Ultrasound (US) has an ever-increasing role in the delivery of therapeutic agents including genetic material, proteins, and chemotherapeutic agents. Cavitating gas bodies such as microbubbles are the mediators through which the energy of relatively non-interactive pressure waves is concentrated to produce forces that permeabilize cell membranes and disrupt the vesicles that carry drugs. Thus the presence of microbubbles enormously enhances delivery of genetic material, proteins and smaller chemical agents. Delivery of genetic material is greatly enhanced by ultrasound in the presence of microbubbles. Attaching the DNA directly to the microbubbles or to gas-containing liposomes enhances gene uptake even further. US-enhanced gene delivery has been studied in various tissues including cardiac, vascular, skeletal muscle, tumor and even fetal tissue. US-enhanced delivery of proteins has found most application in transdermal delivery of insulin. Cavitation events reversibly disrupt the structure of the stratus corneum to allow transport of these large molecules. Other hormones and small proteins could also be delivered transdermally. Small chemotherapeutic molecules are delivered in research settings from micelles and liposomes exposed to ultrasound. Cavitation appears to play two roles: it disrupts the structure of the carrier vesicle and releases the drug; it also makes the cell membranes and capillaries more permeable to drugs. There remains a need to better understand the physics of cavitation of microbubbles and the impact that such cavitation has upon cells and drug-carrying vesicles.

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Ultrasonic Drug Delivery – A General Review

Enhanced delivery of doxorubicin (DXR) to a solid tumor subjected to local hyperthermia was achieved by using long-circulating, thermosensitive liposomes (TSL) composed of dipalmitoyl phosphatidylcholine (DPPC)/distearoyl phosphatidylcholine (DSPC) (9:1, m/m) and 3 mol% amphipathic polyethylene glycol (PEG) in colon 26-bearing mice. Inclusion of 3 mol% of distearoyl phosphatidylethanolamine derivatives of PEG (DSPE-PEG, amphipathic PEG) with a mean molecular weight of 1000 or 5000 in DPPC/DSPC liposomes resulted in decreased reticuloendothelial system (RES) uptake and a concomitant prolongation of circulation time, affording sustained increased blood levels of the liposomes. Concomitantly, DXR levels in blood were also kept high over a long period. The presence of amphipathic PEG did not interfere with the encapsulation of DXR by the pH gradient method (>90% trapping efficiency) or with the temperature-dependent drug release from the liposomes. The optimal size of these liposomes was 180 – 200 nm in mean diameter for thermosensitive drug release and prolonged circulation time. The DXR levels in the tumor after injection of long-circulating TSL (DXR-PEG1000TSL or DXR-PEG5000TSL, at a dose of 5 mg DXR/ kg) with local hyperthermia were much higher than after treatment with DXR-TSL lacking PEG or with free DXR, reaching 7.0 – 8.5 DXR µg/g tumor (approximately 2 times or 6 times higher than that of DXR-TSL or free DXR, respectively). Furthermore, the combination of DXR-PEGTSL and hyperthermia effectively retarded tumor growth and increased survival time. Our results indicate that the combination of drug-loaded, long-circulating, thermosensitive liposomes with local hyperthermia at the tumor site could be clinically useful for delivering a wide range of chemotherapeutic agents in the treatment of solid tumors.

Enhanced delivery and antitumor activity of doxorubicin using long-circulating thermosensitive liposomes containing amphipathic polyethylene glycol in combination with local hyperthermia

Starburst dendrimers (SBDs) of different generations (size) and level of protonations of their surface amino groups and solutions of dimyristoylphosphatidylcholine (DMPC) vesicles were analyzed, both separately and in mixtures of the two components, by negative-staining transmission electron microscopy (TEM), dynamic light scattering (DLS), and, mainly, by computer-aided continuous wave (CW)- and pulsed-electron paramagnetic resonance (EPR). For the EPR study, the SBDs were labeled with a nitroxide radical (SBD-T). TE micrographs showed the vesicles as multilamellar structures of spherical shape with diameters ranging from 0.2 to 1.2 m. DLS measurements provided the mean vesicle diameter (d) at ca. 400 nm, whereas the diameter of generation 6 was 7 nm. No large-sized permanent supramolecular structures (d > 400 nm) were formed. EPR measurements at room temperature were poorly informative, since (1) a fraction of the dendrimers was not interacting with the vesicles, and (b) the labels that were interacting...

Characterization of Starburst Dendrimers and Vesicle Solutions and Their Interactions by CW- and Pulsed-EPR, TEM, and Dynamic Light Scattering

The interactions between polyamidoamine starburst dendrimers (SBDs) and vesicles consisting of dimyristoylphosphatidylcholine (DMPC) and its phosphatidylcholate salt (DMPA-Na) in various relative r...

Interactions between Starburst Dendrimers and Mixed DMPC/DMPA-Na Vesicles Studied by the Spin Label and the Spin Probe Techniques, Supported by Transmission Electron Microscopy

Transmission electron micrographs (TEM) of UO22+-negatively stained starburst dendrimers (SBDs), members of the family of dendritic macromolecules, have been analyzed in the absence and in the presence of dimyristoyl-phosphatidylcoline (DMPC) liposomes and mixed DMPC/DMPA-Na (the sodium salt of DMP-colate) liposomes at different relative percentages of DMPC and DMPA-Na. Under most conditions with dendrimers present, the dendrimers, rather than the liposomes, are visible in the TEM images, demonstrating that the UO22+ is complexed to the dendrimers and not to the liposomes. Only at high composition of DMPA-Na in the liposomes (>40%) and under the condition of high protonation of the dendrimer surface are the liposomes imaged by TEM. Mixed liposomes show a rodlike shape. To confirm the TEM results, an EPR study was performed by adding to the SBD solution various amounts of Cu2+ and UO22+. Uranyl ions compete favorably with copper ions for the complexation with the nitrogen ligand sites at both the external ...

A TEM and EPR Investigation of the Competitive Binding of Uranyl Ions to Starburst Dendrimers and Liposomes: Potential Use of Dendrimers as Uranyl Ion Sponges

http://www.brl.uiuc.edu/Publications/1985/Maynard-ChemPhysLipid-1-1985.pdf

Valerie M. Maynard

Papers

Ultrasonic absorption and permeability for liposomes near phase transition.