Alexander Klibanov PhD, Presenter: Research grant, Koninklijke Philips Electronics NV Stockholder, Targeson, Inc Contract, Targeson, Inc

Talent Shevchenko, Abstract Co-Author: Nothing to Disclose

William Tao Shi PHD, Abstract Co-Author: Employee, Koninklijke Philips Electronics NV

Zhongmin Du PhD, Abstract Co-Author: Nothing to Disclose

Ralf Seip PhD, Abstract Co-Author: Employee, Koninklijke Philips Electronics NV

Eugene Leyvi PhD, Abstract Co-Author: Employee, Koninklijke Philips Electronics NV

Shriram Sethuraman PhD, Abstract Co-Author: Employee, Koninklijke Philips Electronics NV

Balasundar Raju, Abstract Co-Author: Employee, Koninklijke Philips Electronics NV

We apply focused ultrasound tumor treatment following intravenous administration of doxorubicin entrapped in the liposome-microbubble pendant complexes to achieve triggered drug release, with the intent to develop image-guided targeted tumor chemotherapy.

Decafluorobutane microbubbles were prepared by sonication and stabilized with phosphatidylcholine/PEG stearate/biotin-PEG-PE shell. They were decorated with biotinylated liposomes via a streptavidin link. Liposomes in the complex were loaded with doxorubicin using remote loading ammonium citrate protocol (average drug load 0.6 pg per particle). Subcutaneous murine (C57BL/6) hindleg tumor model (MC38 colon adenocarcinoma cells, provided by J. Schlom, NIH) was used (6 animals per experimental group). After average tumor size reached 5mm, anesthetized mice were subjected to ultrasound treatment. First, 3 mg/kg doxorubicin entrapped in microbubble-liposome complex was injected intravenously under ultrasound imaging control performed with iE33 imaging system. Immediately following injection, entire tumor was insonated in a spiral pattern intermittently (15s on and 10s off, for microbubble replenishment) for 6 minutes with 1.2MHz ultrasound (2MPa, 10000-cycle, 10 Hz PRF, TIPS system with 1x1x6 mm focal zone). Ultrasound treatment combined with 1 mg/kg doxorubicin-liposome-microbubble complex was repeated 6 days later. In a control group, animals received doxorubicin entrapped in the carrier without TIPS insonation. Saline-injected animals served as another control. Tumor size and body mass were monitored.  

Ultrasound imaging allowed direct observation of the circulating drug carrier. Combination of TIPS ultrasound treatment with doxorubicin-liposome-microbubble complexes resulted in tumor growth suppression, in comparison with both control groups, and showed statistically significant tumor growth inhibition (p<0.05) for days 4-8 of the 10-day study. In controls, unimpeded tumor growth was observed. Relative body mass change during the study was not statistically significant for animals in all groups.

Insonation of drug-liposome-microbubble complex in the tumor vasculature results in the retardation of tumor growth.

Tumor-targeted focused ultrasound can activate doxorubicin-liposome-microbubble complex in vivo, achieving chemotherapeutic effect. This is a step towards next-generation targeted image-guided therapy

Klibanov, A, Shevchenko, T, Shi, W, Du, Z, Seip, R, Leyvi, E, Sethuraman, S, Raju, B, Ultrasound-triggered Release of Doxorubicin from Liposome-Microbubble Complex Slows Down Tumor Growth in a Murine Model.  Radiological Society of North America 2011 Scientific Assembly and Annual Meeting, November 26 - December 2, 2011 ,Chicago IL. http://archive.rsna.org/2011/11011939.html