Rev. 56 (2004) 1291-1314. 

From the data presented in Chapter 10, it becomes evident that the extreme longevity of the artificial surfactant-stabilized microbubbles described therein is, in part, related to their continuous interaction with the simultaneously formed mixed micelle population in the saturated surfactant solution. More specifically, the surfactant-stabilized microbubbles produced by mechanical agitation of saturated solutions of either CAV-CON s Filmix 2 or Filmix 3 apparently undergo a cyclical (or reversible) process of microbubble formation/coalescence/fission/disappearance, where the end of each cycle is characterized by a collapse of the lipid-coated microbubbles into large micellar structures (i.e., rodlike multimolecular aggregates), only to re-emerge soon after as newly formed, lipid-coated microbubbles (see also below). 

Fig. 11.1. Direct optical imaging of lipid-coated microbubbles (LCM) by phase-measurement interferometric microscopy (see text). (Taken from ref. 527.)...

TARGETED IMAGING OF TUMORS, AND TARGETED CAVITATION THERAPY, WITH LIPID-COATED MICROBUBBLES (L.C.M.)... 

In a subsequent brain-tumor study (ref. 526) using LCM along with a lipid-specific stain (cf. 569), a detailed evaluation of the actual distribution of lipid-coated microbubbles in the tumor and surrounding organ was conducted and compared to the distribution of echoes (from the microbubbles) on the sonogram. 

Fig. 12.1. These coronal scans are representative ultrasound images of a rat cerebral glioma before (top left) and less than 2 minutes after intravenous injection of 0.15 ml/kg of lipid-coated microbubbles (top right). A schematic representation (lower left) of the tumor (shaded) is presented in the context of the coronal scan. This image has been created from the actual map of the pixel intensities of the scan. The results are presented with black and white reversal for ease of interpretation. Lastly, a photomicrograph of the same cerebral tumor site, sectioned in the axial direction, is shown (lower right). (Taken from ref. 525.)...

Fig. 12.2. Microbubble count contour map. Lipid-coated microbubble (LCM) distribution in the tumor is represented by lines of microbubble isodensity in this contour map (bottom right). Notice that the area of needle/expansion artifact seen in the photomicrograph (bottom left) corresponds to a nil microbubble isodensity. The exploded panel from the photomicrograph clearly demonstrates the malignant features of the glioma. There is a significant freezing artifact in the left side of the photograph. (Taken from ref. 526.)...

Fig. 12.4. Demonstration of tumor targeting ability of LCM after i.v. injection into a rat bearing Novikoff hepatoma. All histologic sections were stained with Oil Red-O and counterstained with hematoxylin. (Top panel) A low-power view of the hepatoma and surrounding normal liver tissue. (Bottom panels) High-power insets of the neighboring normal liver parenchyma (bottom left) and the Novikoff hepatoma itself (bottom right). The lipid-coated microbubbles can be appreciated as solid black discs ranging in size from submicron up to 4 or 5 pm. (Taken from ref. 528.)...

C6 glioma cells were grown in F-10 medium supplemented with 10% horse serum and 2.5% fetal calf serum. Cells were plated on glass coverslips (22 mm2) and used when they reached 50% confluence. (LCM, lipid-coated microbubbles S.D., standard deviation.)... 

S.D., standard deviation CRE, cremophor LCM, lipid-coated microbubbles. b Day of killing , not death, as described in text. 

R.H. Simon, S.Y. Ho, C.R. Perkins and J.S. D Arrigo, A quantitative assessment of tumor enhancement by ultrastable lipid-coated microbubbles as a contrast agent, Invest. Radiol. 27 (1992) 29-34. 

J.S. D Arrigo and T. Imae, Physical characteristics of ultrastable lipid-coated microbubbles, J. Colloid Interface Sci.149 (1992) 592-595. 

J.S. D Arrigo, Method for the production of medical-grade lipid-coated microbubbles, paramagnetic labeling of such microbubbles and therapeutic uses of microbubbles, United States Patent No. 5,215,680 (issued 1993). 

G.F. Whalen, Lipid coated microbubble (LCM)-facilitated ultrasonic treatment of liver tumors, Clinical Protocol No. 99-235 filed with Office of Clinical Research, Institutional Review Board (IRB), Univ. of Connecticut Health Ctr. (IRB Approval by full Board for first phase granted 5-13-99) in conjunction with Critical Technologies Funding Competition (G.F. Whalen and J.S. D Arrigo, Co-P.I. s), 1999 (limited distribution reports). 

D.C. Grant, Retention of lipid-coated microbubbles by membrane filters, Report issued 7-19-02 by CT Associates Inc., 2002, 15 pp. (limited distribution report). 

The surfactant-coated microbubbles described in this book range in size from nanoscale (i.e., submicron) to mesoscale (i.e., microns or micrometers), and fall into two categories. First, surfactant-stabilized natural microbubbles ( 0.5-100 pm in diameter), also referred to as dilute gas-in-liquid emulsions, are reviewed and analyzed in Chapters 1-8 of the book. Second, the synthetic or artificially coated microbubbles (from submicron to a few micrometers in diameter), also referred to as concentrated gas-in-liquid emulsions or as lipid-coated microbubbles, are described and their properties examined in detail in Chapters 9-15. 

Lipid Coated Microbubbles and Nanodroplets as Tools for Biomedical Nanotechnology... 

Figure 19.5. Ultrasound image of TNF- induced inflammation in the mouse hindpaw using mouse anti CD-62 conjugated to lipid-coated microbubbles. Left Control image after administration of non-targeted microbubbles. Right Image after administration of targeted microbubbles.

Future work will require continued collaboration between chemists, biologists, ultrasound physicists and hopefully ever increasing involvement by clinical researchers to develop the full utility of lipid coated microbubbles and nanodroplets. 

---