Ultrasound-mediated liposome delivery in an Ex Vivo Murine Artery
Echogenic liposomes (ELIP) have been used to entrap micro- and nanobubbles, enabling enhanced echogenicity and cavitation nucleation. The use of ultrasound to fragment drug-loaded ELIP near the target tissue, rather than relying on more gradual passive release, has the potential to produce a large temporal peak in drug or therapeutic effect. This is particularly important at the endothelium where the constant flow of blood may carry away the released drug rapidly, making it unavailable for uptake across the endothelium. Fluorescently-labeled and anti-ICAM-1-targeted ELIP were flowed through ex-vivo atheromatous murine arteries and treated with 1-MHz ultrasound at pressures above the stable cavitation threshold. Delivery of ELIP into and beyond the endothelium was quantified by examining the fluorescence in the intravascular and extravascular fluids separately. This platform provides a model system for evaluation of delivery methodologies to the arterial wall.
Hitchcock K. E. et al. 2010, Journal of Controlled Release, 144:288-295
Hitchcock K. E., PhD Dissertation, 2010
Ex vivo murine aortas treated with Rhodamine-labeled ELIP delivered via a proximal injection of Rh-ELIP into an intravascular flow of 0.5% BSA at 5.6 mL/min.
Ultrasound-triggered release of tissue plasminogen activator from echogenic liposomes
Recombinant tissue-type Plasminogen Activator (rt-PA), a thrombolytic, was loaded into ELIP. A linear array transducer of a clinical diagnostic ultrasound scanner was used to study ultrasound triggered rt-PA enzymatic activity from rt-PA-loaded ELIP (T-ELIP). T-ELIP samples were exposed to 6.9-MHz B-mode pulses at a low pressure amplitude (600 kPa) to track the echogenicity over time under four experimental conditions: 1) flow alone to monitor gas diffusion from the T-ELIP, 2) pulsed 6.0-MHz color Doppler exposure above the acoustically driven threshold (0.8 MPa) to force gas out of the liposome gently, 3) pulsed 6.0-MHz color Doppler above the rapid fragmentation threshold (2.6 MPa), or 4) Triton X-100 to rupture the T-ELIP chemically as a positive control. Release of rt-PA for each ultrasound exposure protocol was assayed spectrophotometrically. The thrombolytic drug remained associated with the liposome when exposed to low-amplitude B-mode pulses over 60 min and was released when exposed to color Doppler pulses or Triton X-100. A therapeutic concentration of rt-PA can be released by fragmenting the T-ELIP with pulsed 6.0-MHz color Doppler ultrasound above the rapid fragmentation threshold (1.59 MPa).
Smith D.A.B., et al. 2010, Ultrasound in Medicine and Biology, 36:145-157
Smith D.A.B., PhD Dissertation, 2008